Investigating the impact of hypertension with and without diabetes on Alzheimer's disease risk: A clinico‐pathological study

Neurology

Background and ObjectivesMounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition.MethodsWe used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes …

Bipolar disorders

Background Abnormalities in cerebral blood flow (CBF) are common in bipolar disorder (BD). Despite known differences in CBF between healthy adolescent males and females, sex differences in CBF among adolescents with BD have never been studied. Objective To examine sex differences in CBF among adolescents with BD versus healthy controls (HC). Methods CBF images were acquired using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in 123 adolescents (72 BD: 30M, 42F; 51 HC: 22M, 29F) matched for age (13–20 years). Whole brain voxel‐wise analysis was performed in a general linear model with sex and diagnosis as fixed factors, sex–diagnosis interaction effect, and age as a covariate. We tested for main effects of sex, diagnosis, and their interaction. Results were thresholded at cluster forming p = 0.0125, with posthoc Bonferroni correction (p = 0.05/4 groups …

Journal of Affective Disorders

We examine structural brain characteristics across three diagnostic categories: at risk for serious mental illness; first-presenting episode and recurrent major depressive disorder (MDD). We investigate whether the three diagnostic groups display a stepwise pattern of brain changes in the cortico-limbic regions.Integrated clinical and neuroimaging data from three large Canadian studies were pooled (total n = 622 participants, aged 12-66 years). Four clinical profiles were used in the classification of a clinical staging model: healthy comparison individuals with no history of depression (HC, n = 240), individuals at high risk for serious mental illness due to the presence of subclinical symptoms (SC, n = 80), first-episode depression (FD, n = 82), and participants with recurrent MDD in a current major depressive episode (RD, n = 220). Whole-brain volumetric measurements were extracted with FreeSurfer 7.1 and examined …

Biological Psychiatry

BackgroundCardiovascular disease (CVD) is excessively prevalent and premature in bipolar disorder (BD) and is associated with psychiatric illness severity. CVD is also relevant to brain structure, as demonstrated in a seminal study of> 40,000 participants, that found cardiac MRI metrics were associated with brain structure. We examined heart-brain connections in a sample of youth with bipolar disorder (BD) and healthy controls (HC).MethodsParticipants were 75 youth, ages 13-20 years (n= 35 BD, n= 39 controls). Coronary microvascular reactivity (CMVR) was assessed using oxygen-sensitive cardiac magnetic resonance imaging (MRI) and a validated breath-hold protocol. Cardiac structure and function (eg, ejection fraction) and brain structure (ie, total gray matter [GMV] volume and global fractional anisotropy [FA]) were measured using MRI. A clinical cardiac MRI composite score was calculated using a …

Interventional Neuroradiology

ObjectiveCarotid artery webs are an underappreciated cause of recurrent ischemic stroke, and may represent a significant portion of cryptogenic stroke. Evidence-based guidelines for the management of symptomatic carotid webs do not exist. The goal of this study is to audit our local experience for patients with symptomatic carotid artery webs undergoing carotid stenting as a treatment option, along with describing the hypothesized dynamic physiology of carotid webs.MethodsAll patients undergoing stenting for symptomatic carotid artery web at two comprehensive regional stroke centers with high endovascular thrombectomy volume from January 1, 2012 to March 1, 2021 were included. The modified Rankin Scale (mRS) score was used to define functional outcome at 3 months after stenting.ResultsFourteen consecutive patients with symptomatic carotid artery webs underwent stenting. Twelve patients were …

Focused ultrasound (FUS) is an incisionless surgical procedure that uses nonionizing energy to precisely ablate tissue for disconnecting circuits or to perform neuromodulation in treatment-resistant psychiatric disorders. Preliminary open-label studies in obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) demonstrate favorable efficacy and safety profiles. This chapter provides an overview of the FUS technique and its applications in psychiatric disorders.

Alzheimer's & Dementia

INTRODUCTION Apolipoprotein E E4 allele (APOE E4) and slow gait are independently associated with cognitive impairment and dementia. However, it is unknown whether their coexistence is associated with poorer cognitive performance and its underlying mechanism in neurodegenerative diseases. METHODS Gait speed, APOE E4, cognition, and neuroimaging were assessed in 480 older adults with neurodegeneration. Participants were grouped by APOE E4 presence and slow gait. Mediation analyses were conducted to determine if brain structures could explain the link between these factors and cognitive performance. RESULTS APOE E4 carriers with slow gait had the lowest global cognitive performance and smaller gray matter volumes compared to non‐APOE E4 carriers with normal gait. Coexistence of APOE E4 and slow gait best predicted global and domain‐specific poorer cognitive performances …

Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

INTRODUCTION We examined associations between the Clinical Dementia Rating Scale (CDR) and function (Functional Assessment Scale [FAS]), neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire [NPI‐Q]), and cognitive impairment in Alzheimer's disease (AD). METHODS We used data from the National Alzheimer's Coordinating Center Uniform Data Set and defined cognitively unimpaired and AD stages using CDR‐global. RESULTS Functional and neuropsychiatric symptoms occur as early as the mild cognitive impairment (MCI) phase. The adjusted lest square mean FAS (95% confidence interval [CI]) was lowest in cognitively unimpaired (3.88 [3.66, 4.11] to 5.01 [4.76, 5.26]) and higher with more advanced AD (MCI: 8.17 [6.92, 9.43] to 20.87 [19.53, 22.20]; mild: 18.54 [17.57, 19.50] to 28.13 [27.14, 29.12]; moderate: 26.01 [25.31, 26.70] to 29.42 [28.73, 30.10]). FAS and NPI‐Q scores …

Biological Psychiatry

BackgroundType 2 diabetes (T2D) increases the risk of depression and dementia, and the cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) pathway has been associated with both depression and cognitive decline in the diabetes population. Fatty acids can be metabolized by CYP450 to produce anti-inflammatory epoxides, which are quickly metabolized by sEH into less beneficial diols. This study examines interactions between epoxides and diols (“oxylipins”) and depressive symptoms in predicting cognitive performance in participants with T2D.MethodsT2D participants were assessed for depression severity (Beck Depression Inventory-II [BDI-II]), executive function (Stroop Color-Word Interference Test, FAS-Verbal Fluency Test, Digit Symbol Substitution Test, and Trails Making Test-Part B), and verbal memory (California Verbal Learning Test-II). Fasting serum oxylipins were quantified by ultra-high …

Translational Psychiatry

Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined …

Psychoneuroendocrinology

BackgroundThe study of microglial activation patterns are a key translational area for immunopsychiatry researchMethodsThe presentation will describe data from a transdiagnostic systematic review and meta-analysis of all human CNS TSPO PET case-control studies, a clinical longitudinal study of TSPO PET in patients with psychosis, and a post-mortem study of patients with psychosis.Results156 individual case-control studies were included in the transdiagnostic systematic review (2381 healthy controls and 2626 patients). Across all the illness categories, we observed a significantly higher TSPO PET signal in cortical grey matter in patients with Alzheimer’s disease and other neurodegenerative disorders. Cortico-limbic increases were most prominent for Alzheimer’s dementia, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement was …

Psychoneuroendocrinology

BackgroundThe relationship between insulin-like growth factor-1 (IGF-1) and cognition has been studied in healthy individuals, but not extensively with regards to insulin resistance and type 2 diabetes mellitus (T2DM). In this retrospective observational study, we investigated relationships of IGF-1 with memory and executive function across people with normoglycemia, prediabetes, and T2DM.MethodsData from the Midlife in the United States (MIDUS) study were used. Episodic memory and executive function were assessed using the Brief Test of Adult Cognition by Telephone approximately 21.42 ± 12.10 months prior to measuring IGF-1 levels from a fasting blood sample. Normoglycemia was identified as individuals without a physician diagnosis of diabetes and glycated hemoglobin (HbA1c) ≤5.6%. Prediabetes was identified as those without a physician diagnosis of diabetes and HbA1c between 5.7%−6.4 …

The American Journal of Geriatric Psychiatry

Apathy is found in 24-85% patients with Alzheimer's disease (AD), making it the most common neuropsychiatric symptom (NPS) of AD. Apathy in AD is associated with faster disease progression, greater cognitive decline, increased caregiver distress and decreased quality of life, and hence is an important interventional target with no current approved treatments. The recent Apathy in Dementia Methylphenidate Trial 2 (ADMET 2), the largest randomized, double-blind, placebo-controlled, multi-center, phase III clinical trial that investigated the efficacy of methylphenidate for apathy in patients with mild to moderate AD, found that methylphenidate showed some improvement in apathy. As a dopamine and norepinephrine reuptake inhibitor, methylphenidate increases dopamine and norepinephrine levels, dysfunction of which have been linked to apathy in dementia previously.In this symposium, Dr. Rosenberg will …

Neurology

Background and ObjectivesMounting evidence supports sex differences in Alzheimer disease (AD) risk. Vascular and hormonal factors may together contribute to AD risk in female adults. We investigated whether age at menopause, vascular risk, and history of hormone therapy (HT) containing estrogens together influence cognition over a 3-year follow-up period. We hypothesized that earlier menopause and elevated vascular risk would have a synergistic association with lower cognitive scores at follow-up and that HT containing estrogens would attenuate this synergistic association to preserve cognition.MethodsWe used data from postmenopausal female participants and age-matched male participants in the Canadian Longitudinal Study on Aging. Vascular risk was calculated using a summary score of elevated blood pressure, antihypertensive medications, elevated low-density lipoprotein cholesterol, diabetes …

The Lancet Neurology

BackgroundPick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration.MethodsIn this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically …

Molecular Psychiatry

IntroductionRegional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool.Methods15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association …

Psychological Medicine

BackgroundCardiovascular disease (CVD) is excessively prevalent and premature in bipolar disorder (BD), even after controlling for traditional cardiovascular risk factors. The increased risk of CVD in BD may be subserved by microvascular dysfunction. We examined coronary microvascular function in relation to youth BD.MethodsParticipants were 86 youth, ages 13–20 years (n = 39 BD, n = 47 controls). Coronary microvascular reactivity (CMVR) was assessed using quantitative T2 magnetic resonance imaging during a validated breathing-paradigm. Quantitative T2 maps were acquired at baseline, following 60-s of hyperventilation, and every 10-s thereafter during a 40-s breath-hold. Left ventricular structure and function were evaluated based on 12–15 short- and long-axis cardiac-gated cine images. A linear mixed-effects model that controlled for age, sex, and body mass index assessed for between-group …

Biological Psychiatry

BackgroundLipid peroxidation, a potential biomarker of bipolar disorder (BD) neuropathology, has been associated with neuroimaging phenotypes in adults. We sought to extend research on this topic to include youth.MethodsParticipants included 94 youth (BD= 49; healthy controls [HC]= 45), ages 13-20 years. Blood levels of lipid hydroperoxidase (LPH) and 8-isoprostane (8-ISO) were assayed. Cortical thickness, surface area, and volume were measured via 3T MRI. Region of interest (ROI; prefrontal cortex, hippocampus and anterior cingulate cortex [ACC]) and vertex-wise analysis were performed within BD and HC groups, followed by formal tests of interaction.ResultsIn ROI analyses, greater LPH concentration was associated with greater ACC thickness in BD (B= 0.43; p= 0.01) but not in HC (B= 0.15; p= 0.44). Vertex-wise analysis revealed greater LPH concentrations were associated with greater regional …

Alzheimer's & Dementia

INTRODUCTION Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non‐carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus …

Alzheimer's & Dementia

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public‐health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public‐domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating …

Alzheimer's & Dementia

INTRODUCTION Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin‐1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre‐/postcodon 200) influences these pathologic features and dementia at different stages. METHODS Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross‐sectionally evaluated regional Pittsburgh compound B‐positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging‐based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. RESULTS Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® …

Alzheimer's & Dementia

INTRODUCTION Trialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials. METHODS We used data from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants’ responses on the Impact of Event Scale (IES) 24 to 72 hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups. We considered potential effect modification by amyloid status. RESULTS Reactions to disclosure did not significantly differ among participant groups based on self‐reported race and ethnicity. Although the results were not significant when stratified by amyloid status, all racial and ethnic groups except for participants self‐reporting Hispanic/Latino ethnicity were …

Alzheimer's & Dementia

INTRODUCTION Here we set out to create a symptom‐led staging system for the canonical semantic and non‐fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias. METHODS An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed‐methods sequential explanatory design. RESULTS Both PPA syndromes were characterized by initial communication dysfunction and non‐verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages. Milestone symptoms were distilled to create a prototypical progression and severity scale of functional impairment: the PPA Progression Planning Aid (“PPA …

Alzheimer's & Dementia

INTRODUCTION We assessed whether macro‐ and/or micro‐structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid‐β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS Higher global efficiency of the limbic network, as well as free‐water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both …

Alzheimer's & Dementia

INTRODUCTION The U.S. study to protect brain health through lifestyle intervention to reduce risk (U.S. POINTER) is conducted to confirm and expand the results of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) in Americans. METHODS U.S. POINTER was planned as a 2‐year randomized controlled trial of two lifestyle interventions in 2000 older adults at risk for dementia due to well‐established factors. The primary outcome is a global cognition composite that permits harmonization with FINGER. RESULTS U.S. POINTER is centrally coordinated and conducted at five clinical sites (ClinicalTrials.gov: NCT03688126). Outcomes assessments are completed at baseline and every 6 months. Both interventions focus on exercise, diet, cognitive/social stimulation, and cardiovascular health, but differ in intensity and accountability. The study partners with a worldwide …

Alzheimer's & Dementia

INTRODUCTION Apolipoprotein E4 (APOE4) carriers’ tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood‐brain barrier. METHODS Relationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment. RESULTS Levels of 24(S)‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), and 24‐OHC/27‐OHC ratio did not differ by APOE status (p’s > 0.05). Higher 24‐OHC and 27‐OHC were associated with higher total, low density lipoprotein (LDL), non‐high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p’s < 0.05). Higher 24‐OHC/27‐OHC was associated …

Alzheimer's & Dementia

INTRODUCTION The course of depressive symptoms and dementia risk is unclear, as are potential structural neuropathological common causes. METHODS Utilizing joint latent class mixture models, we identified longitudinal trajectories of annually assessed depressive symptoms and dementia risk over 21 years in 957 older women (baseline age 72.7 years old) from the Women's Health Initiative Memory Study. In a subsample of 569 women who underwent structural magnetic resonance imaging, we examined whether estimates of cerebrovascular disease and Alzheimer's disease (AD)‐related neurodegeneration were associated with identified trajectories. RESULTS Five trajectories of depressive symptoms and dementia risk were identified. Compared to women with minimal symptoms, women who reported mild and stable and emerging depressive symptoms were at the highest risk of developing dementia …

Alzheimer's & Dementia

INTRODUCTION This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS AD polygenic risk scores (PRS) were tested for association with DS‐related traits. RESULTS The AD risk PRS was associated with disease status in several cohorts of sporadic late‐ and early‐onset and familial late‐onset AD, but not in familial early‐onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE, p = 2.84 × 10−4; PRS excluding APOE, PRSnonAPOE, p = 1.60 × 10−2). PRSAPOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION These data indicate that the AD genetic architecture …

Alzheimer's & Dementia

INTRODUCTION We assessed whether macro‐ and/or micro‐structural white matter properties are associated with cognitive resilience to Alzheimer's disease pathology years prior to clinical onset. METHODS We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid‐β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties. RESULTS Higher global efficiency of the limbic network, as well as free‐water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both …

Alzheimer's & Dementia

INTRODUCTION Depressive symptoms are among early behavioral changes in Alzheimer's disease (AD); however, the relationship between neurodegeneration and depressive symptoms remains inconclusive. To better understand this relationship in preclinical AD, we examined hippocampal volume and depressive symptoms in cognitively unimpaired carriers of the presenilin‐1 (PSEN1) E280A mutation for autosomal dominant AD. METHODS A total of 27 PSEN1 mutation carriers and 26 non‐carrier family members were included. Linear regression was used to test the relationship between hippocampal volume and 15‐item Geriatric Depression Scale. RESULTS Carriers and non‐carriers did not differ in depressive symptoms or hippocampal volume. Within carriers, lower hippocampal volume was associated with greater depressive symptoms, which remained significant after adjusting for age and cognition …

Alzheimer's & Dementia

INTRODUCTION Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS Using an α‐synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α‐synuclein seeding activity in CSF in vivo. DISCUSSION Results suggest that in …

Alzheimer's & Dementia

INTRODUCTION Trials of effectiveness of treatment options for depression in dementia are an important priority. METHODS Randomized controlled trial to assess adapted Problem Adaptation Therapy (PATH) for depression in mild/moderate dementia caused by Alzheimer's disease. RESULTS Three hundred thirty‐six participants with mild or moderate dementia, >7 on Cornell Scale for Depression in Dementia (CSDD), randomized to adapted PATH or treatment as usual. Mean age 77.0 years, 39.0% males, mean Mini‐Mental State Examination 21.6, mean CSDD 12.9. For primary outcome (CSDD at 6 months), no statistically significant benefit with adapted PATH on the CSDD (6 months: −0.58; 95% CI −1.71 to 0.54). The CSDD at 3 months showed a small benefit with adapted PATH (−1.38; 95% CI −2.54 to −0.21) as did the EQ‐5D (−4.97; 95% CI −9.46 to −0.48). DISCUSSION An eight‐session course of …

Alzheimer's & dementia

INTRODUCTION Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer's disease (AD) risk by independent lines of evidence. We explored this association by comparing the frequencies of viral species identified in a large sample of AD cases and controls. METHODS DNA sequence reads that did not align to the human genome in sequences were mapped to viral reference sequences, quantified, and then were tested for association with AD in whole exome sequences (WES) and whole genome sequences (WGS) datasets. RESULTS Several viruses were significant predictors of AD according to the machine learning classifiers. Subsequent regression analyses showed that herpes simplex type 1 (HSV‐1) (odds ratio [OR] = 3.71, p = 8.03 × 10−4) and human papillomavirus 71 (HPV‐71; OR = 3.56, p = 0.02), were significantly associated with AD after Bonferroni …

Alzheimer's & Dementia

INTRODUCTION Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in …

Alzheimer's & Dementia

INTRODUCTION Alzheimer's disease (AD) and primary age‐related tauopathy (PART) both harbor 3R/4R hyperphosphorylated‐tau (p‐tau)‐positive neurofibrillary tangles (NFTs) but differ in the spatial p‐tau development in the hippocampus. METHODS Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT‐bearing and non‐NFT‐bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS Proteomic measures of synaptic health were inversely correlated with the subregional p‐tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aβ) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION These results suggest subfield‐specific proteome differences that …

Alzheimer's & Dementia

INTRODUCTION Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock‐in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan. METHODS CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non‐invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures. RESULTS Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non‐carriers. Analysis of brain revealed alterations in several enzyme–substrate interactions within the gamma secretase complex prior …

Alzheimer's & Dementia

INTRODUCTION Existing advance care planning (ACP) definitional frameworks apply to individuals with decision‐making capacity. We aimed to conceptualize ACP for dementia in terms of its definition and issues that deserve particular attention. METHODS Delphi study with phases: (A) adaptation of a generic ACP framework by a task force of the European Association for Palliative Care (EAPC); (B) four online surveys by 107 experts from 33 countries, September 2021 to June 2022; (C) approval by the EAPC board. RESULTS ACP in dementia was defined as a communication process adapted to the person's capacity, which includes, and is continued with, family if available. We identified pragmatic boundaries regarding participation and time (i.e., current or end‐of‐life care). Three interrelated issues that deserve particular attention were capacity, family, and engagement and communication. DISCUSSION A …

Alzheimer's & Dementia

INTRODUCTION Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease‐specific semantic memory patterns. Here, we leveraged automated word‐property analysis to capture neurocognitive markers of AD vis‐à‐vis behavioral variant frontotemporal dementia (bvFTD). METHODS Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group‐level discrimination, patient‐level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns. RESULTS Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group …