Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, is viewed as a ...relatively pure form of AD with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses in a consecutive autopsy series of 96 patients with EOAD (median age of onset = 55 years, 44 females) and 48 with late-onset AD (LOAD) (median age of onset = 73 years, 14 females). The UCSF Neurodegenerative Disease Brain Bank database was reviewed to identify patients with a primary pathological diagnosis of AD. Prevalence and stage of Lewy body disease (LBD), limbic age-related TDP-43 encephalopathy (LATE), argyrophilic grain disease (AGD), hippocampal sclerosis (HS), cerebral amyloid angiopathy (CAA), and vascular brain injury (VBI) were compared between the two cohorts. We found at least one non-AD pathological diagnosis in 98% of patients with EOAD (versus 100% of LOAD), and the number of comorbid diagnoses per patient was lower in EOAD than in LOAD (median=2 versus 3, Mann-Whitney Z = 3.00, p = 0.002). LBD and CAA were common in both EOAD and LOAD (CAA: 86% versus 79%, Fisher exact p = 0.33; LBD: 49% versus 42%, p = 0.48, respectively), although amygdala-predominant LBD was more commonly found in EOAD than LOAD (22% versus 6%, p = 0.02). In contrast, LATE (35% versus 8%, p < 0.001), HS (15% versus 3%, p = 0.02), AGD (58% versus 41%, p = 0.052), and VBI (65% versus 39%, p = 0.004) were more common in LOAD than EOAD, respectively. The number of copathologies predicted worse cognitive performance at the time of death on MMSE (1.4 points/pathology (95%CI -2.5, -0.2) and Clinical Dementia Rating - Sum of Boxes (1.15 point/pathology, 95%CI 0.45, 1.84), across the EOAD and the LOAD cohorts. The effect of sex on the number of copathologies was not significant (p = 0.17). Prevalence of at least one APOE ε4 allele was similar across the two cohorts (52% and 54%) and was associated with a greater number of copathologies (+0.40, 95%CI 0.01, 0.79, p = 0.047), independent of age of symptom onset, sex, and disease duration. Females showed higher density of neurofibrillary tangles compared to men, controlling for age of onset, APOE ε4, and disease duration. Our findings suggest that non-AD pathological diagnoses play an important role in the clinical phenotype of EOAD with potentially significant implications for clinical practice and clinical trials design.
Whereas clinical experience in dementia indicates high risk for financial mismanagement, there has been little formal study of real world financial errors in dementia.
We aimed to compare ...caregiver-reported financial mistakes among people with Alzheimer's disease, behavioral variant frontotemporal dementia (bvFTD), and primary progressive aphasia (PPA).
Caregivers reported whether participants with dementia had made financial mistakes within the last year; and if so, categorized these as resulting from: (a) being too trusting or gullible, (b) being wasteful or careless with money, or (c) trouble with memory. In a pre-registered analysis https://archive.org/details/osf-registrations-vupj7-v1), we examined the hypotheses that (1) financial mistakes due to impaired socioemotional function and diminished sensitivity to negative outcomes are more prevalent in bvFTD than in Alzheimer's disease, and (2) financial mistakes due to memory are more prevalent in Alzheimer's disease than in bvFTD. Exploratory analyses addressed vulnerability in PPA and brain-behavior relationships using voxel-based morphometry.
Concordant with our first hypothesis, bvFTD was more strongly associated than Alzheimer's disease with mistakes due to being too trusting/gullible or wasteful/careless; contrary to our second hypothesis, both groups were similarly likely to make mistakes due to memory. No differences were found between Alzheimer's disease and PPA. Exploratory analyses indicated associations between financial errors and atrophy in right prefrontal and insular cortex.
Our findings cohere with documented socioemotional and valuation impairments in bvFTD, and with research indicating comparable memory impairment between bvFTD and Alzheimer's disease.
We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. Our study included 134 clinically normal older ...adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and
APOE
status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p = .94, η
2
< 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aβ accumulation (B = 0.01, p = .08) than those without (N = 19). There was no significant interaction between remote mTBI and Aβ burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aβ burden and does not interact with Aβ burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aβ accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.
Animals have many ways of protecting themselves against stress; for example, they can induce animal-wide, stress-protective pathways and they can kill damaged cells via apoptosis. We have discovered ...an unexpected regulatory relationship between these two types of stress responses. We find that C. elegans mutations blocking the normal course of programmed cell death and clearance confer animal-wide resistance to a specific set of environmental stressors; namely, ER, heat and osmotic stress. Remarkably, this pattern of stress resistance is induced by mutations that affect cell death in different ways, including ced-3 (cell death defective) mutations, which block programmed cell death, ced-1 and ced-2 mutations, which prevent the engulfment of dying cells, and progranulin (pgrn-1) mutations, which accelerate the clearance of apoptotic cells. Stress resistance conferred by ced and pgrn-1 mutations is not additive and these mutants share altered patterns of gene expression, suggesting that they may act within the same pathway to achieve stress resistance. Together, our findings demonstrate that programmed cell death effectors influence the degree to which C. elegans tolerates environmental stress. While the mechanism is not entirely clear, it is intriguing that animals lacking the ability to efficiently and correctly remove dying cells should switch to a more global animal-wide system of stress resistance.
Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES ...overlap with Alzheimer's disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer's neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls.
We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ +), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ +), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ +). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ + or Aβ - and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen's d > 0.50) were interpreted as potentially meaningful.
Cognitively, within the TES group, Aβ + RHI/TES performed worse than Aβ- RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing voxel-wise brain volume, both Aβ + and Aβ - RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ + RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and did not significantly differ from AD. Conversely, Aβ - RHI/TES had higher NfL than HC (p = .004, d = 0.93) and higher IL-6 than all other groups (p's ≤ .004, d's > 1.0).
Presence of Alzheimer's pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ - RHI/TES. Measuring well-validated Alzheimer's biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.
Early‐onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early‐onset AD patients without an identified autosomal dominant ...cause, we hypothesized that their early‐onset disease reflects further enrichment of the common risk‐conferring single nucleotide polymorphisms associated with late‐onset AD.
We applied a previously validated polygenic hazard score for late‐onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early‐onset AD. For comparison, we included 179 participants with late‐onset AD and 70 healthy controls. Polygenic hazard scores were similar in early‐ versus late‐onset AD. The polygenic hazard score was not associated with age‐of‐onset or disease biomarkers within early‐onset AD. Early‐onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late‐onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.
Highlights
There is a unique genetic architecture of early‐ versus late‐onset Alzheimer's disease (AD).
Late‐onset AD polygenic risk is not an explanation for early‐onset AD.
Polygenic risk of late‐onset AD does not predict early‐onset AD biology.
Unique genetic architecture of early‐ versus late‐onset AD parallels AD heterogeneity.
Biomarkers for chronic traumatic encephalopathy (CTE) are currently lacking. The radiotracer fluorine F 18-labeled (18F)-flortaucipir (FTP) detects tau pathology in Alzheimer disease, and positron ...emission tomography (PET) with FTP shows elevated binding in individuals at risk for CTE. No study, however, has assessed the correlation between in vivo FTP PET and postmortem tau in CTE.
To assess the regional association between in vivo FTP binding and postmortem tau pathology in a patient with pathologically confirmed CTE.
A white male former National Football League player with 17 years of US football exposure was clinically diagnosed with traumatic encephalopathy syndrome at a neurology tertiary referral center. 18F-Fludeoxyglucose, carbon 11-labeled Pittsburgh compound B, and FTP PET were performed 52 months prior to death, and magnetic resonance imaging, 50 months prior to death. Brain images were assessed qualitatively for abnormalities blinded to autopsy data. Autopsy was performed using a neurodegenerative research protocol. The FTP standardized uptake value ratios (inferior cerebellar gray reference region) and W-score (age-adjusted z-score) maps were compared with phosphorylated tau immunohistochemical analysis with monoclonal antibody CP13.
Qualitative and quantitative comparisons between antemortem FTP PET and tau pathology at autopsy.
Flortaucipir uptake was distributed in a patchy, frontotemporal-predominant pattern that overlapped with regions showing neurodegeneration on magnetic resonance imaging and hypometabolism on 18F-fludeoxyglucose PET. Pathological assessment revealed stage 4 CTE; limbic argyrophilic grain disease; stage 2 limbic-predominant, age-related transactive response DNA-binding protein 43 encephalopathy; and Braak neurofibrillary tangle stage 3. 18F-Flortaucipir W-maps matched areas of high postmortem tau burden in left fusiform and inferior temporal gyri and juxtacortical frontal white matter. High FTP W-scores with low tau burden were found in the basal ganglia, thalamus, motor cortex, and calcarine cortex. No regions with low FTP W-scores corresponded to areas with high pathological tau burden. A modest correlation, which did not reach statistical significance (ρ = 0.35, P = .17), was found between FTP standardized uptake value ratio and tau area fraction at the regional level.
In this patient, FTP PET findings during life showed a modest correspondence with postmortem pathology in CTE. These findings suggest that FTP may have limited utility as a tau biomarker in CTE.
INTRODUCTION
Older military veterans often present with unique and complex risk factors for Alzheimer's disease (AD) and related dementias. Increasing veteran participation in research studies offers ...one avenue to advance the field and improve health outcomes.
METHODS
To this end, the National Institute on Aging (NIA) and Department of Veterans Affairs (VA) partnered to build infrastructure, improve collaboration, and intensify targeted recruitment of veterans. This initiative, INviting Veterans InTo Enrollment in Alzheimer's Disease Research Centers (INVITE‐ADRC), provided funding for five sites and cross‐site organizing structure. Diverse and innovative recruitment strategies were used.
RESULTS
Across five sites, 172 veterans entered registries, and 99 were enrolled into ADRC studies. Of the enrolled, 39 were veterans from historically underrepresented racial and ethnic groups.
CONCLUSIONS
This initiative laid the groundwork to establish sustainable relationships between the VA and ADRCs. The partnership between both federal agencies demonstrates how mutual interests can accelerate progress. In turn, efforts can help our aging veterans.
•In the clinical stages of AD, females had greater tau- and amyloid-PET than males•Greater cortical tau-PET binding in females was observed in temporoparietal regions•Tau-PET sex differences were ...present when controlling for amyloid-PET, age, and CDR•Tau-PET sex differences were not present in subcortical areas of off-target binding
We assessed sex differences in amyloid- and tau-PET retention in 119 amyloid positive patients with mild cognitive impairment or Alzheimer's disease (AD) dementia. Patients underwent 3T-MRI, 11C-PIB amyloid-PET and 18F-Flortaucipir tau-PET. Linear ordinary least squares regression models tested sex differences in Flortaucipir-PET SUVR in a summary temporal region of interest as well as global PIB-PET. No sex differences were observed in demographics, Clinical Dementia Rating Sum of Boxes (CDR-SoB), Mini-Mental State Exam (MMSE), raw episodic memory scores, or cortical thickness. Females had higher global PIB SUVR (ηp²=.043, p=.025) and temporal Flortaucipir SUVR (ηp²=.070, p=.004), adjusting for age and CDR-SoB. Sex differences in temporal Flortaucipir-PET remained significant when controlling additionally for PIB SUVR and APOE4 status (ηp²=.055, p=.013), or when using partial volume-corrected data. No sex differences were present in areas of known Flortaucipir off-target binding. Overall, females demonstrated greater AD regional tau-PET burden than males despite clinical comparability. Further characterization of sex differences will provide insight into AD pathogenesis and support development of personalized therapeutic strategies.
Introduction
Immune dysfunction is important in aging and neurodegeneration; lacking clinically available tools limits research translation. We tested associations of cerebral spinal fluid (CSF) ...monocyte‐to‐lymphocyte ratio (MLR)—innate immune activation surrogate—with cognition in an aging and dementia cohort, hypothesizing that elevated MLR is associated with poorer executive functioning.
Methods
CSF MLR was calculated in well‐characterized, genotyped participants enrolled in studies of aging and dementia at University of California, San Francisco Memory and Aging Center (n = 199, mean age 57.5 years, SD 11.9). Linear models tested associations with episodic memory and executive function (verbal fluency, speeded set‐shifting).
Results
Aging was associated with higher CSF monocyte, lower lymphocyte counts, and higher MLRs (p < 0.001). MLR was associated with verbal fluency (p < 0.05) only.
Discussion
Using clinical labs, we show an inverse association between CSF MLR and executive function in aging and dementia, supporting the utility of clinical labs in capturing associations between innate immune dysfunction and neurodegeneration.
PDF
