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Elderly become vulnerable to malnutrition owing to inappropriate dietary intake, poor economic status and social deprivation. Elderly are known to be easily subjected to inanition and avitaminosis resulting in multiple nutritional deficiencies. Urban slum dwellers, rural poor and those living alone appear to be at a higher risk of poor dietary intake. Though food consumption patterns of rural and urban elderly show a distinct difference, these are greatly influenced by regional dietary patterns. The diets of institutionalised and free living elderly reveal adequate nutrient intakes except iron and vitamin A. The nutrients least adequately supplied in the diets of Indian elderly are calcium, Iron, vitamin A, riboflavin and niacin along with energy deficits. Changes in body composition which mark the onset of the ageing process, include decline in lean body mass and increase in adipose tissue. A high prevalence of iron deficiency anaemia has also been reported among Indian elderly.

BACKGROUND: Worsening renal function (WRF) is common in hospitalized patients being treated for acute heart failure. However, discriminating clinically significant WRF remains challenging. In patients hospitalized with acute heart failure, we evaluated if blood and urine biomarkers of cardiac and kidney dysfunction were associated with adverse outcomes. METHODS: We identified 175 of 927 participants in the AKINESIS study (Acute Kidney Neutrophil Gelatinase-Associated Lipocalin Evaluation of Symptomatic Heart Failure Study) who met criteria for stage 1 or 2 Kidney Disease: Improvement Global Outcomes acute kidney injury during the first 3 days of hospitalization. We measured 24 blood and urine biomarkers from specimens collected within 24 hours of meeting acute kidney injury criteria. The primary composite outcome consisted of worsening WRF (higher acute kidney injury stage), need for dialysis, or death at 30 days. Biomarkers association with the composite outcome was assessed with logistic regression by tertiles and area under the curve (AUC). RESULTS: Of the 175 participants, 32 (18%) developed the primary composite outcome. Only history of chronic kidney disease was significantly different between those with and without the composite outcome. The highest tertile of plasma Gal-3 (galectin-3) and urine epidermal growth factor were associated with increased odds of the composite outcome compared with the lowest tertile in unadjusted analyses. After adjusting for serum creatinine, systolic blood pressure, and blood urea nitrogen, only the highest tertile of Gal-3 was associated with greater odds of the composite outcome (odds ratio, 4.6 [95% CI, 1.4-16.0). Gal-3 had the highest AUC (0.70 [95% CI, 0.58-0.82]), while epidermal growth factor had a lower AUC (0.63 [95% CI, 0.53-0.74]). Notably, urine biomarkers of kidney tubule injury were not associated with the composite outcome. CONCLUSIONS: Tubular injury does not occur in most patients with acute heart failure experiencing WRF, consistent with the functional mechanisms of WRF in this patient population. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT01291836?term=NCT01291836&rank=1; Unique identifier: NCT01291836.

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106Bs effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

STUDY OBJECTIVES: Disturbances of sleep maintenance and sleep duration are common in older adults and associated with an increased risk for age-related mortality and morbidity. Converging evidence implicates inflammation as an underlying mechanism, especially in females. However, it is unknown what specific aspects of sleep disturbance impact inflammatory mechanisms in older adults. METHODS: Using data from community-dwelling older adults who participated in the Sleep Health and Aging Research (SHARE) field study (n = 262, mean age 71.9 ± 8.0 years), we conducted a secondary analysis to examine whether disturbance of sleep maintenance (i.e. greater amount of wake time after sleep onset [WASO]) and sleep duration (i.e. shorter total sleep time [TST]) assessed by sleep diary and actigraphy are associated with greater activation of nuclear factor (NF)-κB and signal transducer and activator of transcription (STAT) family proteins STAT1, STAT3, and STAT5 in peripheral blood monocytic cells. In addition, moderation effects of sex were explored. RESULTS: Data were available for sleep diary (n = 82), actigraphy (n = 74), and inflammatory signaling and transcriptional measures (n = 132). As assessed by sleep diary, greater amount of WASO (β = 0.39, p < 0.01), but not TST, was associated with higher levels of NF-κB. Whereas diary-assessed sleep measures were not associated with STAT family proteins, a moderation analysis revealed that greater diary-assessed WASO was associated with higher levels of STAT1 (p < 0.05), STAT3 (p < 0.05), and STAT5 (p < 0.01) in females, but not in males. Actigraphy-assessed sleep measures were not associated either with NF-κB or STAT activation. CONCLUSIONS: In older adults, self-reported disturbance of sleep maintenance assessed by sleep diary was uniquely associated with higher levels of NF-κB, along with higher levels of STAT family proteins in females, but not in males. Our data suggest that improvingself-reported sleep maintenance might mitigate age-related increases in inflammatory signaling and transcriptional pathways, possibly more strongly in females, with the potential to reduce mortality risk in older adults.

Late life insomnia may increase risk for accelerated biological aging. Intervening to treat insomnia may provide protection from biological aging by reducing the prevalence of senescent cells in the immune system, as indicated by gene expression of a marker of cellular senescence, p16INK4a. In the present study, we determine whether treatment of insomnia in older adults with cognitive behavioral therapy for insomnia (CBT-I) would reduce p16INK4a gene expression in peripheral blood mononuclear cells (PBMC), compared to a sleep education therapy (SET), an active comparator condition. Secondly, we investigate the relationship between sustained insomnia remission and reduced expression of p16INK4a. Participants 60 + years old with insomnia were enrolled in a randomized controlled trial and assigned to CBT-I or SET. Analyses of 231 older adults (CBT-I = 119; SET = 112) examine baseline, post (2 months), and 24 months gene expression of p16INK4a. Compared to baseline, expression of p16INK4a increased in the SET group over 24 months (P = 0.03), but showed no change in the CBT-I group. Those who received CBT-I and experienced sustained remission of insomnia had a significant decline in p16INK4a expression by 24 months compared to baseline (P = 0.02). Individuals not sustaining remission of insomnia exhibited overall increase expression of p16INK4a by 24 months (P = 0.03). In older adults with insomnia, p16INK4a increases over 24 months, while CBT-I treatment of insomnia mitigates the increase in p16INK4a. Further, sustained remission of insomnia using CBT-I leads to a decrease in p16INK4a. These results suggest that behavioral interventions that are effective at treating insomnia might reduce the population of senescent cells in circulating blood.

ImportancePlasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.ObjectiveTo validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.Design, setting, and participantsThis multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.Main outcome and measuresPlasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.ResultsOf 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P

The present study investigated the contribution of health risk factors (using the Charlson Comorbidity Index [CCI]) on cognitive outcomes in a sample of 380 HIV-positive (HIV+; n = 221) and HIV-seronegative (HIV-; n = 159) African American and European American adults aged 50+.Participants were recruited from HIV clinics and community advertisements. HIV status was confirmed by serological testing. Self-report and chart history review was used to gather information about medical ssscomorbidities. The Charlson Comorbidity Index (CCI) was used to create a comorbidity score. Participants were administered a brief cognitive test battery.As expected, health risks were greater among those with HIV. There was a HIV × Race interaction on CCI scores, such that in the HIV + group, European Americans had significantly higher CCI scores (M = 3.74; SD = 2.1) than African American HIV + participants (M = 2.70; SD = 1.9). However, in the HIV - group, African Americans had significantly higher CCI scores (M = 2.20; SD = 1.1) than HIV - European American participants (M = 1.80; SD = 1.2). Also, consistent with hypotheses, across the entire sample CCI score was significantly associated with global cognition (β = -.24, p = .02).Study results underscore the importance of considering HIV serostatus in studies examining racial disparities in health, and how multiple medical risks relate to cognitive outcomes. Neuropsychologists evaluating patients living with HIV should consider how the presence of multiple medical comorbidities may contribute to the course of cognitive decline as people age.

ImportanceOlder adults with insomnia have a high risk of incident and recurrent depression. Depression prevention is urgently needed, and such efforts have been neglected for older adults.ObjectiveTo examine whether treatment of insomnia disorder with cognitive behavioral therapy for insomnia (CBT-I) compared with an active comparator condition, sleep education therapy (SET), prevents major depressive disorder in older adults.Design, setting, and participantsThis assessor-blinded, parallel-group, single-site randomized clinical trial assessed a community-based sample of 431 people and enrolled 291 adults 60 years or older with insomnia disorder who had no major depression or major health events in past year. Study recruitment was performed from July 1, 2012, to April 30, 2015. The trial protocol was modified to extend follow-up from 24 to 36 months, with follow-up completion in July 2018. Data analysis was performed from March 1, 2019, to March 30, 2020.InterventionsParticipants were randomized to 2 months of CBT-I (n = 156) or SET (n = 135).Main outcomes and measuresThe primary outcome was time to incident major depressive disorder as diagnosed by interview and Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria. Secondary outcome was sustained remission of insomnia disorder before depression event or duration of follow-up.ResultsAmong 291 randomized participants (mean [SD] age, 70.1 [6.7] years; 168 [57.7%] female; 7 [2.4%] Asian, 32 [11.0%] Black, 3 [1.0%] Pacific Islander, 241 [82.8%] White, 6 [2.1%] multiracial, and 2 [0.7%] unknown), 156 were randomized to CBT-I and 135 to SET. A total of 140 participants (89.7%) completed CBT-I and 130 (96.3%) participants completed SET (χ2 = 4.9, P = .03), with 114 (73.1%) completing 24 months of follow-up in the CBT-I group and 117 (86.7%) in the SET group (χ2 = 8.4, P = .004). After protocol modification, 92 (59.0%) of the CBT-I participants and 86 (63.7%) of the SET participants agreed to extended follow-up (χ2 = 0.7, P = .41), with 81 (51.9%) of the CBT-I participants and 77 (57.0%) of the SET group completing 36 months of follow-up (χ2 = 0.8; P = .39). Incident or recurrent major depression occurred in 19 participants (12.2%) in the CBT-I group and in 35 participants (25.9%) in the SET group, with an overall benefit (hazard ratio, 0.51; 95%, CI 0.29-0.88; P = .02) consistent across subgroups. Remission of insomnia disorder continuously sustained before depression event or during follow-up was more likely in CBT-I participants (41 [26.3%]) compared with the SET participants (26 [19.3%], P = .03). Those in the CBT-I group with sustained remission of insomnia disorder had an 82.6% decreased likelihood of depression (hazard ratio, 0.17; 95%, CI 0.04-0.73; P = .02) compared with those in the SET group without sustained remission of insomnia disorder.Conclusions and relevanceThe findings of this randomized clinical trial indicate that treatment of insomnia with CBT-I has an overall benefit in the prevention of incident and recurrent major depression in older adults with insomnia disorder. Community-level screening for insomnia concerns in older adults and wide delivery of CBT-I-based treatment for insomnia could substantially advance public health efforts to treat insomnia and prevent depression in this vulnerable older adult population.Trial registrationClinicalTrials.gov Identifier: NCT01641263.

BackgroundLow-value care, or patient care that offers no net benefit in specific clinical scenarios, is costly and often associated with patient harm. The US Preventive Services Task Force (USPSTF) Grade D recommendations represent one of the most scientifically sound and frequently delivered groups of low-value services, but a more contemporary measurement of the utilization and spending for Grade D services beyond the small number of previously studied measures is needed.ObjectiveTo estimate utilization and costs of seven USPSTF Grade D services among US Medicare beneficiaries.DesignWe conducted a cross-sectional study of data from the National Ambulatory Medical Care Survey (NAMCS) from 2007 to 2016 to identify instances of Grade D services.Setting/participantsNAMCS is a nationally representative survey of US ambulatory visits at non-federal and non-hospital-based offices that uses a multistage probability sampling design. We included all visits by Medicare enrollees, which included traditional fee-for-service, Medicare Advantage, supplemental coverage, and dual-eligible Medicare-Medicaid enrollees.Main measuresWe measured annual utilization of seven Grade D services among adult Medicare patients, using inclusion and exclusion criteria from prior studies and the USPSTF recommendations. We calculated annual costs by multiplying annual utilization counts by mean per-unit costs of services using publicly available sources.Key resultsDuring the study period, we identified 95,121 unweighted Medicare patient visits, representing approximately 2.4 billion visits. Each year, these seven Grade D services were utilized 31.1 million times for Medicare beneficiaries and cost $477,891,886. Three services-screening for asymptomatic bacteriuria, vitamin D supplements for fracture prevention, and colorectal cancer screening for adults over 85 years-comprised $322,382,772, or two-thirds of the annual costs of the Grade D services measured in this study.ConclusionsUS Medicare beneficiaries frequently received a group of rigorously defined and costly low-value preventive services. Spending on low-value preventive care concentrated among a small subset of measures, representing important opportunities to safely lower US health care spending while improving the quality of care.

ObjectiveTau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer's disease (AD). However, there is substantial variability in the T-N relationship - manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region-based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology.MethodsCortical thickness (N) and 18 F-Flortaucipir SUVR (T) were computed in 104 gray matter regions from a cohort of cognitively-impaired, amyloid-positive (A+) individuals. Region-specific residuals from a robust linear fit between SUVR and cortical thickness were computed as a surrogate for T-N mismatch. A summary T-N mismatch metric defined using residuals were correlated with demographic and imaging-based modulatory factors, and to partition the cohort into data-driven subgroups.ResultsThe summary T-N mismatch metric correlated with underlying factors such as age and burden of white matter hyperintensity lesions. Data-driven subgroups based on clustering of residuals appear to represent different biologically relevant phenotypes, with groups showing distinct spatial patterns of higher or lower atrophy than expected.InterpretationThese data support the notion that a measure of deviation from a normative relationship between tau burden and neurodegeneration across brain regions in individuals on the AD continuum captures variability due to multiple underlying factors, and can reveal phenotypes, which if validated, may help identify possible contributors to neurodegeneration in addition to tau, which may ultimately be useful for cohort selection in clinical trials. ANN NEUROL 2021;90:751-762.

ObjectiveWe tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression.MethodsBaseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables.ResultsIn both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers.ConclusionsPlasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials.Trial registration informationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of evidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

ObjectivesObstructive sleep apnoea (OSA) is a risk factor for hypertension (HTN), but the clinical progression of OSA to HTN is unclear. There are also sex differences in prevalence, screening and symptoms of OSA. Our objective was to estimate the time from OSA to HTN diagnoses in females and males.DesignRetrospective analysis of electronic health records (EHR) over 10 years (2006-2015 inclusive).SettingUniversity of California Los Angeles (UCLA) Health System in Los Angeles, California, USA.Participants4848 patients: females n=2086, mean (SD) age=52.8 (13.2) years; males n=2762, age=53.8 (13.5) years. These patients were selected from 1.6 million with diagnoses in the EHR who met these criteria: diagnoses of OSA and HTN; in long-term care defined by ambulatory visits at least 1 year prior and 1 year subsequent to the first OSA diagnosis; no diagnosis of OSA or HTN at intake; and a sleep study performed at UCLA.Primary and secondary outcome measuresThe primary outcome measure in each patient was time from the first diagnosis of OSA to the first diagnosis of HTN (OSA to HTN days). Since HTN and OSA are progressive disorders, a secondary measure was the relationship between OSA to HTN time and age (OSA to HTN=β1×Age+β0).ResultsThe median (lower and upper quartiles) days from OSA to HTN were: all -532 (-1439, -3); females -610 (-1579, -42); and males -451 (-1358, 0). Older age in both sexes was associated with less time to a subsequent HTN diagnosis or more time from a prior HTN diagnosis (β1 days/year: all -16.9, females -18.3, males -15.9).ConclusionsHTN was on average diagnosed years prior to OSA, with a longer separation in females. Our findings are consistent with underscreening of OSA, more so in females than males. Undiagnosed OSA may delay treatment for the sleep disorder and perhaps affect the development and progression of HTN.

Objective/Background: Sleep problems are common in women and caregiving for an adult is a common role among women. However, the effects of caregiving on sleep and related daytime impairment are poorly understood among women veterans. This study compared stress-related sleep disturbances, insomnia symptoms, and sleep-related daytime impairment between women veterans who were caregivers and those who did not have a caregiving role. Participants: Of 12,225 women veterans who received care in one Veterans Administration Healthcare System, 1,457 completed data on a postal survey (mean age = 51.7 ± 15.9 years). Two hundred forty three (17%) respondents (mean age 53.8 ± 12.7 years) were caregivers for an adult, predominantly for a parent, providing transportation. Methods: The survey included items that addressed insomnia symptoms, total sleep time, sleep-related daytime impairments, caregiving characteristics, self-rated health, pain, stress, body mass index, and demographic information. Results: In adjusted analyses, caregiver status did not directly predict sleep complaints alone. However, in multiple regression analyses, being a caregiver (odds ratio 1.7, p = .001) significantly predicted stress-related sleep disturbance, even after adjusting for age, pain, self-rated health, and other characteristics. Furthermore, being a caregiver (β = 3.9, p = .031) significantly predicted more symptoms of sleep-related daytime impairment after adjusting for age, pain, self-rated health, and other factors. Conclusions: Compared to noncaregivers, women veterans who were caregivers for an adult were more likely to report stress causing poor sleep, and more daytime impairment due to poor sleep. These findings suggest the need to target stress and other factors when addressing sleep disturbance among women veterans who are caregivers.

ObjectivesBeliefs about aging can contribute to health and well-being in older adults. Feeling generative, or that one is caring for and contributing to the well-being of others, can also impact health and well-being. In this study, we hypothesized that those with more positive expectations regarding aging (ERA) in the mental health domain would report greater levels of perceived social support (PSS) and lower levels of loneliness in response to a generativity intervention (vs control condition).MethodParticipants in this study (n = 73, 100% female) were randomly assigned to a 6-week generativity condition, which involved writing about life experiences and sharing advice with others, or to a control condition, which involved writing about neutral topics. Pre- and postintervention, PSS, and feelings of loneliness were measured.ResultsThose in the generativity condition with more positive ERA in the mental health domain reported greater PSS and lower loneliness postintervention.DiscussionThese results highlight the importance of psychological factors, such as ERA, in moderating the efficacy of interventions to promote social well-being in older adults.

ObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

AimsLewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing.MethodsHippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aβ. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing.ResultsLBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P

ObjectivesTo investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).MethodsWe studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ1-42  > 0.3) (LBD+AD, N = 19), and those without AD co-pathology (LBD-AD, N = 53). We also included a reference group of 25 patients with CSF biomarker-confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD-AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post-mortem burdens of tau, Aβ, and alpha-synuclein using digital histopathology in five representative neocortical regions.ResultsThe LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P

ObjectivesTo assess the benefits of training in mindfulness-based stress reduction (MBSR) or moderate intensity exercise (EX) for improving sleep quality.DesignRandomized controlled trial.SettingOutpatient, community-based.ParticipantsHealthy adults (n = 413) aged 30-69 who did not regularly exercise or practice meditation, and who had no known prior sleep problems.Interventions1) 8-weeks of MBSR training; 2) matched EX training; or 3) wait-list control.MeasurementsThe Pittsburgh Sleep Quality Index (PSQI) was administered at baseline and at 1, 3, 5, and 7-month follow-up visits.AnalysisTotal PSQI scores and three PSQI factors (perceived sleep quality; daily disturbance, sleep efficiency) were assessed using linear mixed effects regression models for longitudinal data.ResultsCompared to controls, PSQI global scores improved significantly for EX (mean change -0.98 points [95% CI -1.56, -0.41] p = 0.001) and marginally for MBSR (-0.53 [-1.10, 0.04] p = 0.07). The perceived sleep quality factor improved for both EX (-0.18 [-0.30, -0.07] p = 0.002) and MBSR (-0.12 [-0.24, -0.01] p = 0.035). The daily disturbance factor improved slightly more for MBSR (-0.13 [-0.22, -0.033] p = 0.008) than EX (-0.09 [-0.19, 0.004] p = 0.06). The sleep efficiency factor did not improve after MBSR (0.08 [-0.045, 0.21] p = 0.2) or EX (-0.07 [-0.20, 0.06] p = 0.3). Improvements in the sleep quality were sustained over 7 months for both groups.ConclusionsTraining in MBSR and EX produced small but statistically significant and sustained improvements in sleep quality. For EX participants, this improvement was due primarily to improvements in perceived sleep quality. For MBSR, the decrease in daily disturbance was more important.

Objectives: Circulating cytokines have been associated with depression, but their detection has limitations, which may be overcome by direct detection of intracellular cytokines (ICCs) after lipopolysaccharide (LPS) stimulation in vitro. This study compared circulating versus LPS-induced inflammatory markers as correlates of subthreshold depressive symptoms.Methods: Secondary data analysis of a cross-sectional insomnia study in healthy community-dwelling older adults was conducted. In 117 participants (≥55 years), plasma tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP) and in vitro LPS-induced monocyte production of IL-6 and TNF-α were assayed. Depressive symptoms were assessed using the clinician-rated Inventory of Depressive Symptomatology (IDS-C). Multivariate linear regression was conducted to test the associations between inflammatory markers and subthreshold depressive symptoms in the entire sample as well as in subgroups stratified into higher and lower inflammation levels.Results: LPS-induced TNF-α (adjusted β = 0.28, p = .04), IL-6 (0.29, p = .03) and TNF-α + IL-6 (0.43, p = .001) significantly positively correlated with subthreshold depressive symptoms only in higher inflammation subgroups. No circulating biomarkers positively correlated in any subgroups. In the entire sample, no biomarkers were significantly associated with subthreshold depressive symptoms.Conclusions: LPS-induced cytokines may be more sensitive correlates of subthreshold depressive symptoms than circulating cytokines, particularly in older adults with higher systemic inflammation.Clinical Trials Registry: ClinicalTrials.gov NCT00280020.

ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid-β 1 to 42 (Aβ42 ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models.ResultsWe found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1-3,297.0; p

Insomnia is a well-established risk factor for late-life depression, yet the intermediary mechanisms are not known. One plausible mechanism is dysregulation of the reward system, a common feature of depression. The main objective of the current study was to determine whether late-life insomnia is associated with reduced motivation and reduced sensitivity for monetary reward. Secondary exploratory objectives were to test for sex-specific effects and whether elevated inflammation potentiated these associations. Nondepressed community dwelling older adults (n = 104; aged 60-80) who either met (n = 31) or did not meet (n = 73) criteria for insomnia disorder as assessed by the Structured Clinical Interview for DSM-5 completed the Effort Expenditure for Rewards Task and provided blood samples for the assessment of C-reactive protein (CRP). Older adults with late-life insomnia showed reduced reward motivation 95% CI [-0.955, -0.569] and reduced reward sensitivity 95% CI [-0.430, -0.075] relative to comparison controls. In secondary exploratory analyses, late-life insomnia was associated with reduced motivation to a greater degree in males than in females 95% CI [0.072, 0.775], particularly when CRP was also elevated 95% CI [0.672, 1.551]. Late-life insomnia is associated with reduced motivation and sensitivity for monetary reward, which suggests insomnia may confer risk for late-life depression by dysregulation of reward mechanisms. Exploratory analyses suggest that older males with insomnia and elevated CRP may be particularly vulnerable to deficits in reward motivation. Although in need of replication and further study, results suggest that interventions that target insomnia or deficits in reward processing may mitigate the risk of depression in nondepressed older adults, especially older males with insomnia.

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.

ObjectiveThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other.MethodsIndividuals were classified using the Clinical Dementia Rating (CDR® ) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated.ResultsThe cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = -0.20, P = .001), as were ZBI and DEMQOL (r = -0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P

ObjectiveTo investigate whether the Revised Self-Monitoring Scale (RSMS), an informant measure of socioemotional sensitivity, is a potential clinical endpoint for treatment trials for patients with behavioral variant frontotemporal dementia (bvFTD).MethodsWe investigated whether RSMS informant ratings reflected disease severity in 475 participants (71 bvFTD mutation+, 154 bvFTD mutation-, 12 behavioral mild cognitive impairment [MCI] mutation+, 98 asymptomatic mutation+, 140 asymptomatic mutation-). In a subset of 62 patients (20 bvFTD mutation+, 35 bvFTD mutation-, 7 MCI mutation+) who had at least 2 time points of T1-weighted images available on the same 3T scanner, we examined longitudinal changes in RSMS score over time and its correspondence to progressive gray matter atrophy.ResultsRSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F 4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] -1.90 to -0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI -0.30 to -0.11).ConclusionsThe RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

ObjectiveCurrent abdominal aortic aneurysm (AAA) surveillance guidelines lack any follow-up recommendations after initial abdominal aortic screening diameter of less than 3.0 cm. Some reports have demonstrated patients with late AAA formation and late ruptures after initial ultrasound screening detection of patients with an aortic diameter of 2.5 to 2.9 cm (ectatic aorta). The purpose of this study was to determine ectatic aorta prevalence, AAA development, rupture risk, and risk factor profile in patients with detected ectatic aortas in a AAA screening program.MethodsA retrospective chart review of all patients screened for AAA from January 1, 2007, to December 31, 2016, within a regional health care system was conducted. Screening criteria were men 65 to 75 years of age that smoked a minimum of 100 cigarettes in their lifetime. An ectatic aorta was defined as a maximum aortic diameter from 2.5 to 2.9 cm. An AAA was defined as an aortic diameter of 3 cm or greater. Patients screened with ectatic aortas who had subsequent follow-up imaging of the aorta with a minimum of 1-year follow-up were analyzed for associated clinical and cardiovascular risk factors. All data were collected through December 3,/2018. A logistic regression of statistically significant variables from univariate and χ2 analyses were performed to identify risks associated with the development of AAA from an initially diagnosed ectatic aorta. A Cox proportional hazard model was used to assess survival data. A P value of less than .05 was considered statistically significant.ResultsFrom a screening pool of 19,649 patients, 3205 (16.3%) with a mean age of 72.1 ± 5.3 years were identified to have an ectatic aorta from January 1, 2007, to December 31, 2016. The average screening ectatic aortic diameter was 2.6 ± 0.1 cm. There were 672 patients (21.0%) with a mean age of 73.0 ± 5.7 years who received subsequent imaging for other clinical indications and 193 of these patients (28.7%) with ectatic aortas developed an AAA from the last follow-up scan (4.2 ± 2.5 years). The average observation length of all patients was 6.4 ± 2.9 years. No ruptures were reported, but 27.8% of deaths were of unknown cause. One patient had aortic growth to 5.5 cm or greater (0.15%). Larger initial screening diameter (P < .01), presence of chronic obstructive pulmonary disease (P < .01), and active smoking (P = .01) were associated with AAA development.ConclusionsPatients with diagnosed ectatic aortas from screening who are active smokers or have chronic obstructive pulmonary disease are likely to develop an AAA.

Distinct neuronal and glial tau pathologies define corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Additional Alzheimer disease, TDP-43, and Lewy body copathologies are also common. The interplay of these pathologies with clinical symptoms remains unclear as individuals can present with corticobasal syndrome, frontotemporal dementia, PSP, or atypical Parkinsonism and may have additional secondary impairments. We report clinical, pathological, and genetic interactions in a cohort of CBD and PSP cases. Neurofibrillary tangles and plaques were common. Apolipoprotein E (APOE)ε4 carriers had more plaques while PSP APOEε2 carriers had fewer plaques. TDP-43 copathology was present and age-associated in 14% of PSP, and age-independent in 33% of CBD. Lewy body copathology varied from 9% to 15% and was not age-associated. The primary FTD-Tau burden-a sum of the neuronal, astrocytic and oligodendrocytic tau-was not age-, APOE-, or MAPT-related. In PSP, FTD-Tau, independent of copathology, associated with executive, language, motor, and visuospatial impairments, while PSP with Parkinsonism had a lower FTD-Tau burden, but this was not the case in CBD. Taken together, our results indicate that the primary tauopathy burden is the strongest correlate of clinical PSP, while copathologies are principally determined by age and genetic risk factors.

Generativity, or concern for and contribution to the well-being of younger generations, plays an important role in successful aging. The purpose of this study was to develop a novel, writing-based intervention to increase feelings of generativity and test the effect of this intervention on well-being and inflammation in a sample of older women. Participants in this study (n = 73; mean age = 70.9 years, range 60-86 years) were randomly assigned to a 6-week generativity writing condition (writing about life experiences and sharing advice with others) or a control writing condition (neutral, descriptive writing). Self-reported measures of social well-being, mental health, and physical health, as well as objective measures of systemic and cellular levels of inflammation (plasma pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α; genome-wide RNA transcriptional profiling), were assessed pre- and post-intervention. The generativity intervention led to significant improvements across multiple domains, including increases in participation in social activities, decreases in psychological distress, more positive expectations regarding aging in the physical health domain, and decreases in pro-inflammatory gene expression. Thus, this study provides preliminary evidence for the ability of a novel, low-cost, low-effort intervention to favorably impact inflammation and well-being in older women.

BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

BACKGROUND: The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category probable 4-repeat (4R)-tauopathy for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration. OBJECTIVES: To validate the accuracy of these clinical criteria for probable 4R-tauopathy to predict underlying 4R-tauopathy pathology. METHODS: Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinsons disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies). RESULTS: We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of probable 4R-tauopathy was 10% and 99% in the first year and 59% and 88% at final record. CONCLUSIONS: The new diagnostic category probable 4R-tauopathy showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

IntroductionWe created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD.MethodsThe CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants.ResultsThe CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants.DiscussionThe global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

IntroductionLeisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD).MethodsA total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans.ResultsGreater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates.DiscussionActive lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60-88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4-stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription (STAT1, STAT3, STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p's < .05) and with increases in STAT1, STAT3, and STAT5 activation (p's < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4-stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.

Objective: Older adults are at higher risk of experiencing social isolation, which has been linked to impaired physical and mental health. The link between social isolation and health might be due to objective deprivation of social network and/or subjective experience of loneliness. This community-based cross-sectional study examined whether the associations between social isolation and behavioral symptoms including sleep disturbance, depression, and fatigue are mostly explained by its subjective component. Methods: Randomly selected 2541 community-dwelling individuals in Los Angeles aged ≥60 years were telephone-interviewed regarding their objective and subjective social isolation (respectively social network size and loneliness), sleep disturbance, depression, and fatigue. Results: When objective and subjective social isolation were separately included in multivariate regression models, both were significantly associated with behavioral symptoms. However, once they were simultaneously included in the same multivariate models, while subjective social isolation remained strongly associated (adjusted beta 0.24 for sleep disturbance [P

BackgroundSemantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD.MethodsThis large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset).ResultsCSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p

BackgroundInterseasonal influenza outbreaks are not unusual in countries with temperate climates and well-defined influenza seasons. Usually, these are small and diminish before the main influenza season begins. However, the 2018/19 summer-autumn interseasonal influenza period in Australia saw unprecedented large and widespread influenza outbreaks.AimOur objective was to determine the extent of the intense 2018/19 interseasonal influenza outbreaks in Australia epidemiologically and examine the genetic, antigenic and structural properties of the viruses responsible for these outbreaks.MethodsThis observational study combined the epidemiological and virological surveillance data obtained from the Australian Government Department of Health, the New South Wales Ministry of Health, sentinel outpatient surveillance, public health laboratories and data generated by the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne and the Singapore Agency for Science, Technology and Research.ResultsThere was a record number of laboratory-confirmed influenza cases during the interseasonal period November 2018 to May 2019 (n= 85,286; 5 times the previous 3-year average) and also more institutional outbreaks, hospitalisations and deaths, than what is normally seen.ConclusionsThe unusually large interseasonal influenza outbreaks in 2018/19 followed a mild 2018 influenza season and resulted in a very early start to the 2019 influenza season across Australia. The reasons for this unusual event have yet to be fully elucidated but are likely to be a complex mix of climatic, virological and host immunity-related factors. These outbreaks reinforce the need for year-round surveillance of influenza, even in temperate climates with strong seasonality patterns.

BackgroundThe Movement Disorder Society criteria for progressive supranuclear palsy define diagnostic allocations, stratified by certainty levels and clinical predominance types. We aimed to study the frequency of ambiguous multiple allocations and to develop rules to eliminate them.MethodsWe retrospectively collected standardized clinical data by chart review in a multicenter cohort of autopsy-confirmed patients with progressive supranuclear palsy, to classify them by diagnostic certainty level and predominance type and to identify multiple allocations.ResultsComprehensive data were available from 195 patients. More than one diagnostic allocation occurred in 157 patients (80.5%). On average, 5.4 allocations were possible per patient. We developed four rules for Multiple Allocations eXtinction (MAX). They reduced the number of patients with multiple allocations to 22 (11.3%), and the allocations per patient to 1.1.ConclusionsThe proposed MAX rules help to standardize the application of the Movement Disorder Society criteria for progressive supranuclear palsy. © 2019 International Parkinson and Movement Disorder Society.

Study objectivesSleep disturbances and sleep apnea are associated with increased vulnerability to age-related disease, altering molecular pathways affecting biological aging. Telomere length captures one component of biological aging. We evaluated whether objectively assessed sleep and sleep apnea relate to leukocyte telomere length (LTL) in the Multi-Ethnic Study of Atherosclerosis (MESA).MethodsMen and women aged 44-84 years (n = 672) from the MESA Stress and MESA Sleep studies underwent polysomnography and 7 day actigraphy (at Exam 5) and assessment of LTL (at baseline [Exam 1] and about 10 years later [Exam 5]).ResultsGeneral linear models adjusting for age, sex, race/ethnicity, BMI, physical activity, and smoking found that severe obstructive sleep apnea (OSA; apnea-hypopnea index > 30) was cross-sectionally associated with shorter LTL (p = 0.007). Modest associations of shorter LTL with less rapid eye movement sleep, more stage 1 sleep, wake after sleep onset >30 min, and long sleep duration were found, but these effects were diminished after adjusting for lifestyle and OSA. Exploratory analyses found that higher arousal index at Exam 5 was associated with greater LTL decline over the prior 10 years (p = 0.004).ConclusionsOSA was associated with shorter LTL. Individuals with high-arousal frequency had greater leukocyte telomere attrition over the prior decade. These findings suggest that sleep apnea and sleep fragmentation are associated with accelerated biological aging.

BackgroundEnd colostomy rates following colorectal resection vary across institutions in high-income settings, being influenced by patient, disease, surgeon and system factors. This study aimed to assess global variation in end colostomy rates after left-sided colorectal resection.MethodsThis study comprised an analysis of GlobalSurg-1 and -2 international, prospective, observational cohort studies (2014, 2016), including consecutive adult patients undergoing elective or emergency left-sided colorectal resection within discrete 2-week windows. Countries were grouped into high-, middle- and low-income tertiles according to the United Nations Human Development Index (HDI). Factors associated with colostomy formation versus primary anastomosis were explored using a multilevel, multivariable logistic regression model.ResultsIn total, 1635 patients from 242 hospitals in 57 countries undergoing left-sided colorectal resection were included: 113 (6·9 per cent) from low-HDI, 254 (15·5 per cent) from middle-HDI and 1268 (77·6 per cent) from high-HDI countries. There was a higher proportion of patients with perforated disease (57·5, 40·9 and 35·4 per cent; P

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

ObjectivesCenter of Epidemiologic Studies-Depression Scale (CES-D) provides a snapshot of symptom severity at a single point in time. However, the best way of using CES-D to classify long-term depression is unclear.MethodTo identify long-term depression among HIV-infected and HIV-uninfected 50+ year-old men who have sex with men (MSM) with at least 5 years of follow-up, we compared sensitivities and specificities of CES-D-based metrics (baseline CES-D; four consecutive CES-Ds; group-based trajectory models) thresholded at 16 and 20 to a clinician's evaluation of depression phenotype based on all available data including CES-D history, depression treatment history, drug use history, HIV disease factors, and demographic characteristics.ResultsA positive depressive phenotype prevalence was common among HIV-infected (prevalence = 33.1%) and HIV-uninfected MSM (prevalence = 23.2%). Compared to the depressive phenotype, trajectory models of CES-D≥20 provided highest specificities among HIV-infected (specificity = 99.9%, 95% Confidence Interval [CI]:99.4%-100.0%) and HIV-uninfected MSM (specificity = 99.0%, 95% CI:97.4%-99.7%). Highest sensitivities resulted from classifying baseline CES-D ≥ 16 among HIV-infected MSM (sensitivity = 75.0%, 95% CI:67.3%-81.7%) and four consecutive CES-Ds ≥ 16 among HIV-uninfected MSM (sensitivity = 81.0%, 95% CI:73.7%-87.0%).ConclusionChoice of method should vary, depending on importance of false positive or negative rate for long-term depression in HIV-infected and HIV-uninfected MSM.

BackgroundFatigue is one of the most common and disabling side effects of cancer and its treatment. Although research typically has focused on fatigue that occurs during and after treatment, patients may experience fatigue even before treatment onset. The current study was designed to identify biobehavioral risk factors associated with fatigue before adjuvant therapy in women with early-stage breast cancer.MethodsPatients with stage 0 to stage IIIA breast cancer (270 women) were recruited before the onset of adjuvant or neoadjuvant therapy with radiotherapy, chemotherapy, and/or endocrine therapy. Host factors that may influence fatigue were identified from an empirically based, biobehavioral model and assessed using self-report questionnaires, medical record review, and blood collection (for genetic data). Fatigue was assessed by questionnaire. Linear regression analyses were used to evaluate the association between host factors and dimensions of fatigue, with general fatigue as the primary dimension of interest.ResultsFatigue was elevated at the pretreatment assessment compared with published controls. Bivariate analyses identified demographic, cancer-related, and biobehavioral correlates of fatigue. In the multivariable model, predictors of general fatigue included younger age, lower educational level, lower cancer stage, and history of childhood maltreatment (all P values

BackgroundBiological aging pathways accelerated by cancer treatments may be a mechanism for cognitive impairment in cancer survivors. The goal of the current study was to examine whether indicators of biological aging, namely elevated levels of DNA damage, reduced telomerase enzymatic activity, and shorter peripheral blood mononuclear cell (PBMC) telomere length (TL) would be related to cognitive function in a cohort of survivors of breast cancer.MethodsThe authors evaluated a cross-sectional sample of 94 women aged 36 to 69 years who were treated for early-stage breast cancer 3 to 6 years previously. Leukocyte DNA damage, PBMC telomerase enzymatic activity, PBMC TL, and the inflammatory marker soluble tumor necrosis factor receptor II (sTNF-RII) were determined from blood samples. Cognitive function was assessed using a neuropsychological test battery and self-report. Linear regression models examined the relationship between biological aging predictors and cognitive outcomes.ResultsBoth higher DNA damage and lower telomerase were found to be statistically significantly related to lower executive function scores adjusting for age, body mass index, race, years from treatment, and intelligence score (standardized coefficients [B], -0.23 and 0.30; all P values

Background:Childhood abuse is a risk factor for the development of cognitive deficits in adulthood, a relation that is likely mediated by stress-sensitive psychological and physiological indicators. Purpose:To evaluate whether the link between exposure to childhood abuse and cognitive function in middle adulthood is mediated by interleukin-6 (IL-6), metabolic risk, and depressive mood symptoms. Methods:Participants were 770 adults aged 40-65 recruited from the community, who completed the following: (i) a questionnaire assessing exposure to abuse prior to age 18, (ii) a phone interview assessing current depressive mood symptoms, and (iii) a home visit that included blood sampling for evaluation of IL-6 and assessment of metabolic risk indices. A follow-up telephone assessment evaluating cognitive function was completed by 555 of the participants. Structural equation modeling was used to test study hypotheses. Results:Childhood abuse predicted higher levels of IL-6, depressive mood symptoms, and metabolic risk scores (p < .05). The relation between childhood abuse and poorer cognitive performance was mediated by IL-6 (p = .046) and depressive mood symptoms (p = .023), but not metabolic risk. IL-6 and depressive mood symptoms significantly mediated the relation between childhood abuse and adult cognitive function. Conclusions:Exposure to early abuse conveys enduring physiological and psychological effects, which may contribute to cognitive deficits that are evident by middle adulthood. Increased vulnerability for cognitive decline among adults with a history of early trauma and the mediating roles of IL-6 and depressive mood symptoms point to the potential value of interventions that address inflammation or depression, singly or together, to prevent cognitive decline in this at-risk population.

ObjectiveLatino immigrants experience acculturative stress and increased depression risk. Mindfulness meditation improves depressive symptoms, yet the vast majority of research has focused on English speaking populations.MethodsIn this randomized clinical trial with 2 parallel treatment groups, adults with moderate levels of perceived stress (n = 76) were recruited from the Los Angeles community from October 2015 to March 2016, stratified into Spanish- (n = 36) and English speaking (n = 40) language groups, and randomized for 6 weeks of treatment with standardized mindful awareness practices (MAPs) or health education (HE). Main outcome measure was depressive symptoms, measured by the Beck Depression Inventory.ResultsUsing an intent-to-treat analysis, the primary outcome, depressive symptoms as indexed by the Beck Depression Inventory, showed greater improvement in MAPs vs. HE, with a between-group post-intervention mean difference of -2.2 (95% CI -4.4 - -0.07) and effect size of 0.28; similar effect sizes were found in the the Spanish- (0.29) and English speaking (0.30) groups. MAPs showed significant improvement relative to HE on secondary outcome of mindfulness with between group difference of 10.7 (95% CI4.5-16.9), but not perceived stress.ConclusionThe comparable efficacy of Spanish and English formats of mindfulness meditation in improving depressive symptoms suggests that this community based intervention may mitigate depression risk in Latino adults who are experiencing social adversity.Trial registrationClinicalTrials.gov NCT03545074.

ObjectivesPersons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. The sleep-inflammation link has been reported to be stronger in women within the general population. This study sought to examine the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical and cognitive variables.DesignCross-sectional case-control study.ParticipantsCommunity-dwelling outpatients with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26-65 years.MeasurementsReported sleep disturbances (sleep quality and duration), and mental and physical health were assessed. Cognitive assessments included executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status - modified.) Inflammatory biomarkers included pro-inflammatory cytokines [high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-α (TNF-α)] and an anti-inflammatory cytokine (IL-10).ResultsThe schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-α compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels.ConclusionsSleep disturbances and increased inflammation, which were common in schizophrenia, were associated in persons with schizophrenia. Moreover, women with schizophrenia had worse sleep quality and inflammation than men. Further examination of the sleep-inflammation links, their contribution to clinical outcomes, and sex-specific factors is warranted.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case-control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A "vascular endothelial index" (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

ObjectiveTo estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants.MethodsWe conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-β pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models.ResultsAmyloid-β positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.