[An attempt to deconstruct the French "syndrome de glissement"]. / Essai de déconstruction du syndrome de glissement.

The "syndrome de glissement" is a French term used to describe end-of-life situations where the elderly person becomes adynamic and any therapeutic intervention seems ineffective until the patient dies. It is close to failure to thrive. Although its use, which is widespread, seems appropriate to briefly describe a complex situation, it has the major disadvantage of leading to an absence of clinical and therapeutic approach, which represents a loss of chance for the patient. In clinical practice, we consider that what is referred to as a sliding syndrome is actually a situation of apathy associated with a deterioration in general condition. A diagnostic approach should therefore look for all organic pathologies that associate deterioration in general condition and apathy, and neuropsychiatric situations such as episodes of major depression that produce such symptoms. Once these diagnoses have been ruled out, the person should be considered for palliative care and benefit from the expertise that goes with this practice. Any elderly person in a situation resembling what is known as a syndrome de glissement should therefore benefit from a rigorous clinical approach, and not be considered beyond any therapeutic resources. It is a matter of dignity and quality of care.

The Pathobiology of Behavioral Changes in Multiple System Atrophy: An Update.

While cognitive impairment, which was previously considered a red flag against the clinical diagnosis of multiple system atrophy (MSA), is a common symptom of this rare neurodegenerative disorder, behavioral disorders are reported in 30 to 70% of MSA patients. They include anxiety, apathy, impaired attention, compulsive and REM sleep behavior disorders (RBD), and these conditions, like depression, are early and pervasive features in MSA, which may contribute to disease progression. Despite changing concepts of behavioral changes in this synucleinopathy, the underlying pathophysiological and biochemical mechanisms are poorly understood. While specific neuropathological data are unavailable, neuroimaging studies related anxiety disorders to changes in the cortico-limbic system, apathy (and depression) to dysfunction of prefrontal-subcortical circuits, and compulsive behaviors to impairment of basal ganglia networks and involvement of orbito-frontal circuits. Anxiety has also been related to α-synuclein (αSyn) pathology in the amygdala, RBD to striatal monoaminergic deficit, and compulsive behavior in response to dopamine agonist therapy in MSA, while the basic mechanisms of the other behavioral disorders and their relations to other non-motor dysfunctions in MSA are unknown. In view of the scarcity of functional and biochemical findings in MSA with behavioral symptoms, further neuroimaging and biochemical studies are warranted in order to obtain better insight into their pathogenesis as a basis for the development of diagnostic biomarkers and future adequate treatment modalities of these debilitating comorbidities.

Adverse effects of methylphenidate for apathy in patients with Alzheimer's disease (ADMET2 trial).

OBJECTIVES: To examine clinically important adverse events (AEs) associated with methylphenidate (MPH) treatment of apathy in Alzheimer's Disease (AD) versus placebo, including weight loss, vital signs, falls, and insomnia. METHODS: The Apathy in Dementia Methylphenidate Trial 2 (ADMET2) trial was a multicenter randomized, placebo-controlled trial of MPH to treat apathy in individuals with apathy and AD. Participants in ADMET2 had vital signs and weight measured at monthly visits through 6 months. AEs, including insomnia, falls, and cardiovascular events, were reported at every visit by participants and families using a symptom checklist. RESULTS: The study included 98 participants in the MPH group and 101 in the placebo group. Participants in the MPH group experienced greater weight loss on average than the placebo through the 6-month follow-up, with a difference in change between MPH and placebo of 2.8 lb (95% confidence interval, CI: 0.7, 4.9 lb). No treatment group differences in change during the trial were found in systolic and diastolic blood pressure. More participants in the MPH group reported falls during the follow-up, 10 versus 6 in MPH and placebo groups, respectively. No differences in post-baseline insomnia were observed between the treatment groups. No participants reported instances of myocardial infarction, congestive heart failure, arrhythmia, stroke, or cardiomyopathy throughout the study period. CONCLUSIONS: MPH use in AD patients for treating apathy is relatively safe, particularly notable given the many medical comorbidities in this population. There was a statistically significant but modest weight loss associated with MPH use, and clinicians are thus advised to monitor weight during MPH treatment.

The Impact of Subthalamic Deep Brain Stimulation on Apathy in Parkinson's Disease Patients.

AIM: To investigate the impact of subthalamic deep brain stimulation (STN DBS) on apathy and the possible relationship between apathy, depression, and levodopa equivalent dosage (LED) in Parkinson's Disease (PD) patients. MATERIAL AND METHODS: A total of 26 patients have been evaluated via the Unified Parkinson Disease Rating Scale (UPDRS), Beck Depression Inventory (Beck D), and Beck Anxiety Inventory (Beck A), Montreal Cognitive Assessment (MoCA), Parkinson Disease Questionnaire (PDQ-39) just before and 6 months after DBS. RESULTS: Apathy scores (AES) showed a slight decrease from 54.00 ± 10.30 to 52.69 ± 8.88 without any statistical significance (p=0.502) after DBS therapy. No correlation was detected between the post-treatment changes in apathy and UPDRS scores, Beck D, Beck A. Although the direction of the correlation between changes in AES scores and LED values was negative, the results did not reach statistical significance. CONCLUSION: STN DBS therapy does not have a negative effect on apathy in PD Patients. Despite the satisfactory motor improvement, conservative dopaminergic dose reduction after surgery seems to be the main point to prevent apathy increase in PD patients after STN DBS.

Association between cannabis use disorder and greater apathy in adults with HIV.

BACKGROUND: Apathy is prevalent among people with HIV (PWH) and is associated with poor clinical outcomes. Cannabis use and Cannabis Use Disorder (CUD) are also disproportionately prevalent among PWH. CUD and younger onset of cannabis use may be linked to apathy in the general population; however, patterns of use most strongly associated with apathy have not been firmly established, and it is unclear whether cannabis use is linked to apathy in PWH. METHODS: We examined associations in 311 adult PWH between Apathy Evaluation Scale-Self (AES-S) scores and CUD history (current/past/no CUD/no cannabis use) and between AES-S scores and age of CUD onset (adolescent-onset/adult-onset). We also examined robustness of associations to adjustment for depressive symptoms (which may overlap with apathy symptoms) and alcohol use. RESULTS: Current CUD was associated with greater AES-S scores relative to cannabis users with no CUD history (ß = 2.13, 95 % CI = 0.37-3.90, p = 0.018). Adolescent-onset CUD was not associated with greater apathy relative to adult-onset CUD (ß = 0.56, 95 % CI = -2.57 - 3.68, p = 0.7). Associations became nonsignificant after adjustment for depressive symptoms, but not after adjustment for alcohol use. Alcohol use was correlated with apathy (r = 0.19, 95 % CI: 0.076-0.29, p = 0.001). CONCLUSIONS: Cannabis Use Disorder and at-risk alcohol use are associated with apathy among PWH; this finding highlights the need for substance use disorder prevention and treatment among PWH.

Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large longitudinal studies are lacking while the literature is inconsistent about even cross-sectional associations. We aimed to determine the longitudinal predictors of apathy development in a large cohort of people with PD and its cross-sectional associations and trajectories over time, using sophisticated Bayesian modeling techniques. METHODS: People with PD followed up in the longitudinal New Zealand Parkinson's progression project were included. Apathy was defined using the neuropsychiatric inventory subscale ≥4, and analyses were also repeated using a less stringent cutoff of ≥1. Both MoCA and comprehensive neuropsychological testing were used as appropriate to the model. Depression was assessed using the hospital anxiety and depression scale. Cross-sectional Bayesian regressions were conducted, and a multistate predictive model was used to identify factors that predict the initial onset of apathy in nonapathetic PD, while also accounting for the competing risk of death. The relationship between apathy presence and mortality was also investigated. RESULTS: Three hundred forty-six people with PD followed up for up to 14 years across a total of 1,392 sessions were included. Apathy occurrence did not vary significantly across the disease course (disease duration odds ratio [OR] = 0.55, [95% CI 0.28-1.12], affecting approximately 11% or 22% of people at any time depending on the NPI cutoff used. Its presence was associated with a significantly higher risk of death after controlling for all other factors (hazard ratio [HR] = 2.92 [1.50-5.66]). Lower cognition, higher depression levels, and greater motor severity predicted apathy development in those without motivational deficits (HR [cognition] = 0.66 [0.48-0.90], HR [depression] = 1.45 [1.04-2.02], HR [motor severity] = 1.37 [1.01-1.86]). Cognition and depression were also associated with apathy cross-sectionally, along with male sex and possibly lower dopaminergic therapy level, but apathy still occurred across the full spectrum of each variable (OR [cognition] = 0.58 [0.44-0.76], OR [depression] = 1.43 [1.04-1.97], OR [female sex] = 0.45 [0.22-0.92], and OR [levodopa equivalent dose] = 0.78 [0.59-1.04]. DISCUSSION: Apathy occurs across the PD time course and is associated with higher mortality. Depressive symptoms and cognitive impairment in particular predict its future development in those with normal motivation.

[A longitudinal study of the association between physical activity and apathy among community-dwelling older adults].

AIM: This study clarified the association between the amount of physical activity and apathy after one year among community-dwelling older adults. METHODS: Two hundred community-dwelling older adults (mean age: 74.3±5.0 years old, female: 52.5%) who participated in the 2018 and 2019 "Kasama Longevity Health Examination" were included. Apathy was assessed using the Apathy Scale (0-42 points; the higher the score, the lower the motivation), physical activity by Physical Activity Scale for the Elderly (PASE), and Geriatric Depression Scale-15 (GDS). The 2018 PASE data were grouped into tertiles. A multiple regression analysis was performed with the 2019 Apathy Scale as the dependent variable and the 2018 PASE as the independent variable, and the sex, age, years of education, economic situation, body mass index, chronic illness, smoking history, alcohol drinking habits, physical function, cognitive function, GDS, and the 2018 Apathy Scale as adjustment variables. The PASE subcategories (leisure-time, household, and work-related activities) were examined using a similar method. RESULTS: The mean Apathy Scale in 2019 was 14.0±6.2 for the low physical activity group, 12.8±6.0 for the medium physical activity group, and 10.1±5.9 for the high physical activity group. The high physical activity group showed a significant negative association with the Apathy Scale (B=-1.56, 95% confidence interval=-2.91 to -0.21, p=0.023). No association was found for any activity of the PASE sub-items. CONCLUSIONS: A high level of physical activity may protect against apathy among community-dwelling older adults.

Resistance training in women with myotonic dystrophy type 1: a multisystemic therapeutic avenue.

Myotonic dystrophy type 1 (DM1) is a hereditary disease characterized by muscular impairments. Fundamental and clinical positive effects of strength training have been reported in men with DM1, but its impact on women remains unknown. We evaluated the effects of a 12-week supervised strength training on physical and neuropsychiatric health. Women with DM1 performed a twice-weekly supervised resistance training program (3 series of 6-8 repetitions of squat, leg press, plantar flexion, knee extension, and hip abduction). Lower limb muscle strength, physical function, apathy, anxiety and depression, fatigue and excessive somnolence, pain, and patient-reported outcomes were assessed before and after the intervention, as well as three and six months after completion of the training program. Muscle biopsies of the vastus lateralis were also taken before and after the training program to assess muscle fiber growth. Eleven participants completed the program (attendance: 98.5 %). Maximal hip and knee extension strength (p < 0.006), all One-Repetition Maximum strength measures (p < 0.001), apathy (p = 0.0005), depression (p = 0.02), pain interference (p = 0.01) and perception of the lower limb function (p = 0.003) were significantly improved by training. Some of these gains were maintained up to six months after the training program. Strength training is a good therapeutic strategy for women with DM1.

Quantifying Apathy in Late-Life Depression: Unraveling Neurobehavioral Links Through Daily Activity Patterns and Brain Connectivity Analysis.

BACKGROUND: Better understanding apathy in late-life depression would help improve prediction of poor prognosis of diseases such as dementia. Actimetry provides an objective and ecological measure of apathy from patients' daily motor activity. We aimed to determine whether patterns of motor activity were associated with apathy and brain connectivity in networks that underlie goal-directed behaviors. METHODS: Resting-state functional magnetic resonance imaging and diffusion magnetic resonance imaging were collected from 38 nondemented participants with late-life depression. Apathy was evaluated using the diagnostic criteria for apathy, Apathy Evaluation Scale, and Apathy Motivation Index. Functional principal components (fPCs) of motor activity were derived from actimetry recordings taken for 72 hours. Associations between fPCs and apathy were estimated by linear regression. Subnetworks whose connectivity was significantly associated with fPCs were identified via threshold-free network-based statistics. The relationship between apathy and microstructure metrics was estimated along fibers by diffusion tensor imaging and a multicompartment model called neurite orientation dispersion and density imaging via tractometry. RESULTS: We found 2 fPCs associated with apathy: mean diurnal activity, negatively associated with Apathy Evaluation Scale scores, and an early chronotype, negatively associated with Apathy Motivation Index scores. Mean diurnal activity was associated with increased connectivity in the default mode, cingulo-opercular, and frontoparietal networks, while chronotype was associated with a more heterogeneous connectivity pattern in the same networks. We did not find significant associations between microstructural metrics and fPCs. CONCLUSIONS: Our findings suggest that mean diurnal activity and chronotype could provide indirect ambulatory measures of apathy in late-life depression, associated with modified functional connectivity of brain networks that underlie goal-directed behaviors.

Characterisation of behaviours relevant to apathy syndrome in the aged male rat.

Apathy is a complex psychiatric syndrome characterised by motivational deficit, emotional blunting and cognitive changes. It occurs alongside a broad range of neurological disorders, but also occurs in otherwise healthy ageing. Despite its clinical prevalence, apathy does not yet have a designated treatment strategy. Generation of a translational animal model of apathy syndrome would facilitate the development of novel treatments. Given the multidimensional nature of apathy, a model cannot be achieved with a single behavioural test. Using a battery of behavioural tests we investigated whether aged rats exhibit behavioural deficits across different domains relevant to apathy. Using the effort for reward and progressive ratio tasks we found that aged male rats (21-27 months) show intact reward motivation. Using the novelty supressed feeding test and position-based object exploration we found aged rats showed increased anxiety-like behaviour inconsistent with emotional blunting. The sucrose preference test and reward learning assay showed intact reward sensitivity and reward-related cognition in aged rats. However, using a bowl-digging version of the probabilistic reversal learning task, we found a deficit in cognitive flexibility in aged rats that did not translate across to a touchscreen version of the task. While these data reveal important changes in cognitive flexibility and anxiety associated with ageing, aged rats do not show deficits across other behavioural domains relevant to apathy. This suggests that aged rats are not a suitable model for age-related apathy syndrome. These findings contrast with previous work in mice, revealing important species differences in behaviours relevant to apathy syndrome in ageing.

Adaptive coding of reward in schizophrenia, its change over time and relationship to apathy.

Adaptive coding of reward is the process by which neurons adapt their response to the context of available compensations. Higher rewards lead to a stronger brain response, but the increase of the response depends on the range of available rewards. A steeper increase is observed in a narrow range and a more gradual slope in a wider range. In schizophrenia, adaptive coding appears to be affected in different domains, especially in the reward domain. Here, we tested adaptive coding of reward in a large group of patients with schizophrenia (n = 86) and control subjects (n = 66). We assessed: (i) the association between adaptive coding deficits and symptoms; (ii) the longitudinal stability of deficits (the same task was performed 3 months apart); and (iii) the stability of results between two experimental sites. We used functional MRI and the monetary incentive delay task to assess adaptation of participants to two different reward ranges: a narrow range and a wide range. We used a region-of-interest analysis to evaluate adaptation within striatal and visual regions. Patients and control subjects underwent a full demographic and clinical assessment. We found reduced adaptive coding in patients, with a decreased slope in the narrow reward range with respect to that of control participants, in striatal but not visual regions. This pattern was observed at both research sites. Upon retesting, patients increased their narrow-range slopes, showing improved adaptive coding, whereas control subjects slightly reduced them. At retesting, patients with overly steep slopes in the narrow range also showed higher levels of negative symptoms. Our data confirm deficits in reward adaptation in schizophrenia and reveal an effect of practice in patients, leading to improvement, with steeper slopes upon retesting. However, in some patients, an excessively steep slope may result in poor discriminability of larger rewards, owing to early saturation of the brain response. Together, the loss of precision of reward representation in new (first exposure, underadaptation) and more familiar (retest, overadaptation) situations might contribute to the multiple motivational symptoms in schizophrenia.

Neuropsychiatric symptoms with focus on apathy and irritability in sporadic and hereditary cerebral amyloid angiopathy.

BACKGROUND: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA. METHODS: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences. RESULTS: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.ß = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women. DISCUSSION: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately.

Unique transcriptional signatures correlate with behavioral and psychological symptom domains in Alzheimer's disease.

Despite the significant burden, cost, and worse prognosis of Alzheimer's disease (AD) with behavioral and psychological symptoms of dementia (BPSD), little is known about the molecular causes of these symptoms. Using antemortem assessments of BPSD in AD, we demonstrate that individual BPSD can be grouped into 4 domain factors in our cohort: affective, apathy, agitation, and psychosis. Then, we performed a transcriptome-wide analysis for each domain utilizing bulk RNA-seq of post-mortem anterior cingulate cortex (ACC) tissues. Though all 4 domains are associated with a predominantly downregulated pattern of hundreds of differentially expressed genes (DEGs), most DEGs are unique to each domain, with only 22 DEGs being common to all BPSD domains, including TIMP1. Weighted gene co-expression network analysis (WGCNA) yielded multiple transcriptional modules that were shared between BPSD domains or unique to each domain, and NetDecoder was used to analyze context-dependent information flow through the biological network. For the agitation domain, we found that all DEGs and a highly associated transcriptional module were functionally enriched for ECM-related genes including TIMP1, TAGLN, and FLNA. Another unique transcriptional module also associated with the agitation domain was enriched with genes involved in post-synaptic signaling, including DRD1, PDE1B, CAMK4, and GABRA4. By comparing context-dependent changes in DEGs between cases and control networks, ESR1 and PARK2 were implicated as two high-impact genes associated with agitation that mediated significant information flow through the biological network. Overall, our work establishes unique targets for future study of the biological mechanisms of BPSD and resultant drug development.

Study Partner Report of Apathy in Older Adults is Associated with AD Biomarkers: Findings from the Harvard Aging Brain Study.

OBJECTIVES: We examined relationships between apathy (self and study-partner-reported) and markers of Alzheimer's disease (AD) in older adults. DESIGN: The study utilized a well-characterized sample of participants from the Harvard Aging Brain Study (HABS), a longitudinal cohort study. Participants were cognitively unimpaired without clinically significant neuropsychiatric symptoms at HABS baseline. The dependent variables, apathy evaluation scale-self (AES-S) and informant (AES-I), were administered cross-sectionally between years 6-9 and compared to the independent variables, amyloid and tau PET neuroimaging, from the same year. SETTING: Community-dwelling participants assessed at research visits in an academic medical center. PARTICIPANTS: Participants (n = 170) completed assessments within 1.5 years of their neuroimaging visit. At the time of apathy assessment, N = 156 were cognitively unimpaired and 14 had progressed to mild cognitive impairment (n = 8) or dementia (n = 6). MEASUREMENTS: We utilized linear regression models to assess cross-sectional associations of AES-S and AES-I with AD PET imaging measures (beta-amyloid (Pittsburgh Compound B) and tau (Flortaucipir)), covarying for age, sex, education, and the time between PET scan-apathy assessment. RESULTS: AES-I was significantly associated with beta-amyloid and temporal lobe tau, and the associations were retained after further adjusting for depressive symptoms. The associations between AES-S and AD biomarkers were not significant. In an exploratory subgroup analysis of cognitively unimpaired individuals with elevated Aß, we observed an association between AES-I and inferior temporal tau. CONCLUSIONS: Study-partner-reported, but not self-reported, apathy in older adults is associated with AD pathology, and we observed this relationship starting from the preclinical stage. Our findings highlight the importance of collateral information in capturing AD-related apathy.

The Effect of Apathy and Depressive Syndromes on Functional Outcomes in Alzheimer's Disease.

Background: Alzheimer's disease (AD) is the most common cause of dementia. Its initially characterized by progressive short-term memory loss followed by cross-domain cognitive decline in later stages resulting in significant functional deficits and loss of activities of daily living (ADLs) independence. Apathy and depression are frequent neuropsychiatric sequelae in AD, but their contribution to functional deficits is poorly understood. Objective: We aimed to quantitatively investigate if apathy and depressive symptoms predict ADLs in AD. We also wanted to fractionate apathy dimensions by factor-analyzing the apathy evaluation scale (AES) and then investigate the dimensions' relation to ADLs. Methods: We recruited a sample of 115 patients with probable or possible AD and assessed them for depression, apathy, and ADLs alongside other measures. We hypothesized that apathy and depressive symptoms would predict ADLs and that AES items will load into cognitive, behavioral, and affective factors that would differentially relate to ADLs. Results: Our results indicated that apathy symptoms predict ADLs deficits. The AES items resolved into a three-factor solution but the manner of clustering diverged from that proposed by AES authors. When these factors were regressed simultaneously, only behavioral apathy predicted global ADLs. Distinguishing basic from instrumental ADLs showed that behavioral and cognitive apathy symptoms associate with ADLs deficits while affective symptoms do not. Conclusions: Our results highlight the influence of apathy on ADLs in AD. This has important implications for patient care considering the high prevalence of apathy in AD and other dementing illnesses.

Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Sex-specific neuropsychological correlates of apathy and depression across neurodegenerative disorders.

BACKGROUND: Apathy and depression are common neuropsychiatric symptoms across neurodegenerative disorders and are associated with impairment in several cognitive domains, yet little is known about the influence of sex on these relationships. OBJECTIVES: We examined the relationship between these symptoms with neuropsychological performance across a combined cohort with mild or major neurodegenerative disorders, then evaluated the impact of sex. DESIGN, SETTING AND PARTICIPANTS: We conducted a cohort analysis of participants in the COMPASS-ND study with mild cognitive impairment (MCI), vascular MCI, Alzheimer's disease, mixed dementia, Parkinson's disease, frontotemporal dementia, and cognitively unimpaired (CU) controls. MEASUREMENTS: Participants with neurodegenerative disease and CU controls were stratified by the presence (severity ≥1 on Neuropsychiatric Inventory Questionnaire) of either depressive symptoms alone, apathy symptoms alone, both symptoms, or neither. A neuropsychological battery evaluated executive function, verbal fluency, verbal learning, working memory, and visuospatial reasoning. Analysis of covariance was used to assess group differences with age, sex, and education as covariates. RESULTS: Groups included depressive symptoms only (n = 70), apathy symptoms only (n = 52), both (n = 68), or neither (n = 262). The apathy and depression + apathy groups performed worse than the neither group on tests of working memory (t(312)  = -2.4, p = 0.02 and t(328)  = -3.8, p = 0.001, respectively) and visuospatial reasoning (t(301)  = -2.3, p = 0.02 and t(321)  = -2.6, p = 0.01, respectively). The depression, apathy, and depression + apathy groups demonstrated a similar degree of impairment on tests of executive function, processing speed, verbal fluency, and verbal learning when compared to participants without apathy or depression. Sex-stratified analyses revealed that compared to the male neither group, the male apathy and depression + apathy groups were impaired broadly across all cognitive domains except for working memory. Females with depression alone showed deficits on tests of executive function (t(166)  = 2.4, p = 0.01) and verbal learning (t(167)  = -4.3, p = 0.001) compared to the female neither group. CONCLUSIONS: This study demonstrated that in neurodegenerative diseases, apathy with or without depression in males was associated with broad cognitive impairments. In females, depression was associated with deficits in executive function and verbal learning. These findings highlight the importance of effectively treating apathy and depression across the spectrum of neurodegenerative disorders with the goal of optimizing neuropsychological outcomes.