Perminder S. Sachdev

Background: The structure of psychopathology can be organized hierarchically into a set of transdiagnostic dimensional phenotypes. No studies have examined whether these phenotypes are associated with brain structure or dementia in older adults. Methods: Data were drawn from a longitudinal study of older adults aged 70-90 years at baseline (N = 1072; 44.8% male). Confirmatory factor models were fit to baseline psychiatric symptoms, with model fit assessed via traditional fit indices, model-based reliability estimates, and evaluation of model parameters. Bayesian plausible values were generated from the best-fitting model for use in subsequent analyses. Linear mixed models examined intraindividual change in global and regional gray matter volume (GMV) and cortical thickness over 6 years. Logistic regression examined whether symptom dimensions predicted incident dementia over 12 years. Results: A higher-order model showed a good fit to the data (BIC = 28,691.85; ssaBIC = 28,396.47; CFI = 0.926; TLI = 0.92; RMSEA = 0.047), including a general factor and lower-order dimensions of internalizing, disinhibited externalizing, and substance use. Baseline symptom dimensions did not predict change over time in total cortical and subcortical GMV or average cortical thickness; regional GMV or cortical thickness in the frontal, parietal, temporal, or occipital lobes; or regional GMV in the hippocampus and cerebellum (all p-values >0.5). Finally, baseline symptom dimensions did not predict incident dementia across follow-ups (all p-values >0.5). Conclusions: We found no evidence that transdiagnostic dimensions are associated with gray matter structure or dementia in older adults. Future research should examine these relationships using psychiatric indicators capturing past history of chronic mental illness rather than current symptoms.

Objective: To estimate point prevalence of apathy in older adults, examine its overlap with depression and fatigue, and explore its associations with multimorbidity and objective markers of health. Methods: Sydney Memory and Ageing Study, an Australian population-based cohort. Methods: Community dwellings between 2005-2007. Methods: 1,030 older adults, without dementia, aged 70-90. Methods: Apathy was classified using strict (=3) and standard (≥2) cutoff scores on the self-report Geriatric Depression Scale (GDS)-3A, and a validated cutoff score (>0) on the informant-report Neuropsychiatric Inventory. Depression was assessed with strict and standard cutoffs on the GDS-12D, and fatigue with the Assessment of Quality of Life-6D. Multimorbidity (≥2 chronic conditions; computed with and without cardiovascular conditions), physical performance (walking speed, sit-to-stand, lateral stability, grip strength), adiposity (BMI, waist circumference), blood pressure, cholesterol and glucose were assessed. Results: Prevalence of apathy on the self-reported measure was 15.8 % (strict cutoff) or 48.9 % (standard). Informant-reported apathy was lower (2.9 %). Prevalence of self-reported depression was 5.9 % (strict cutoff) or 15.8 % (standard), and fatigue 9.8 %. Apathy overlapped very little with depression or fatigue (κ = .18, 95 % CI .14-.21). Apathy was associated with multimorbidity (even when excluding cardiovascular conditions), adiposity, fasting blood glucose level and physical performance, but not blood pressure or cholesterol. Conclusions: Apathy is more common than depression or fatigue in dementia-free older adults. It does not typically co-occur with these symptoms, but is accompanied by poorer physical health, including multimorbidity and metabolic dysregulation. Apathy may be relevant for public health and an important consideration in clinical care.

Objective: Recent advancements in molecular biomarkers and therapeutic options for Alzheimer's disease have brought into focus the need for greater progress in the second most common cause of dementia, vascular cognitive impairment and dementia (VCID). We examine how the study of monogenic causes of VCID has contributed to the understanding of its pathophysiology and potential biomarker and treatment research. Results: It is widely accepted that conditions which disrupt the cerebral small vessels contribute to vascular pathologies including stroke and cerebral microbleeds, ultimately leading to vascular cognitive impairment and dementia. Among these conditions are a range of monogenic small vessel diseases (SVDs) such as CADASIL, CARASIL, Fabry disease and COL4A-related disorders. Conclusions: This review indicates the importance of furthering research into monogenic SVDs in order to gain insight into the pathomechanisms of VCID more broadly. Monogenic conditions are easier to model than sporadic VCID and can serve as a guide for identifying biomarkers for diagnosis, monitoring and intervention outcomes.

Background: Limited research has examined how older adults' lifestyles intersect with multimorbidity to influence mortality risk. Methods: In this community-dwelling prospective cohort, the Sydney Memory and Ageing Study, principal component analysis was used to identify lifestyle patterns using baseline self-reported data on nutrition, lifestyle factors, and social engagement activities. Multimorbidity was defined by self-reported physician diagnoses. Multivariable logistic regression was used to estimate odds ratios (ORs) for multimorbidity cross-sectionally, and Cox proportional hazards models were used to assess hazard ratios (HRs) for mortality risk longitudinally. Results: Of 895 participants (mean age: 78.2 years; 56.3% female) with complete lifestyle data, 597 had multimorbidity. Two distinct lifestyle patterns emerged: (i) a nutrition pattern characterised by higher intakes of protein, fibre, iron, zinc, magnesium, potassium, and folate, and (ii) an exercise-sleep-social pattern marked by weekly physical activities like bowling, bicycling, sleep quality (low snoring/sleepiness), and high social engagement. Neither pattern was associated with multimorbidity cross-sectionally. Over a median 5.8-year follow-up (n = 869; 140 deaths), participants in the upper tertiles for combined lifestyle pattern scores had a 20% lower mortality risk than those in the lowest tertile [adjusted HR: 0.80 (95% CI: 0.65-0.97); p-trend = 0.02]. This association was stronger in participants with multimorbidity, with a 29% lower risk [0.71 (0.56-0.89); p-trend = 0.01], likely due to multimorbidity modifying the relationship between nutrition and mortality risk (p-interaction < 0.05). While multimorbidity did not modify the relationship between the exercise-sleep-social pattern and risk of mortality, it was consistently associated with a 19-20% lower risk (p-trend < 0.03), regardless of the multimorbidity status. Conclusions: Older adults with multimorbidity may particularly benefit from adopting healthy lifestyles focusing on nutrition, physical activity, sleep quality, and social engagement to reduce their mortality risk.

Background: Copy number variants (CNVs) increase risk for neurodevelopmental conditions. The neurobiological mechanisms linking these high-risk genetic variants to clinical phenotypes are largely unknown. An important question is whether brain abnormalities in individuals carrying CNVs are associated with their degree of penetrance. Methods: We investigated if increased CNV-penetrance for schizophrenia and other developmental disorders was associated with variations in cortical and subcortical morphology. We pooled T1-weighted brain magnetic resonance imaging and genetic data from 22 cohorts from the ENIGMA-CNV consortium. In the main analyses, we included 9,268 individuals (aged 7 to 90 years, 54% females), from which we identified 398 carriers of 36 neurodevelopmental CNVs at 20 distinct loci. A secondary analysis was performed including additional neuroimaging data from the ENIGMA-22q consortium, including 274 carriers of the 22q11.2 deletion and 291 non-carriers. CNV-penetrance was estimated through penetrance scores that were previously generated from large cohorts of patients and controls. These scores represent the probability risk to develop either schizophrenia or other developmental disorders (including developmental delay, autism spectrum disorder and congenital malformations). Results: For both schizophrenia and developmental disorders, increased penetrance scores were associated with lower surface area in the cerebral cortex and lower intracranial volume. For both conditions, associations between CNV-penetrance scores and cortical surface area were strongest in regions of the occipital lobes, specifically in the cuneus and lingual gyrus. Conclusions: Our findings link global and regional cortical morphometric features with CNV-penetrance, providing new insights into neurobiological mechanisms of genetic risk for schizophrenia and other developmental disorders.