Impact of androgen receptor pathway inhibitors on cognitive function in elderly patients treated for metastatic prostate cancer

Impact of androgen receptor pathway inhibitors on cognitive function in elderly patients treated for metastatic prostate cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Impact of androgen receptor pathway inhibitors on cognitive function in elderly patients treated for metastatic prostate cancer Antoine Boué, Giulia Baciarello, Emmanuel Meyer, François Christy, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5657760/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Androgen receptor pathway inhibitors (ARPI) are commonly used in addition to androgen deprivation therapy (ADT) for metastatic prostate cancer (mPC). However, there is limited data on their cognitive impact in elderly patients. This prospective multicenter trial recruited castration-resistant mPC patients aged ≥70 receiving ADT+ARPI, patients receiving ADT alone, and healthy controls (HC). Cognition was assessed with a self-report questionnaire (subjective cognition) and cognitive tests addressing six domains: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions (objective cognition). At baseline (before starting ARPI for ADT+ARPI patients), objective cognitive impairment concerned 36 (51%), 5 (26%) and 3 (10%) ADT+ARPI patients, ADT patients and HC, respectively. After 3 and 6 months of follow-up, adjusted scores showed poorer subjective cognition in ADT+ARPI patients than in ADT patients (p≤0.033). ADT+ARPI patients also had lower objective performance in processing speed/attention domain at all visits (p≤0.010). Although limited by small sample sizes, our study shows for the first time that ARPI+ADT can increase the risk of impacting objective and subjective cognition in elderly mPC patients, compared to ADT alone. Health sciences/Oncology/Cancer/Urological cancer/Prostate cancer Health sciences/Health care/Quality of life Androgen receptor pathway inhibitors Cancer-related cognitive impairment Elderly Metastatic prostate cancer Figures Figure 1 Figure 2 Figure 3 Introduction Enzalutamide and abiraterone acetate are the first agents of the second generation of androgen receptor pathway inhibitors (ARPI) for metastatic prostate cancer (mPC). Demonstrating a large benefit on survival compared to standard androgen deprivation therapy (ADT) alone, they have become the standard of care for castration-resistant mPC (mCRPC)[ 1 ] and hormone-sensitive mPC (mHSPC)[ 2 ]. While they are generally well tolerated, ADT and ARPI can have side-effects on cognition[ 3 ]. These are of particular concern in elderly patients, who are at increased risk of cognitive impairment[ 4 ], with potential repercussions on autonomy, quality of life and cancer-related mortality[ 5 , 6 ]. Preliminary results suggested an association between ARPI and cognitive impairment[ 7 ], particularly with enzalutamide[ 8 ]. Most studies to date focused on the frequency of adverse events reported in medical charts, or were based on cognitive screening tests ( e.g. Montréal Cognitive Assessment, MoCA[ 9 ]). These measures do not make it possible to identify which domains of objective cognition are most impacted. One study using specific cognitive measures showed lower verbal memory in patients treated with enzalutamide compared with darolutamide[ 10 ]. Another study using questionnaires showed poorer subjective cognition in patients treated with enzalutamide compared with abiraterone acetate[ 11 , 12 ]. However, neither of these studies compared patients receiving ARPI with patients receiving ADT alone[ 10 – 12 ]. Since ARPI are systematically combined with ADT to date, the specific effect of these new agents remains elusive. The objectives of this trial were (i) to estimate the frequency of overall objective and subjective cognitive impairment before ARPI initiation and decline during treatment in elderly mPC patients, (ii) to describe differences in objective domains and subjective cognition between patients receiving ADT + ARPI and those receiving ADT alone, and (iii) to identify some baseline factors associated with cognitive changes. Results Between November 2016 and October 2021, 106 ADT + ARPI patients, 24 ADT patients and 33 healthy controls (HC) were included in a prospective, multicenter, comparative trial. Among the ADT + ARPI, ADT and HC groups, 32 (30%), 5 (21%) and 3 (9%) participants respectively were not considered for analyses, mainly due to withdrawal of consent before the 3-month visit (Fig. 1 ). The final sample included 74 ADT + ARPI patients, 19 ADT patients and 30 HC patients. Non-analyzed participants were older and had poorer geriatric outcomes. The most frequent reasons for subsequent dropouts were: discontinuation of treatment (n = 21), concomitant disease or disability impeding the administration of cognitive tests (n = 7) and withdrawal of consent (n = 4). Baseline characteristics The ADT + ARPI, ADT and HC groups had a mean age of 78, 74 and 75 years, respectively ( p = 0.002, Table 1 ). At baseline ( i.e. before ARPI initiation), patients had received previous androgen deprivation for a median duration of 13 months in the ADT + ARPI group and 21 months in the ADT group, with no significant difference ( ns ). In addition, 14 (22%) ADT + ARPI patients and 1 (5%) ADT patient had received analgesic treatment ( ns ). Compared with the ADT group, ADT + ARPI patients had poorer geriatric outcomes according to the G8 screening tool[ 13 ], Instrumental activities of daily life (IADL)[ 14 ], and Timed up and go[ 15 ] ( p ≤ 0.030). Table 1 Participants’ baseline characteristics ADT + ARPI n = 74 ADT n = 19 HC n = 30 p Demographic data Age, years: mean (SD) 78.2 (6.09) 74.4 (3.95) 74.7 (4.41) 0.002 Married/cohabiting: n (%) 59 (80%) 15 (79%) 27 (90%) 0.423 Education, years of schooling: mean (SD) 12.6 (3.55) 12.0 (2.65) 13.7 (3.08) 0.179 Clinical data ECOG performance status e 0.002 0: n (%) 31 (45%) 17 (89%) 1: n (%) 32 (46%) 2 (11%) 2: n (%) 6 (9%) 0 (0%) Body mass index, kg/m²: mean (SD) 27.8 (3.55) i 28.2 (5.16) b 0.762 Charlson index: mean (SD) 1.19 (1.29) 0.95 (1.18) 0.440 Psychotropic drugs: n (%) 9 (12%) 2 (11%) 1.000 Analgesic drugs : n (%) 16 (22%) 1 (5%) 0.180 ADT duration, months: median (IQR) 13.0 (2.8–28.2) b 21.1 (9.4–48.6) 0.094 Previous treatment Chemotherapy: n (%) 3 (4%) 0 (0%) 1.000 Radiotherapy: n (%) 55 (74%) 18 (95%) 0.064 Time since diagnosis, years: mean (SD) 14.6 (6.87) 15.4 (5.83) 0.573 Testosterone, abnormal: n (%) 64 (91%) d 16 (89%) a 0.664 TSH, abnormal: n (%) 7 (10%) d 0 (0%) b 0.337 PSA, abnormal: n (%) 49 (80%) h 4 (24%) b < 0.001 Gleason score f 0.746 4–6: n (%) 12 (18%) 4 (21%) ≥7: n (%) 55 (82%) 15 (79%) d’Amico risk classification g 0.221 low: n (%) 0 (0%) 1 (5%) intermediate: n (%) 14 (22%) 5 (26%) high: n (%) 49 (78%) 13 (69%) Initially metastatic: n (%) 17 (23%) 4 (21%) 1.000 Geriatric data G8 screening tool: mean (SD) 14.6 (3.06) 16.1 (1.77) 0.007 IADL: mean (SD) 5.59 (1.00) 5.87 (0.23) 0.030 MNA: mean (SD) 26.5 (2.10) j 27.3 (2.13) c 0.205 Timed up and go: mean (SD) 3.73 (1.01) 4.00 (0.00) 0.024 Premorbid intellectual functioning and cognitive screening fNART: mean (SD) 26.9 (6.66) c 26.1 (6.97) a 29.2 (5.72) 0.193 MoCA: mean (SD) 24.0 (3.53) 25.9 (3.45) 27.2 (1.76) < 0.001 Other PROs HADS – total, symptomatic: n (%) 24 (34%) c 3 (17%) a 4 (13%) 0.075 depression: mean (SD) 4.19 (3.33) c 3.57 (2.73) a 3.47 (2.67) anxiety: mean (SD) 5.18 (3.10) c 5.00 (3.16) a 5.03 (3.29) ISI, symptomatic: n (%) 13 (18%) c 1 (6%) a 1 (3%) 0.075 FACIT-F, symptomatic: n (%) 30 (42%) c 4 (22%) a 1 (3%) < 0.001 Visual analogue scale: mean (SD) 2.34 (2.41) g 2.65 (3.10) a 1.58 (1.76) 0.244 ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. ECOG: Eastern Cooperative Oncology Group. FACIT-F: Functional Assessment of Chronic Illness Therapy – Fatigue. fNART: French National Adult Reading Test. HADS: Hospital Anxiety and Depression Scale. HC: healthy controls. IADL: Instrumental Activities of Daily Life. IQR: interquartile range. ISI: Insomnia Severity Index. MoCA: Montréal Cognitive Assessment. MNA: Mini-Nutritional Assessment. PROs: Patient reported outcomes. PSA: prostatic specific antigen. SD: standard deviation. TSH: thyroid-stimulating hormone. Missing data: a n=1 b n=2 c n=3 d n=4 e n=5 f n=7 g n=11 h n=13 i n=14 j n=19 There was a difference between groups for cognitive status (MoCA[ 9 ], p < 0.001), with the lowest mean scores observed in the ADT + ARPI group. Fatigue (Functional Assessment of Chronic Illness Therapy - Fatigue, FACIT-F[ 16 ]) was reported in 30 (42%) ADT + ARPI, 4 (22%) ADT and 1 (3%) HC ( p < 0.001). There was no significant difference in the levels of depression, anxiety and pain between groups. Among the ADT + ARPI group, patients treated with enzalutamide had more comorbidities than patients treated with abiraterone acetate (mean Charlson index: 1.41 vs. 1.19, p = 0.040, Supplementary information 1). Cognitive outcomes in all patients (ADT+/-ARPI) compared with HC At baseline, 41 (46%) of all patients had overall objective cognitive impairment vs. 3 (10%) HC ( p < 0.001, Table 2 ), and 21 (24%) and 16 (18%) of all patients had subjective cognitive impairment according to the Perceived cognitive impairment (PCI) and abilities (PCA) subscale of the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)[ 17 ] questionnaire, vs. 2 (7%) of HC on both subscales ( ns ). During follow-up, there was no significant difference in the frequency of overall objective or subjective decline (Table 3 ). Table 2 Cognitive impairment at baseline according to treatment group (unadjusted) All patients (ADT+/-ARPI) ADT + ARPI ADT HC p 3 z impairment z impairment z impairment impairment All patients vs. HC ADT + ARPI vs. ADT Baseline n = 93 n = 74 n = 19 n = 30 Overall objective impairment 1 46% (41) 51% (36) 26% (5) 10% (3) < 0.001 0.072 Processing speed/attention -0.977 24% (22) -1.171 28% (21) -0.221 5% (1) 3% (1) Working memory -0.530 8% (7) -0.487 4% (3) -0.700 21% (4) 0% (0) Verbal memory -0.880 34% (31) -1.055 42% (30) -0.216 5% (1) 10% (3) Visual memory 0.015 9% (8) -0.053 11% (8) 0.279 0% (0) 7% (2) Visuospatial abilities -0.408 29% (27) -0.412 30% (22) -0.396 26% (5) 7% (2) Executive functions -0.901 59% (48) -1.004 60% (37) -0.518 58% (11) 20% (6) Subjective impairment 2 PCI 24% (21) 24% (17) 22% (4) 7% (2) 0.059 1.000 PCA 18% (16) 20% (14) 11% (2) 7% (2) 0.236 0.509 ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. PCI: Perceived cognitive abilities. PCI: Perceived cognitive impairment. 1 Proportion of participants impaired in at least two objective domains according to ICCTF guidelines[ 32 ]. 2 Proportion of participants with a FACT-Cog – PCI and PCA score of ≤ 10th percentile of norms[ 39 ]. 3 Comparison of percentage of participants with cognitive impairment. χ² or Fisher exact test. significant difference: p < 0.05. Table 3 Cognitive decline during follow-up according to treatment group (unadjusted) All patients (ADT+/-ARPI) ADT + ARPI ADT HC p 3 RCI decline RCI decline RCI decline decline All patients vs. HC ADT + ARPI vs. ADT 3-month n = 93 n = 74 n = 19 n = 30 Overall objective decline 1 3% (3) 3% (2) 5% (1) 0% (0) 1.000 0.500 Processing speed/attention -0.209 5% (5) -0.281 7% (5) 0.063 0% (0) 3% (1) Working memory -0.304 2% (2) -0.411 3% (2) 0.105 0% (0) 0% (0) Verbal memory 0.025 5% (4) 0.117 3% (2) -0.323 11% (2) 3% (1) Visual memory -0.620 19% (17) -0.670 21% (15) -0.430 11% (2) 0% (0) Visuospatial abilities 0.077 1% (1) 0.044 1% (1) 0.196 0% (0) 0% (0) Executive functions 0.132 0% (0) 0.209 0% (0) -0.148 0% (0) 0% (0) Subjective decline 2 PCI 22% (18) 25% (16) 11% (2) 17% (5) 0.792 0.335 PCA 27% (23) 26% (17) 33% (6) 30% (9) 0.815 0.558 6-month n = 71 n = 54 n = 17 n = 28 Overall objective decline 1 4% (3) 6% (3) 0% (0) 0% (0) 0.556 1.000 Processing speed/attention -0.055 3% (2) -0.037 4% (2) -0.117 0% (0) 0% (0) Working memory -0.174 3% (2) -0.236 4% (2) 0.033 0% (0) 0% (0) Verbal memory 0.046 2% (1) 0.048 2% (1) 0.040 0% (0) 4% (1) Visual memory -0.423 3% (2) -0.440 4% (2) -0.370 0% (0) 4% (1) Visuospatial abilities -0.274 8% (5) -0.377 10% (5) 0.045 0% (0) 0% (0) Executive functions 0.152 0% (0) 0.207 0% (0) -0.017 0% (0) 0% (0) Subjective decline 2 PCI 27% (18) 34% (17) 6% (1) 32% (9) 0.628 0.050 PCA 41% (27) 46% (23) 25% (4) 25% (7) 0.165 0.158 12-month n = 55 n = 42 n = 13 n = 29 Overall objective decline 1 4% (2) 2% (1) 8% (1) 0% (0) 0.542 0.420 Processing speed/attention -0.202 5% (3) -0.256 5% (2) -0.027 8% (1) 0% (0) Working memory -0.184 0% (0) -0.297 0% (0) 0.182 0% (0) 0% (0) Verbal memory -0.218 10% (5) -0.227 8% (3) -0.191 15% (2) 0% (0) Visual memory -0.346 7% (4) -0.385 7% (3) -0.220 8% (1) 0% (0) Visuospatial abilities -0.112 2% (1) -0.157 2% (1) 0.027 0% (0) 3% (1) Executive functions -0.110 2% (1) 0.016 2% (1) -0.496 0% (0) 0% (0) Subjective decline 2 PCI 35% (18) 41% (16) 17% (2) 24% (7) 0.329 0.174 PCA 39% (20) 41% (16) 33% (4) 31% (9) 0.629 0.743 ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. RCI: reliable change index. PCI: Perceived cognitive abilities. PCI: Perceived cognitive impairment. 1 Proportion of participants declining in at least two objective domains according to RCI 2 Proportion of participants with a FACT-Cog – PCI and PCA score decreasing ≥ 10% from baseline 3 Comparison of percentage of participants with cognitive decline. χ² or Fisher exact test. Significant difference: p < 0.05 When considering adjusted scores, patients performed significantly worse than the HC group at 3 months in all assessed objective domains except visual memory (Fig. 2 ). Between-group differences remained significant throughout follow-up for processing speed/attention, working memory, verbal memory and executive functions. Patients also had poorer subjective cognition according to PCI at each visit. Cognitive outcomes in ADT + ARPI group compared with ADT At baseline, 36 (51%) ADT + ARPI patients vs. 5 (26%) ADT patients had overall objective cognitive impairment ( ns , Table 2 ). Subjective cognitive impairment according to PCI and PCA was observed in respectively 17 (24%) and 14 (20%) ADT + ARPI patients, vs. 5 (22%) and 2 (11%) ADT patients ( ns ). During follow-up, the highest rates of overall objective cognitive decline were observed at 6 months after ARPI initiation for ADT + ARPI patients (6%), with no difference with ADT patients (Table 3 ). For subjective cognition, 17 (34%) ADT + ARPI patients declined at 6 months in PCI, vs. 1 (6%) ADT patient ( p = 0.050). Considering adjusted scores (including previous ADT duration), ADT + ARPI patients had lower performance compared to the ADT group at 3 months in processing speed/attention ( p = 0.007, Fig. 3 ). These significant differences persisted at 6 ( p = 0.006) and 12 months ( p = 0.010). There was a decrease in adjusted scores in the majority of objective domains between baseline and the 3-month visit. Even when there was a decrease after the introduction of ARPI, scores then increased between 6 and 12 months in 5 out of 6 objective domains. For subjective cognition, a decrease in scores was also observed up to 6 months, before stabilizing up to 12 months. In addition, ADT + ARPI patients reported poorer subjective cognition compared to ADT, with lower PCA at 3 ( p = 0.033) and 6 months ( p = 0.015), and a trend for PCI at 3 months ( p = 0.065). Among the ADT + ARPI group, 19 patients (41%) treated with enzalutamide and 17 (68%) patients treated with abiraterone acetate had overall objective cognitive impairment at baseline (Supplementary information 2). During follow-up, the highest rates of overall objective cognitive decline were observed at 6 months in both subgroups (6%). Almost a quarter of enzalutamide and abiraterone patients had subjective cognitive impairment before treatment initiation. Subjective cognitive decline also reached higher rates at 6 months in abiraterone acetate patients (PCA: 67%), and at 12 months in enzalutamide patients (PCA: 46%). Baseline factors associated with cognitive changes in ADT + ARPI patients A lower estimate of premorbid intellectual functioning (French National Adult Reading Test, fNART[ 18 ]) was associated with decreasing scores in working memory (3 months and 6 months, p = 0.016 and p = 0.022, respectively) and processing speed/attention (6 months, p = 0.021). Other important factors included fatigue (FACIT-F), which was associated with decreasing scores in visuospatial abilities (6 months, p = 0.048), visual memory (12 months, p = 0.021) and subjective cognition ( e.g. PCI at 3 months, p = 0.036, Supplementary information 3). Discussion This trial aimed to evaluate the impact of ADT + ARPI on both objective and subjective cognition in elderly mPC patients, marking the first comparison with patients receiving ADT alone. Our results showed poorer cognition in patients receiving hormonal treatments, particularly when treated with ADT + ARPI. At baseline, 46% of mPC patients treated with hormone therapy had overall objective cognitive impairment, ( vs. 10% of HC). This mPC group comprised both ARPI candidates and ADT patients already treated with ADT for a median duration exceeding one year. ADT is suspected of negatively impacting cognition from the third month of treatment[ 19 ]. Previous studies showed that up to 69% of patients treated with ADT experienced a decline in at least one objective domain following the start of treatment[ 20 ], which makes our baseline impairment rate potentially reflective of the cognitive impact of androgen suppression. Among mPC patients, objective cognitive impairment was reported at baseline in 51% of those assigned to ADT + ARPI, a higher rate than in the ADT group (21%). However, these patients had more advanced disease than ADT patients with a high consumption of analgesic drugs, which is also likely to contribute to cognitive impairment[ 21 ]. During follow-up, there was no difference in rates of overall objective cognitive decline between patients and HC. In ADT + ARPI patients, these rates did not exceed 6%. This finding is in line with that of a previous ADT + ARPI cohort which experienced a 5% decline in objective cognition at two months of treatment[ 22 ]. However, adjusted domain-specific scores showed lower performance with ADT + ARPI compared to ADT in processing speed/attention. To our knowledge, this is the first comparison of the objective cognitive effects of ADT + ARPI with those of ADT alone. Regarding subjective cognition, mPC patients reported greater impairment than HC throughout follow-up (adjusted PCI scores). Similarly, a meta-analysis showed a decline in subjective cognition during treatment with ADT alone, or in addition with ARPI[ 23 ]. However, it did not allow the effects of the two generations of hormone therapy to be distinguished. In the present study, ADT + ARPI patients reported poorer subjective cognition than those receiving ADT alone. Among ADT + ARPI patients, objective and subjective impairment were frequent at baseline in the enzalutamide and abiraterone acetate subgroups. The introduction of ARPI was followed by subjective cognitive decline, regardless of the treatment. One study reported a higher risk of subjective cognitive impairment in patients treated with enzalutamide than in those treated with abiraterone acetate[ 11 , 12 ]. However, previous studies that used specific measures of objective cognition did not show any difference between the two treatments[ 22 , 24 ]. The COG-PRO trial focused on the cognitive impact of ARPI in elderly patients. This population is particularly sensitive to cognitive impairment associated with cancer and its treatments[ 4 ]. In our sample, ADT + ARPI patients were older and had poorer geriatric outcomes than ADT patients. Age itself is correlated with hormonal, cerebral, and subsequent cognitive changes. In addition to impacting the autonomy of elderly patients, decline in cognition can affect the course of care by impeding the ability to make decisions in relation to increasingly complex treatment pathways, and it can compromise compliance with oral therapies[ 25 ]. In addition, performance in processing speed/attention could impact autonomy in older adults, including money management and time planning[ 26 ]. The compensatory abilities developed by patients to cope with changes in cognition are supported by their cognitive reserve[ 27 ]. This phenomenon of cognition resisting neuropathological damage is partially subsumed by premorbid intellectual functioning related to development, education, and lifestyle. In our ADT + ARPI, patients the fNART score was associated with processing speed/attention and working memory. Moreover, subjective cognitive changes (PCI) in the ADT + ARPI group were associated with fatigue, i.e. a symptom frequent in elderly cancer patients[ 28 ]. Fatigue could affect 43% of patients treated with ADT, and there is growing evidence of its association with subjective cognitive impairment during treatment[ 29 ]. The risk of fatigue is also known to increase during treatment with ARPI[ 7 ], especially with enzalutamide[ 11 , 12 ]. The small size of the ADT group and subgroups of patients treated with enzalutamide and abiraterone acetate is one limitation of this study. In addition, ARPI had no indication for mHSPC at the start of the inclusion, and selected mCRPC patients could exhibit greater frailty. This frailty and the length of the cognitive assessment may explain the frequency of requests to withdraw consent between baseline and the 3-month visit. The introduction of ARPI in the earlier stages of prostate cancer, coupled with the increasing life expectancy of patients, is resulting in a longer duration of administration. The long-term comparison of different ARPI in a homogeneous population ( i.e. in mHSPC) would be useful to characterize their respective impacts. In addition, measures of subjective cognition are increasingly implemented in cognitive cancer research, as it can impact quality of life[ 30 ]. A better understanding of the predictors of these outcomes, both objective and subjective, could enhance the detection of patients at risk of cognitive decline. The challenge is to inform patients before initiating treatments, to anticipate the onset of cognitive impairment and, if necessary, to propose strategies to manage cognitive changes and their consequences. In conclusion, this study supports previous results demonstrating the impact of hormone therapy on cognition, and shows how it can be exacerbated by ARPI when added to ADT. To assess treatment-induced cognitive changes, clinicians should use specific measures of objective and subjective cognition. Methods Participants and procedure COG-PRO (NCT02907372) was a prospective, multicenter, comparative trial, approved by an independent ethics committee. The protocol has been previously described[ 31 ]. ADT + ARPI and ADT groups were included in six French hospitals following the treatment decision of the participating physicians. The ADT + ARPI patient group had mCRPC and had to be candidates for treatment by enzalutamide or abiraterone acetate. The ADT patient group had been treated for mHSPC for at least 3 months. The group of HC was recruited though local advertisements. ADT + ARPI, ADT and HC participants were aged ≥ 70 without neurological sequelae of brain impairment or neurodegenerative disease (Table 4 ). Clinical data were collected at baseline, prior to the initiation of treatment for ADT + ARPI patients. Cognitive data were collected at baseline and after 3, 6, and 12 months. Table 4 Selection criteria ADT + ARPI ADT HC mCRPC Already treated with ADT Candidate for treatment with enzalutamide or abiraterone acetate mHSPC Already started ADT for at least 3 months No history of cancer No chemotherapy except one line per docetaxel for hormone-sensitive disease and completed for at least 18 months prior to inclusion Asymptomatic or pauci-symptomatic (visual analogue scale ≤ 3) ECOG performance status ≤ 2 No known brain metastasis 70 years old or more No neurological sequalae of brain impairment including traumatic brain injury, stroke, neuro-degenerative disease No personality disorders or known progressive psychiatric disorder No drug use including heavy drinking No inability or refusal to comply with requirements of protocol At least level 3 (end of primary school) on Barbizet scale Signed informed consent ADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. ECOG: Eastern Cooperative Oncology Group. HC: healthy controls. mCRPC: metastatic castration-resistant prostate cancer. mHSPC: metastatic hormone-sensitive prostate cancer. Measures Objective cognition was assessed with nine cognitive tests, selected according to the recommendations of the International Cognition and Cancer Task Force (ICCTF)[ 32 ] and previous studies on the cognitive impact of ADT[ 19 ]. Measures were grouped into six objective domains (Table 5 ) using an adaptation of an international classification of cognitive tests[ 33 ]: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions. Subjective cognition was assessed with the PCI and PCA subscales of the FACT-Cog questionnaire[ 17 ]. In addition, cognitive status and premorbid intellectual functioning at baseline were assessed with MoCA[ 9 ] and the fNART[ 18 ], respectively. Table 5 A : Cognitive measures and corresponding tests and questionnaires according to adapted classification of Lezak and colleagues[ 1 ] Cognitive domain 1 Test or questionnaire (battery) Measure Processing speed/attention Digit symbol-coding (WAIS-III)[ 42 ] correct reproductions TMT (GREFEX)[ 43 ] time A Working memory Digit span (WAIS-III)[ 42 ] score forward score backward Verbal memory Grober-Buschke test (GREMEM)[ 44 ] sum of three free recalls sum of three total recalls free delayed recall total delayed recall Visual memory Doors test[ 45 ] test A test B Visuospatial abilities Rey-Osterrieth complex figure[ 46 ] ECPA copy score[ 47 ] Number location (VOSP)[ 48 ] total score Executive functions Stroop Victoria[ 49 ] time interference/colors total errors interference Verbal fluencies (GREFEX)[ 43 ] letter fluency category fluency TMT (GREFEX)[ 43 ] time B/A errors B Subjective cognition FACT-Cog[ 17 ] PCI PCA ECPA: Editions of the Center for Applied Psychology (France). FACT-Cog: Functional Assessment of Cancer Therapy - Cognitive Function. PCA: Perceived cognitive abilities. GREFEX: Task Force on Executive Function Assessment (France). GREMEM: Task Force on Memory Assessment (France). PCI: Perceived cognitive impairment. TMT: Trail-Making Test. VOSP: Visual Object and Space Perception battery. WAIS-III: Wechsler Adult Intelligent Scale, third edition. 1 adaptations by consensus between two neuropsychologists (AB and ML) based on previous studies on the cognitive impact of androgen deprivation therapy[ 19 ]: separation of working memory from processing speed/attention, addition of a new domain referring to visuospatial abilities. Table 5 B : Geriatric assessment and other PROs Group Dimension Measure Threshold value 1 Geriatric assessment Geriatric frailty G8 screening tool[ 13 ] - Instrumental activities of daily life IADL[ 14 ] - Nutrition status MNA[ 35 ] - Mobility Timed up and go[ 15 ] Other PROs Anxiety - Depression HADS – total score[ 36 ] ≥ 13 [ 50 ] Insomnia ISI[ 37 ] ≥ 15 [ 51 ] Fatigue FACIT-F[ 16 ] ≤ 36 [ 51 ] Pain Visual analogue scale[ 52 ] - FACIT-F: Functional Assessment of Chronic Illness Therapy - Fatigue. HADS: Hospital Anxiety and Depression Scale. IADL: Instrumental Activities of Daily Life. ISI: Insomnia Severity Index. MNA: Mini-Nutritional Assessment. PROs: Patient reported outcomes. Geriatric data included screening for frailty (G8[ 13 ]), comorbidities (Charlson index[ 34 ]), instrumental activities of daily life (IADL[ 14 ]), nutritional status (Mini-Nutritional Assessment, MNA[ 35 ]), and mobility (Timed up and go[ 15 ]). Other patient-reported outcomes (PROs) included anxiety and depression (Hospital Anxiety and Depression Scale, HADS[ 36 ]), insomnia (Insomnia Severity Index, ISI[ 37 ]), fatigue (FACIT-F[ 16 ]), and pain (Visual analogue scale[ 38 ]). Cognitive impairment and decline Baseline objective cognitive impairment was estimated using the ICCTF criterion[ 32 ] (Supplementary information 4). Overall objective cognitive impairment corresponds to impairment in at least two of the six objective domains. During follow-up, objective decline was estimated using a composite reliable change index (RCI), corrected for practice effect. Overall objective cognitive decline corresponds to decline in at least two of the six objective domains. Subjective cognitive impairment at baseline was defined as ratings ≤ 10th percentile of the norms[ 39 ] for PCI and PCA. During follow-up, subjective cognitive decline was defined as a ≥ 10% decrease since baseline[ 40 ]. Statistical analyses To be considered in the analyses, participants had to have completed at least the baseline and the 3-month visits. Between-group differences for participants’ baseline characteristics were examined using the Wilcoxon and Kruskal-Wallis tests for continuous variables, and the χ² or Fisher exact test for categorical variables, as appropriate. Between-group differences in cognitive functioning were expressed in the following ways: (1) rates of patients with overall objective and subjective cognitive impairment and decline, estimated with the aforementioned criteria, were analyzed using the χ² or Fisher exact test, as appropriate; (2) composite Z-scores in each objective domain (mean Z-scores of the corresponding measures), PCI and PCA scores for subjective cognition were examined with multivariate linear models, adjusted for baseline cognition, age, education, fatigue and previous ADT duration. Multivariable linear analyses were performed in ADT + ARPI patients to examine the association between baseline characteristics and changes in objective domains and in subjective cognition. Analyses were performed using R 4.2.1[ 41 ]. Statistical tests were two-tailed, and p-values < 0.05 were considered statistically significant. Declarations Data availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Additional methods and data are available in the Supplementary information file. Ethics approval and consent to participate The COG-PRO study has received ethical approval from the North West III Committee for the Protection of Individuals and from National Agency for Medical and Health products Safety (Reference: 2016–001248-20). All patients gave their informed consent before any study-related assessment was started. Acknowledgements This study was supported by a public grant overseen by the French National Institute of Cancer (Institut national du cancer, INCa) as part of the program “Research in Social and Human Sciences, Epidemiology and Public Health” (SHS-E-SP-2015-9528), and by a specific donation from Astellas Pharma. The funders had no role in study design, data collection, data analysis, data interpretation or writing of the report. This study was made possible thanks to the commitment of Giulia Binarelli, Aurélie Capel, Marie Fernette, Chantal Rieux, and Chankannira San. We extend our sincere appreciation to thank all investigators, patients and non-cancer participants. CRediT authorship contribution statement Antoine Boué: methodology, formal analysis, investigation, data curation, writing - original draft, visualization. Giulia Baciarello: investigation. Emmanuel Meyer: investigation. François Christy: methodology, formal analysis, data curation, visualization. Nedjla Allouache: investigation. Raffaele Ratta: investigation. Philippe Beuzeboc: investigation. Pierre-Emmanuel Brachet: investigation. Estelle Guerdoux: investigation, writing - review & editing. Amélie Darlix: investigation, writing - review & editing. Mathieu Boone: investigation. Sophie Gouerant: investigation. Alexandra Leconte: conceptualization, project administration. Justine Lequesne: methodology, formal analysis. Bénédicte Clarisse: conceptualization, project administration. Karim Fizazi: investigation, writing - review & editing. Marie Lange: conceptualization, methodology, investigation, writing - review & editing, supervision. Florence Joly: conceptualization, methodology, investigation, writing - review & editing, supervision, funding acquisition. Declaration of Interest Statement Giulia Baciarello: Astellas (advisory board, invited speaker). Emmanuel Meyer: Astellas (invited speaker), Ipsen (invited speaker), Recordati (invited speaker). Raffaele Ratta: Astellas (invited speaker), AstraZeneca (advisory board), Bristol Meyer Squibb (advisory board), Ipsen (invited speaker), Janssen (advisory board), Merck (advisory board), Novartis (advisory board), Pfizer (advisory board). Estelle Guerdoux: CanceroConsult (invited speaker). Amélie Darlix: Novocure (advisory board), Servier (advisory board). Mathieu Boone: Novocure (invited speaker), Servier (advisory board). Bénédicte Clarisse: Astellas (institutional financial support), Pfizer (institutional financial support, product samples). Karim Fizazi: AAA (advisory board), Arvinas (advisory board), Astellas (advisory board, invited speaker), AstraZeneca (advisory board, invited speaker, research grant, principal investigator), Bayer (advisory board, invited speaker, research grant, principal investigator), BMS (research grant, principal investigator), Clovis (principal investigator), Curevac (advisory board), Daiichi Sankyo (advisory board), Janssen (adivsory board, invited speaker, trial chair, research grant), Macrogenics (advisory board), Merck (principal investigator), MSD (advisory board, invited speaker, research grant), Novartis (invited speaker), Novartis/AAA (advisory board, principal investigator), Orion (advisory board, research grant, principal investigator), Pfizer (advisory board, invited speaker, research grant, principal investigator), Sanofi (invited speaker). Florence Joly: Amgen (invited speaker), Astellas (advisory board, research grant), AstraZeneca (advisory board, invited speaker, coordinating principal investigator), Bayer (advisory board), BMS (research grant), Chugai (travel and congress), Esai (advisory board, invited speaker, travel), GCIG (member), GSK (advisory board, invited speaker, coordinating principal investigator, travel), Ipsen (advisory board, invited speaker, travel and congress), Janssen (advisory board, invited speaker, research grant, funding), MSD (advisory board, invited speaker, travel and congress), Novartis/AAA (invited speaker), Novocure (advisory board), Pfizer (advisory board), Seagen (Advisory board), Viatris (invited speaker). References Henríquez I, Roach M, Morgan TM, Bossi A, Gómez JA, Abuchaibe O, et al. Current and Emerging Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC). Biomedicines 2021;9:1247. https://doi.org/10.3390/biomedicines9091247. 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Estelle Guerdoux: CanceroConsult (invited speaker). Amélie Darlix: Novocure (advisory board), Servier (advisory board). Mathieu Boone: Novocure (invited speaker), Servier (advisory board). Bénédicte Clarisse: Astellas (institutional financial support), Pfizer (institutional financial support, product samples). Karim Fizazi: AAA (advisory board), Arvinas (advisory board), Astellas (advisory board, invited speaker), AstraZeneca (advisory board, invited speaker, research grant, principal investigator), Bayer (advisory board, invited speaker, research grant, principal investigator), BMS (research grant, principal investigator), Clovis (principal investigator), Curevac (advisory board), Daiichi Sankyo (advisory board), Janssen (adivsory board, invited speaker, trial chair, research grant), Macrogenics (advisory board), Merck (principal investigator), MSD (advisory board, invited speaker, research grant), Novartis (invited speaker), Novartis/AAA (advisory board, principal investigator), Orion (advisory board, research grant, principal investigator), Pfizer (advisory board, invited speaker, research grant, principal investigator), Sanofi (invited speaker). Florence Joly: Amgen (invited speaker), Astellas (advisory board, research grant), AstraZeneca (advisory board, invited speaker, coordinating principal investigator), Bayer (advisory board), BMS (research grant), Chugai (travel and congress), Esai (advisory board, invited speaker, travel), GCIG (member), GSK (advisory board, invited speaker, coordinating principal investigator, travel), Ipsen (advisory board, invited speaker, travel and congress), Janssen (advisory board, invited speaker, research grant, funding), MSD (advisory board, invited speaker, travel and congress), Novartis/AAA (invited speaker), Novocure (advisory board), Pfizer (advisory board), Seagen (Advisory board), Viatris (invited speaker). 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Baclesse","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Lange","suffix":""},{"id":392935576,"identity":"f229a420-0435-4090-b040-ac5d30f4272c","order_by":17,"name":"Florence Joly","email":"","orcid":"","institution":"INSERM, Normandie Univ, UNICAEN, U1086 ANTICIPE","correspondingAuthor":false,"prefix":"","firstName":"Florence","middleName":"","lastName":"Joly","suffix":""}],"badges":[],"createdAt":"2024-12-17 03:10:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5657760/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5657760/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-025-01302-x","type":"published","date":"2025-12-23T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":94844726,"identity":"0cb8757a-1f56-4d4e-8e4e-9d83b5f5907c","added_by":"auto","created_at":"2025-10-31 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06:58:30","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":198179,"visible":true,"origin":"","legend":"","description":"","filename":"NCOMMS24834090structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/69a0af16d05588dce566ee3e.xml"},{"id":94844739,"identity":"cf390cb4-196e-47ac-82f0-cdd774d5df25","added_by":"auto","created_at":"2025-10-31 10:05:07","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":213128,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/bfdfc8cf78ad6f0467efd412.html"},{"id":94844725,"identity":"91803f33-e712-41d6-a48b-2643fc06a175","added_by":"auto","created_at":"2025-10-31 10:05:07","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":72153,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of patients receiving ADT+ARPI, ADT and for HC\u003c/p\u003e\n\u003cp\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/47724f492755afde160da9a0.png"},{"id":94985066,"identity":"3efed78d-7d74-489c-97ad-df17c9c2fd9f","added_by":"auto","created_at":"2025-11-03 06:57:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":80199,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted cognitive scores during 12-month follow-up in all patients (ADT+/-ARPI) and HC\u003c/p\u003e\n\u003cp\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. Multivariable linear models, adjusted for baseline cognition, age, education and fatigue. Low scores reflect poor cognition.\u003c/p\u003e\n\u003cp\u003e* p\u0026lt;0.050, ** p\u0026lt;0.010, *** p\u0026lt;0.001. \u0026nbsp;\u003csup\u003e1 \u0026nbsp;\u003c/sup\u003eAdjusted composite Z-scores\u0026nbsp;\u0026nbsp; \u003csup\u003e2 \u0026nbsp;\u003c/sup\u003eAdjusted FACT-Cog – PCI and PCA raw scores.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/83ab9eb0a9378d5d481218a0.png"},{"id":94844729,"identity":"86bd1c01-8a5e-47f8-8638-aff1f17c0f5e","added_by":"auto","created_at":"2025-10-31 10:05:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":84896,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted cognitive scores during 12-month follow-up according to treatment group\u003c/p\u003e\n\u003cp\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. Multivariable linear models, adjusted for baseline cognition, age, education, fatigue and previous ADT duration. Low scores reflect poor cognition. * p\u0026lt;0.050, ** p\u0026lt;0.010, *** p\u0026lt;0.001.\u0026nbsp; \u003csup\u003e1 \u0026nbsp;\u003c/sup\u003eAdjusted composite Z-scores\u0026nbsp;\u0026nbsp; \u003csup\u003e2 \u0026nbsp;\u003c/sup\u003eAdjusted FACT-Cog – PCI and PCA raw scores.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/bf2e6d0b52e5c88ffed1fe25.png"},{"id":100863342,"identity":"f9363628-5a96-415d-8e80-5f849a5d1398","added_by":"auto","created_at":"2026-01-22 08:07:43","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1561298,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/2e4bb77d-ee22-4d23-a0e2-e92900d93899.pdf"},{"id":94984891,"identity":"8544f983-f46e-4892-b95b-f3e0052b0234","added_by":"auto","created_at":"2025-11-03 06:56:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":476454,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5657760/v1/f2e516e0ead0b92aa50c941c.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nGiulia Baciarello: Astellas (advisory board, invited speaker). Emmanuel Meyer: Astellas (invited speaker), Ipsen (invited speaker), Recordati (invited speaker). Raffaele Ratta: Astellas (invited speaker), AstraZeneca (advisory board), Bristol Meyer Squibb (advisory board), Ipsen (invited speaker), Janssen (advisory board), Merck (advisory board), Novartis (advisory board), Pfizer (advisory board). Estelle Guerdoux: CanceroConsult (invited speaker). Amélie Darlix: Novocure (advisory board), Servier (advisory board). Mathieu Boone: Novocure (invited speaker), Servier (advisory board). Bénédicte Clarisse: Astellas (institutional financial support), Pfizer (institutional financial support, product samples). Karim Fizazi: AAA (advisory board), Arvinas (advisory board), Astellas (advisory board, invited speaker), AstraZeneca (advisory board, invited speaker, research grant, principal investigator), Bayer (advisory board, invited speaker, research grant, principal investigator), BMS (research grant, principal investigator), Clovis (principal investigator), Curevac (advisory board), Daiichi Sankyo (advisory board), Janssen (adivsory board, invited speaker, trial chair, research grant), Macrogenics (advisory board), Merck (principal investigator), MSD (advisory board, invited speaker, research grant), Novartis (invited speaker), Novartis/AAA (advisory board, principal investigator), Orion (advisory board, research grant, principal investigator), Pfizer (advisory board, invited speaker, research grant, principal investigator), Sanofi (invited speaker). Florence Joly: Amgen (invited speaker), Astellas (advisory board, research grant), AstraZeneca (advisory board, invited speaker, coordinating principal investigator), Bayer (advisory board), BMS (research grant), Chugai (travel and congress), Esai (advisory board, invited speaker, travel), GCIG (member), GSK (advisory board, invited speaker, coordinating principal investigator, travel), Ipsen (advisory board, invited speaker, travel and congress), Janssen (advisory board, invited speaker, research grant, funding), MSD (advisory board, invited speaker, travel and congress), Novartis/AAA (invited speaker), Novocure (advisory board), Pfizer (advisory board), Seagen (Advisory board), Viatris (invited speaker).","formattedTitle":"Impact of androgen receptor pathway inhibitors on cognitive function in elderly patients treated for metastatic prostate cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEnzalutamide and abiraterone acetate are the first agents of the second generation of androgen receptor pathway inhibitors (ARPI) for metastatic prostate cancer (mPC). Demonstrating a large benefit on survival compared to standard androgen deprivation therapy (ADT) alone, they have become the standard of care for castration-resistant mPC (mCRPC)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] and hormone-sensitive mPC (mHSPC)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While they are generally well tolerated, ADT and ARPI can have side-effects on cognition[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These are of particular concern in elderly patients, who are at increased risk of cognitive impairment[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], with potential repercussions on autonomy, quality of life and cancer-related mortality[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePreliminary results suggested an association between ARPI and cognitive impairment[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], particularly with enzalutamide[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Most studies to date focused on the frequency of adverse events reported in medical charts, or were based on cognitive screening tests (\u003cem\u003ee.g.\u003c/em\u003e Montr\u0026eacute;al Cognitive Assessment, MoCA[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]). These measures do not make it possible to identify which domains of objective cognition are most impacted. One study using specific cognitive measures showed lower verbal memory in patients treated with enzalutamide compared with darolutamide[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Another study using questionnaires showed poorer subjective cognition in patients treated with enzalutamide compared with abiraterone acetate[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, neither of these studies compared patients receiving ARPI with patients receiving ADT alone[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Since ARPI are systematically combined with ADT to date, the specific effect of these new agents remains elusive.\u003c/p\u003e \u003cp\u003eThe objectives of this trial were (i) to estimate the frequency of overall objective and subjective cognitive impairment before ARPI initiation and decline during treatment in elderly mPC patients, (ii) to describe differences in objective domains and subjective cognition between patients receiving ADT\u0026thinsp;+\u0026thinsp;ARPI and those receiving ADT alone, and (iii) to identify some baseline factors associated with cognitive changes.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBetween November 2016 and October 2021, 106 ADT\u0026thinsp;+\u0026thinsp;ARPI patients, 24 ADT patients and 33 healthy controls (HC) were included in a prospective, multicenter, comparative trial. Among the ADT\u0026thinsp;+\u0026thinsp;ARPI, ADT and HC groups, 32 (30%), 5 (21%) and 3 (9%) participants respectively were not considered for analyses, mainly due to withdrawal of consent before the 3-month visit (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The final sample included 74 ADT\u0026thinsp;+\u0026thinsp;ARPI patients, 19 ADT patients and 30 HC patients. Non-analyzed participants were older and had poorer geriatric outcomes. The most frequent reasons for subsequent dropouts were: discontinuation of treatment (n\u0026thinsp;=\u0026thinsp;21), concomitant disease or disability impeding the administration of cognitive tests (n\u0026thinsp;=\u0026thinsp;7) and withdrawal of consent (n\u0026thinsp;=\u0026thinsp;4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eBaseline characteristics\u003c/h2\u003e \u003cp\u003eThe ADT\u0026thinsp;+\u0026thinsp;ARPI, ADT and HC groups had a mean age of 78, 74 and 75 years, respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At baseline (\u003cem\u003ei.e.\u003c/em\u003e before ARPI initiation), patients had received previous androgen deprivation for a median duration of 13 months in the ADT\u0026thinsp;+\u0026thinsp;ARPI group and 21 months in the ADT group, with no significant difference (\u003cem\u003ens\u003c/em\u003e). In addition, 14 (22%) ADT\u0026thinsp;+\u0026thinsp;ARPI patients and 1 (5%) ADT patient had received analgesic treatment (\u003cem\u003ens\u003c/em\u003e). Compared with the ADT group, ADT\u0026thinsp;+\u0026thinsp;ARPI patients had poorer geriatric outcomes according to the G8 screening tool[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], Instrumental activities of daily life (IADL)[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], and Timed up and go[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026le;\u0026thinsp;0.030).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eParticipants\u0026rsquo; baseline characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eADT\u0026thinsp;+\u0026thinsp;ARPI\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;74\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eADT\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;19\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e78.2 (6.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.4 (3.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74.7 (4.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarried/cohabiting: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEducation, years of schooling: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.6 (3.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.0 (2.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.7 (3.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.179\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG performance status\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csub\u003ee\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index, kg/m\u0026sup2;: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.8 (3.55)\u003csup\u003ei\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28.2 (5.16)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.762\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson index: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.19 (1.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.95 (1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.440\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePsychotropic drugs: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnalgesic drugs : n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.180\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eADT duration, months: median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.0 (2.8\u0026ndash;28.2)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.1 (9.4\u0026ndash;48.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime since diagnosis, years: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.6 (6.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.4 (5.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTestosterone, abnormal: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (91%)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (89%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.664\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH, abnormal: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (10%)\u003csup\u003ed\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.337\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePSA, abnormal: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (80%)\u003csup\u003eh\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (24%)\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGleason score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csub\u003ef\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.746\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u0026ndash;6: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;7: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ed\u0026rsquo;Amico risk classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csub\u003eg\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.221\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003elow: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eintermediate: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehigh: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitially metastatic: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (21%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGeriatric data\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eG8 screening tool: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.6 (3.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.1 (1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIADL: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.59 (1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.87 (0.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMNA: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.5 (2.10)\u003csup\u003ej\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.3 (2.13)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.205\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTimed up and go: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.73 (1.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.00 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.024\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ePremorbid intellectual functioning and cognitive screening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003efNART: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.9 (6.66)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.1 (6.97)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.2 (5.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoCA: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.0 (3.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.9 (3.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e27.2 (1.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther PROs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHADS \u0026ndash; total, symptomatic: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (34%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (17%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edepression: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.19 (3.33)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.57 (2.73)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.47 (2.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eanxiety: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.18 (3.10)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.00 (3.16)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.03 (3.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eISI, symptomatic: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (18%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (6%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFACIT-F, symptomatic: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (42%)\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (22%)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual analogue scale: mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.34 (2.41)\u003csup\u003eg\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.65 (3.10)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.58 (1.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.244\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. ECOG: Eastern Cooperative Oncology Group. FACIT-F: Functional Assessment of Chronic Illness Therapy \u0026ndash; Fatigue. fNART: French National Adult Reading Test. HADS: Hospital Anxiety and Depression Scale. HC: healthy controls. IADL: Instrumental Activities of Daily Life. IQR: interquartile range. ISI: Insomnia Severity Index. MoCA: Montr\u0026eacute;al Cognitive Assessment. MNA: Mini-Nutritional Assessment. PROs: Patient reported outcomes. PSA: prostatic specific antigen. SD: standard deviation. TSH: thyroid-stimulating hormone.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eMissing data: \u003csup\u003ea\u003c/sup\u003en=1 \u003csup\u003eb\u003c/sup\u003en=2 \u003csup\u003ec\u003c/sup\u003en=3 \u003csup\u003ed\u003c/sup\u003en=4 \u003csup\u003ee\u003c/sup\u003en=5 \u003csup\u003ef\u003c/sup\u003en=7 \u003csup\u003eg\u003c/sup\u003en=11 \u003csup\u003eh\u003c/sup\u003en=13 \u003csup\u003ei\u003c/sup\u003en=14 \u003csup\u003ej\u003c/sup\u003en=19\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThere was a difference between groups for cognitive status (MoCA[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with the lowest mean scores observed in the ADT\u0026thinsp;+\u0026thinsp;ARPI group. Fatigue (Functional Assessment of Chronic Illness Therapy - Fatigue, FACIT-F[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]) was reported in 30 (42%) ADT\u0026thinsp;+\u0026thinsp;ARPI, 4 (22%) ADT and 1 (3%) HC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There was no significant difference in the levels of depression, anxiety and pain between groups. Among the ADT\u0026thinsp;+\u0026thinsp;ARPI group, patients treated with enzalutamide had more comorbidities than patients treated with abiraterone acetate (mean Charlson index: 1.41 \u003cem\u003evs.\u003c/em\u003e 1.19, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040, Supplementary information 1).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCognitive outcomes in all patients (ADT+/-ARPI) compared with HC\u003c/h3\u003e\n\u003cp\u003eAt baseline, 41 (46%) of all patients had overall objective cognitive impairment \u003cem\u003evs.\u003c/em\u003e 3 (10%) HC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and 21 (24%) and 16 (18%) of all patients had subjective cognitive impairment according to the Perceived cognitive impairment (PCI) and abilities (PCA) subscale of the Functional Assessment of Cancer Therapy - Cognitive Function (FACT-Cog)[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] questionnaire, \u003cem\u003evs.\u003c/em\u003e 2 (7%) of HC on both subscales (\u003cem\u003ens\u003c/em\u003e). During follow-up, there was no significant difference in the frequency of overall objective or subjective decline (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCognitive impairment at baseline according to treatment group (unadjusted)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eAll patients (ADT+/-ARPI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eADT\u0026thinsp;+\u0026thinsp;ARPI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eADT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ez\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eimpairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ez\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eimpairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ez\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003eimpairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eimpairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eAll patients \u003cem\u003evs.\u003c/em\u003e HC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eADT\u0026thinsp;+\u0026thinsp;ARPI \u003c/p\u003e \u003cp\u003e\u003cem\u003evs.\u003c/em\u003e ADT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall objective impairment\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e51%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.072\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcessing speed/attention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.977\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.171\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorking memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.530\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.487\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.700\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerbal memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.880\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e42%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.216\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisuospatial abilities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.412\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExecutive functions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.901\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-1.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.518\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e58%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjective impairment\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e22%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.509\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. PCI: Perceived cognitive abilities. PCI: Perceived cognitive impairment.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e1\u003c/sup\u003e Proportion of participants impaired in at least two objective domains according to ICCTF guidelines[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e2\u003c/sup\u003e Proportion of participants with a FACT-Cog \u0026ndash; PCI and PCA score of \u0026le;\u0026thinsp;10th percentile of norms[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e3\u003c/sup\u003e Comparison of percentage of participants with cognitive impairment. χ\u0026sup2; or Fisher exact test. significant difference: p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCognitive decline during follow-up according to treatment group (unadjusted)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"14\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eAll patients (ADT+/-ARPI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eADT\u0026thinsp;+\u0026thinsp;ARPI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eADT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003eHC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003edecline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eRCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003edecline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003edecline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003edecline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eAll patients \u003cem\u003evs.\u003c/em\u003e HC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eADT\u0026thinsp;+\u0026thinsp;ARPI \u003c/p\u003e \u003cp\u003e\u003cem\u003evs.\u003c/em\u003e ADT\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3-month\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall objective decline\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcessing speed/attention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.281\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.063\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorking memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.304\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerbal memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.323\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.670\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.430\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisuospatial abilities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.077\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExecutive functions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.209\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjective decline\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.792\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e33%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.815\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6-month\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall objective decline\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcessing speed/attention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.055\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorking memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.236\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerbal memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.423\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.440\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.370\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisuospatial abilities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.377\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExecutive functions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjective decline\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e34%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e32%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.628\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e25%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.158\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e12-month\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c10\" namest=\"c9\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall objective decline\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.420\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcessing speed/attention\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.202\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.256\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWorking memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVerbal memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.218\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.227\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.191\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e15%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisual memory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.346\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.385\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.220\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisuospatial abilities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-0.157\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExecutive functions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-0.496\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubjective decline\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e24%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.329\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.174\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e33%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e(9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.629\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.743\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. HC: healthy controls. RCI: reliable change index. PCI: Perceived cognitive abilities. PCI: Perceived cognitive impairment.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e1\u003c/sup\u003e Proportion of participants declining in at least two objective domains according to RCI\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e2\u003c/sup\u003e Proportion of participants with a FACT-Cog \u0026ndash; PCI and PCA score decreasing\u0026thinsp;\u0026ge;\u0026thinsp;10% from baseline\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e3\u003c/sup\u003e Comparison of percentage of participants with cognitive decline. χ\u0026sup2; or Fisher exact test. Significant difference: p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWhen considering adjusted scores, patients performed significantly worse than the HC group at 3 months in all assessed objective domains except visual memory (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Between-group differences remained significant throughout follow-up for processing speed/attention, working memory, verbal memory and executive functions. Patients also had poorer subjective cognition according to PCI at each visit.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eCognitive outcomes in ADT + ARPI group compared with ADT\u003c/h3\u003e\n\u003cp\u003eAt baseline, 36 (51%) ADT\u0026thinsp;+\u0026thinsp;ARPI patients \u003cem\u003evs.\u003c/em\u003e 5 (26%) ADT patients had overall objective cognitive impairment (\u003cem\u003ens\u003c/em\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Subjective cognitive impairment according to PCI and PCA was observed in respectively 17 (24%) and 14 (20%) ADT\u0026thinsp;+\u0026thinsp;ARPI patients, \u003cem\u003evs.\u003c/em\u003e 5 (22%) and 2 (11%) ADT patients (\u003cem\u003ens\u003c/em\u003e). During follow-up, the highest rates of overall objective cognitive decline were observed at 6 months after ARPI initiation for ADT\u0026thinsp;+\u0026thinsp;ARPI patients (6%), with no difference with ADT patients (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For subjective cognition, 17 (34%) ADT\u0026thinsp;+\u0026thinsp;ARPI patients declined at 6 months in PCI, \u003cem\u003evs.\u003c/em\u003e 1 (6%) ADT patient (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.050).\u003c/p\u003e \u003cp\u003eConsidering adjusted scores (including previous ADT duration), ADT\u0026thinsp;+\u0026thinsp;ARPI patients had lower performance compared to the ADT group at 3 months in processing speed/attention (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These significant differences persisted at 6 (\u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.006) and 12 months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010). There was a decrease in adjusted scores in the majority of objective domains between baseline and the 3-month visit. Even when there was a decrease after the introduction of ARPI, scores then increased between 6 and 12 months in 5 out of 6 objective domains. For subjective cognition, a decrease in scores was also observed up to 6 months, before stabilizing up to 12 months. In addition, ADT\u0026thinsp;+\u0026thinsp;ARPI patients reported poorer subjective cognition compared to ADT, with lower PCA at 3 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.033) and 6 months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015), and a trend for PCI at 3 months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.065).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the ADT\u0026thinsp;+\u0026thinsp;ARPI group, 19 patients (41%) treated with enzalutamide and 17 (68%) patients treated with abiraterone acetate had overall objective cognitive impairment at baseline (Supplementary information 2). During follow-up, the highest rates of overall objective cognitive decline were observed at 6 months in both subgroups (6%). Almost a quarter of enzalutamide and abiraterone patients had subjective cognitive impairment before treatment initiation. Subjective cognitive decline also reached higher rates at 6 months in abiraterone acetate patients (PCA: 67%), and at 12 months in enzalutamide patients (PCA: 46%).\u003c/p\u003e\n\u003ch3\u003eBaseline factors associated with cognitive changes in ADT + ARPI patients\u003c/h3\u003e\n\u003cp\u003eA lower estimate of premorbid intellectual functioning (French National Adult Reading Test, fNART[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]) was associated with decreasing scores in working memory (3 months and 6 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022, respectively) and processing speed/attention (6 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021). Other important factors included fatigue (FACIT-F), which was associated with decreasing scores in visuospatial abilities (6 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.048), visual memory (12 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) and subjective cognition (\u003cem\u003ee.g.\u003c/em\u003e PCI at 3 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.036, Supplementary information 3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis trial aimed to evaluate the impact of ADT + ARPI on both objective and subjective cognition in elderly mPC patients, marking the first comparison with patients receiving ADT alone. Our results showed poorer cognition in patients receiving hormonal treatments, particularly when treated with ADT + ARPI.\u003c/p\u003e \u003cp\u003eAt baseline, 46% of mPC patients treated with hormone therapy had overall objective cognitive impairment, (\u003cem\u003evs.\u003c/em\u003e 10% of HC). This mPC group comprised both ARPI candidates and ADT patients already treated with ADT for a median duration exceeding one year. ADT is suspected of negatively impacting cognition from the third month of treatment[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Previous studies showed that up to 69% of patients treated with ADT experienced a decline in at least one objective domain following the start of treatment[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which makes our baseline impairment rate potentially reflective of the cognitive impact of androgen suppression. Among mPC patients, objective cognitive impairment was reported at baseline in 51% of those assigned to ADT + ARPI, a higher rate than in the ADT group (21%). However, these patients had more advanced disease than ADT patients with a high consumption of analgesic drugs, which is also likely to contribute to cognitive impairment[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDuring follow-up, there was no difference in rates of overall objective cognitive decline between patients and HC. In ADT + ARPI patients, these rates did not exceed 6%. This finding is in line with that of a previous ADT + ARPI cohort which experienced a 5% decline in objective cognition at two months of treatment[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, adjusted domain-specific scores showed lower performance with ADT + ARPI compared to ADT in processing speed/attention. To our knowledge, this is the first comparison of the objective cognitive effects of ADT + ARPI with those of ADT alone.\u003c/p\u003e \u003cp\u003eRegarding subjective cognition, mPC patients reported greater impairment than HC throughout follow-up (adjusted PCI scores). Similarly, a meta-analysis showed a decline in subjective cognition during treatment with ADT alone, or in addition with ARPI[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. However, it did not allow the effects of the two generations of hormone therapy to be distinguished. In the present study, ADT + ARPI patients reported poorer subjective cognition than those receiving ADT alone.\u003c/p\u003e \u003cp\u003eAmong ADT + ARPI patients, objective and subjective impairment were frequent at baseline in the enzalutamide and abiraterone acetate subgroups. The introduction of ARPI was followed by subjective cognitive decline, regardless of the treatment. One study reported a higher risk of subjective cognitive impairment in patients treated with enzalutamide than in those treated with abiraterone acetate[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, previous studies that used specific measures of objective cognition did not show any difference between the two treatments[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe COG-PRO trial focused on the cognitive impact of ARPI in elderly patients. This population is particularly sensitive to cognitive impairment associated with cancer and its treatments[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In our sample, ADT + ARPI patients were older and had poorer geriatric outcomes than ADT patients. Age itself is correlated with hormonal, cerebral, and subsequent cognitive changes. In addition to impacting the autonomy of elderly patients, decline in cognition can affect the course of care by impeding the ability to make decisions in relation to increasingly complex treatment pathways, and it can compromise compliance with oral therapies[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In addition, performance in processing speed/attention could impact autonomy in older adults, including money management and time planning[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe compensatory abilities developed by patients to cope with changes in cognition are supported by their cognitive reserve[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. This phenomenon of cognition resisting neuropathological damage is partially subsumed by premorbid intellectual functioning related to development, education, and lifestyle. In our ADT + ARPI, patients the fNART score was associated with processing speed/attention and working memory. Moreover, subjective cognitive changes (PCI) in the ADT + ARPI group were associated with fatigue, \u003cem\u003ei.e.\u003c/em\u003e a symptom frequent in elderly cancer patients[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Fatigue could affect 43% of patients treated with ADT, and there is growing evidence of its association with subjective cognitive impairment during treatment[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The risk of fatigue is also known to increase during treatment with ARPI[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], especially with enzalutamide[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe small size of the ADT group and subgroups of patients treated with enzalutamide and abiraterone acetate is one limitation of this study. In addition, ARPI had no indication for mHSPC at the start of the inclusion, and selected mCRPC patients could exhibit greater frailty. This frailty and the length of the cognitive assessment may explain the frequency of requests to withdraw consent between baseline and the 3-month visit.\u003c/p\u003e \u003cp\u003eThe introduction of ARPI in the earlier stages of prostate cancer, coupled with the increasing life expectancy of patients, is resulting in a longer duration of administration. The long-term comparison of different ARPI in a homogeneous population (\u003cem\u003ei.e.\u003c/em\u003e in mHSPC) would be useful to characterize their respective impacts. In addition, measures of subjective cognition are increasingly implemented in cognitive cancer research, as it can impact quality of life[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. A better understanding of the predictors of these outcomes, both objective and subjective, could enhance the detection of patients at risk of cognitive decline. The challenge is to inform patients before initiating treatments, to anticipate the onset of cognitive impairment and, if necessary, to propose strategies to manage cognitive changes and their consequences.\u003c/p\u003e \u003cp\u003eIn conclusion, this study supports previous results demonstrating the impact of hormone therapy on cognition, and shows how it can be exacerbated by ARPI when added to ADT. To assess treatment-induced cognitive changes, clinicians should use specific measures of objective and subjective cognition.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\n \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003eParticipants and procedure\u003c/h2\u003e\n\u003cp\u003eCOG-PRO (NCT02907372) was a prospective, multicenter, comparative trial, approved by an independent ethics committee. The protocol has been previously described[\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e]. ADT\u0026thinsp;+\u0026thinsp;ARPI and ADT groups were included in six French hospitals following the treatment decision of the participating physicians. The ADT\u0026thinsp;+\u0026thinsp;ARPI patient group had mCRPC and had to be candidates for treatment by enzalutamide or abiraterone acetate. The ADT patient group had been treated for mHSPC for at least 3 months. The group of HC was recruited though local advertisements. ADT\u0026thinsp;+\u0026thinsp;ARPI, ADT and HC participants were aged\u0026thinsp;\u0026ge;\u0026thinsp;70 without neurological sequelae of brain impairment or neurodegenerative disease (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Clinical data were collected at baseline, prior to the initiation of treatment for ADT\u0026thinsp;+\u0026thinsp;ARPI patients. Cognitive data were collected at baseline and after 3, 6, and 12 months.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eSelection criteria\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADT\u0026thinsp;+\u0026thinsp;ARPI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eADT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHC\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emCRPC\u003c/p\u003e\n \u003cp\u003eAlready treated with ADT\u003c/p\u003e\n \u003cp\u003eCandidate for treatment with enzalutamide or abiraterone acetate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emHSPC\u003c/p\u003e\n \u003cp\u003eAlready started ADT for at least\u003c/p\u003e\n \u003cp\u003e3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eNo history of cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eNo chemotherapy except one line per docetaxel for hormone-sensitive disease and completed for at least 18 months prior to inclusion\u003c/p\u003e\n \u003cp\u003eAsymptomatic or pauci-symptomatic (visual analogue scale\u0026thinsp;\u0026le;\u0026thinsp;3)\u003c/p\u003e\n \u003cp\u003eECOG performance status\u0026thinsp;\u0026le;\u0026thinsp;2\u003c/p\u003e\n \u003cp\u003eNo known brain metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003e70 years old or more\u003c/p\u003e\n \u003cp\u003eNo neurological sequalae of brain impairment including traumatic brain injury, stroke,\u003c/p\u003e\n \u003cp\u003eneuro-degenerative disease\u003c/p\u003e\n \u003cp\u003eNo personality disorders or known progressive psychiatric disorder\u003c/p\u003e\n \u003cp\u003eNo drug use including heavy drinking\u003c/p\u003e\n \u003cp\u003eNo inability or refusal to comply with requirements of protocol\u003c/p\u003e\n \u003cp\u003eAt least level 3 (end of primary school) on Barbizet scale\u003c/p\u003e\n \u003cp\u003eSigned informed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eADT: patients treated with androgen deprivation therapy. ARPI: patients treated with androgen receptor pathway inhibitors. ECOG: Eastern Cooperative Oncology Group. HC: healthy controls. mCRPC: metastatic castration-resistant prostate cancer. mHSPC: metastatic hormone-sensitive prostate cancer.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eMeasures\u003c/h3\u003e\n\u003cp\u003eObjective cognition was assessed with nine cognitive tests, selected according to the recommendations of the International Cognition and Cancer Task Force (ICCTF)[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e] and previous studies on the cognitive impact of ADT[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Measures were grouped into six objective domains (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e) using an adaptation of an international classification of cognitive tests[\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions. Subjective cognition was assessed with the PCI and PCA subscales of the FACT-Cog questionnaire[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition, cognitive status and premorbid intellectual functioning at baseline were assessed with MoCA[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e] and the fNART[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e], respectively.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e: Cognitive measures and corresponding tests and questionnaires according to adapted classification of Lezak and colleagues[\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCognitive domain\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTest or questionnaire (battery)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMeasure\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProcessing speed/attention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDigit symbol-coding (WAIS-III)[\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecorrect reproductions\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMT (GREFEX)[\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etime A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWorking memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDigit span (WAIS-III)[\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003escore forward\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003escore backward\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVerbal memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eGrober-Buschke test (GREMEM)[\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esum of three free recalls\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esum of three total recalls\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efree delayed recall\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etotal delayed recall\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisual memory\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDoors test[\u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etest A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etest B\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eVisuospatial abilities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRey-Osterrieth complex figure[\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eECPA copy score[\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber location (VOSP)[\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etotal score\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExecutive functions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStroop Victoria[\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etime interference/colors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etotal errors interference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVerbal fluencies (GREFEX)[\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eletter fluency\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecategory fluency\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTMT (GREFEX)[\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etime B/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eerrors B\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSubjective cognition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFACT-Cog[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePCI\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePCA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eECPA: Editions of the Center for Applied Psychology (France). FACT-Cog: Functional Assessment of Cancer Therapy - Cognitive Function. PCA: Perceived cognitive abilities. GREFEX: Task Force on Executive Function Assessment (France). GREMEM: Task Force on Memory Assessment (France). PCI: Perceived cognitive impairment. TMT: Trail-Making Test. VOSP: Visual Object and Space Perception battery. WAIS-III: Wechsler Adult Intelligent Scale, third edition.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003e\u003csup\u003e1\u003c/sup\u003e adaptations by consensus between two neuropsychologists (AB and ML) based on previous studies on the cognitive impact of androgen deprivation therapy[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]: separation of working memory from processing speed/attention, addition of a new domain referring to visuospatial abilities.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cstrong\u003eB\u003c/strong\u003e: Geriatric assessment and other PROs\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDimension\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMeasure\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eThreshold value\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003eGeriatric assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGeriatric frailty\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eG8 screening tool[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInstrumental activities of daily life\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIADL[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNutrition status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMNA[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMobility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTimed up and go[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003eOther PROs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAnxiety - Depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHADS \u0026ndash; total score[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;13 [\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInsomnia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eISI[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026ge;\u0026thinsp;15 [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFatigue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFACIT-F[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;36 [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVisual analogue scale[\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\"\u003eFACIT-F: Functional Assessment of Chronic Illness Therapy - Fatigue. HADS: Hospital Anxiety and Depression Scale. IADL: Instrumental Activities of Daily Life. ISI: Insomnia Severity Index. MNA: Mini-Nutritional Assessment. PROs: Patient reported outcomes.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eGeriatric data included screening for frailty (G8[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]), comorbidities (Charlson index[\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]), instrumental activities of daily life (IADL[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]), nutritional status (Mini-Nutritional Assessment, MNA[\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]), and mobility (Timed up and go[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]). Other patient-reported outcomes (PROs) included anxiety and depression (Hospital Anxiety and Depression Scale, HADS[\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e]), insomnia (Insomnia Severity Index, ISI[\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]), fatigue (FACIT-F[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]), and pain (Visual analogue scale[\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]).\u003c/p\u003e\n\u003ch2\u003eCognitive impairment and decline\u003c/h2\u003e\n\u003cp\u003eBaseline objective cognitive impairment was estimated using the ICCTF criterion[\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e] (Supplementary information 4). Overall objective cognitive impairment corresponds to impairment in at least two of the six objective domains. During follow-up, objective decline was estimated using a composite reliable change index (RCI), corrected for practice effect. Overall objective cognitive decline corresponds to decline in at least two of the six objective domains.\u003c/p\u003e\n\u003cp\u003eSubjective cognitive impairment at baseline was defined as ratings\u0026thinsp;\u0026le;\u0026thinsp;10th percentile of the norms[\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e] for PCI and PCA. During follow-up, subjective cognitive decline was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;10% decrease since baseline[\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e\n\u003ch2\u003eStatistical analyses\u003c/h2\u003e\n\u003cp\u003eTo be considered in the analyses, participants had to have completed at least the baseline and the 3-month visits. Between-group differences for participants\u0026rsquo; baseline characteristics were examined using the Wilcoxon and Kruskal-Wallis tests for continuous variables, and the \u0026chi;\u0026sup2; or Fisher exact test for categorical variables, as appropriate.\u003c/p\u003e\n\u003cp\u003eBetween-group differences in cognitive functioning were expressed in the following ways: (1) rates of patients with overall objective and subjective cognitive impairment and decline, estimated with the aforementioned criteria, were analyzed using the \u0026chi;\u0026sup2; or Fisher exact test, as appropriate; (2) composite Z-scores in each objective domain (mean Z-scores of the corresponding measures), PCI and PCA scores for subjective cognition were examined with multivariate linear models, adjusted for baseline cognition, age, education, fatigue and previous ADT duration.\u003c/p\u003e\n\u003cp\u003eMultivariable linear analyses were performed in ADT\u0026thinsp;+\u0026thinsp;ARPI patients to examine the association between baseline characteristics and changes in objective domains and in subjective cognition.\u003c/p\u003e\n\u003cp\u003eAnalyses were performed using R 4.2.1[\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]. Statistical tests were two-tailed, and p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request. Additional methods and data are available in the Supplementary information file.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe COG-PRO study has received ethical approval from the North West III Committee for the Protection of Individuals and from National Agency for Medical and Health products Safety (Reference: 2016\u0026ndash;001248-20). All patients gave their informed consent before any study-related assessment was started.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by a public grant overseen by the French National Institute of Cancer (Institut national du cancer, INCa) as part of the program \u0026ldquo;Research in Social and Human Sciences, Epidemiology and Public Health\u0026rdquo; (SHS-E-SP-2015-9528), and by a specific donation from Astellas Pharma. The funders had no role in study design, data collection, data analysis, data interpretation or writing of the report. This study was made possible thanks to the commitment of Giulia Binarelli, Aur\u0026eacute;lie Capel, Marie Fernette, Chantal Rieux, and Chankannira San. We extend our sincere appreciation to thank all investigators, patients and non-cancer participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003cbr\u003e\u003c/strong\u003eAntoine Bou\u0026eacute;: methodology, formal analysis, investigation, data curation, writing - original draft, visualization. Giulia Baciarello: investigation. Emmanuel Meyer: investigation. Fran\u0026ccedil;ois Christy: methodology, formal analysis, data curation, visualization. Nedjla Allouache: investigation. Raffaele Ratta: investigation. Philippe Beuzeboc: investigation. Pierre-Emmanuel Brachet: investigation. Estelle Guerdoux: investigation, writing - review \u0026amp; editing. Am\u0026eacute;lie Darlix: investigation, writing - review \u0026amp; editing. Mathieu Boone: investigation. Sophie Gouerant: investigation. Alexandra Leconte: conceptualization, project administration. Justine Lequesne: methodology, formal analysis. B\u0026eacute;n\u0026eacute;dicte Clarisse: conceptualization, project administration. Karim Fizazi: investigation, writing - review \u0026amp; editing. Marie Lange: conceptualization, methodology, investigation, writing - review \u0026amp; editing, supervision. Florence Joly: conceptualization, methodology, investigation, writing - review \u0026amp; editing, supervision, funding acquisition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Interest Statement\u003cbr\u003e\u003c/strong\u003eGiulia Baciarello: Astellas (advisory board, invited speaker). Emmanuel Meyer: Astellas (invited speaker), Ipsen (invited speaker), Recordati (invited speaker). Raffaele Ratta: Astellas (invited speaker), AstraZeneca (advisory board), Bristol Meyer Squibb (advisory board), Ipsen (invited speaker), Janssen (advisory board), Merck (advisory board), Novartis (advisory board), Pfizer (advisory board). Estelle Guerdoux: CanceroConsult (invited speaker). Am\u0026eacute;lie Darlix: Novocure (advisory board), Servier (advisory board). Mathieu Boone: Novocure (invited speaker), Servier (advisory board). B\u0026eacute;n\u0026eacute;dicte Clarisse: Astellas (institutional financial support), Pfizer (institutional financial support, product samples). Karim Fizazi: AAA (advisory board), Arvinas (advisory board), Astellas (advisory board, invited speaker), AstraZeneca (advisory board, invited speaker, research grant, principal investigator), Bayer (advisory board, invited speaker, research grant, principal investigator), BMS (research grant, principal investigator), Clovis (principal investigator), Curevac (advisory board), Daiichi Sankyo (advisory board), Janssen (adivsory board, invited speaker, trial chair, research grant), Macrogenics (advisory board), Merck (principal investigator), MSD (advisory board, invited speaker, research grant), Novartis (invited speaker), Novartis/AAA (advisory board, principal investigator), Orion (advisory board, research grant, principal investigator), Pfizer (advisory board, invited speaker, research grant, principal investigator), Sanofi (invited speaker). Florence Joly: Amgen (invited speaker), Astellas (advisory board, research grant), AstraZeneca (advisory board, invited speaker, coordinating principal investigator), Bayer (advisory board), BMS (research grant), Chugai (travel and congress), Esai (advisory board, invited speaker, travel), GCIG (member), GSK (advisory board, invited speaker, coordinating principal investigator, travel), Ipsen (advisory board, invited speaker, travel and congress), Janssen (advisory board, invited speaker, research grant, funding), MSD (advisory board, invited speaker, travel and congress), Novartis/AAA (invited speaker), Novocure (advisory board), Pfizer (advisory board), Seagen (Advisory board), Viatris (invited speaker).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHenr\u0026iacute;quez I, Roach M, Morgan TM, Bossi A, G\u0026oacute;mez JA, Abuchaibe O, et al. Current and Emerging Therapies for Metastatic Castration-Resistant Prostate Cancer (mCRPC). 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JCO 1998;16:139\u0026ndash;44. https://doi.org/10.1200/JCO.1998.16.1.139.\u003c/li\u003e\n\u003cli\u003eScott J, Huskisson EC. Graphic representation of pain. Pain 1976;2:175\u0026ndash;84.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Androgen receptor pathway inhibitors, Cancer-related cognitive impairment, Elderly, Metastatic prostate cancer","lastPublishedDoi":"10.21203/rs.3.rs-5657760/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5657760/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAndrogen receptor pathway inhibitors (ARPI) are commonly used in addition to androgen deprivation therapy (ADT) for metastatic prostate cancer (mPC). However, there is limited data on their cognitive impact in elderly patients.\u003cem\u003e \u003c/em\u003eThis prospective multicenter trial recruited castration-resistant mPC patients aged ≥70 receiving ADT+ARPI, patients receiving ADT alone, and healthy controls (HC). Cognition was assessed with a self-report questionnaire (subjective cognition) and cognitive tests addressing six domains: processing speed/attention, working memory, verbal memory, visual memory, visuospatial abilities, and executive functions (objective cognition). At baseline (before starting ARPI for ADT+ARPI patients), objective cognitive impairment concerned 36 (51%), 5 (26%) and 3 (10%) ADT+ARPI patients, ADT patients and HC, respectively. After 3 and 6 months of follow-up, adjusted scores showed poorer subjective cognition in ADT+ARPI patients than in ADT patients (p≤0.033). ADT+ARPI patients also had lower objective performance in processing speed/attention domain at all visits (p≤0.010). Although limited by small sample sizes, our study shows for the first time that ARPI+ADT can increase the risk of impacting objective and subjective cognition in elderly mPC patients, compared to ADT alone.\u003c/p\u003e","manuscriptTitle":"Impact of androgen receptor pathway inhibitors on cognitive function in elderly patients treated for metastatic prostate cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-31 10:05:02","doi":"10.21203/rs.3.rs-5657760/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c6333439-74ab-403b-8898-afb64a23c2d9","owner":[],"postedDate":"October 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":41892916,"name":"Health sciences/Oncology/Cancer/Urological cancer/Prostate cancer"},{"id":41892917,"name":"Health sciences/Health care/Quality of life"}],"tags":[],"updatedAt":"2026-01-22T08:07:38+00:00","versionOfRecord":{"articleIdentity":"rs-5657760","link":"https://doi.org/10.1038/s43856-025-01302-x","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2025-12-23 05:00:00","publishedOnDateReadable":"December 23rd, 2025"},"versionCreatedAt":"2025-10-31 10:05:02","video":"","vorDoi":"10.1038/s43856-025-01302-x","vorDoiUrl":"https://doi.org/10.1038/s43856-025-01302-x","workflowStages":[]},"version":"v1","identity":"rs-5657760","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5657760","identity":"rs-5657760","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}