Accrual of Alzheimer's disease pathology as a function of proximity to parental dementia onset.

Introduction: Whether temporal proximity to parental onset of dementia (PPO) can be used to estimate timing of the preclinical stage of sporadic Alzheimer's disease (AD) remains uncertain.

Methods: We investigated cross-sectionally adults aged > 50 without dementia included in the European Prevention of Alzheimer's Dementia (EPAD) study. PPO was tested as a predictor of quantitative levels of cerebrospinal fluid (CSF) β-amyloid (1-42) (Aβ1-42) in those with a parental history of dementia ( = 688) and of phosphorylated tau (p-tau) and EPAD neuropsychological examination (ENE) subscores in an amyloid positive subgroup ( = 226).

Influence of alpha-synuclein on glucose metabolism in Alzheimer's disease continuum: Analyses of α-synuclein seed amplification assay and FDG-PET.

Introduction: We investigated the association between alpha-synuclein (α-syn) pathology and brain glucose metabolism across the cognitive spectrum of Alzheimer's disease (AD) co-pathologies.

Methods: Fluorodeoxyglucose positron emission tomography (FDG-PET) data from 829 Alzheimer's Disease Neuroimaging Initiative participants (648 cognitively impaired [CI], 181 unimpaired [CU]) were compared between α-syn seed amplification assay (SAA) positive and negative groups. Interactions with cerebrospinal fluid (CSF) AD biomarkers were examined.

Polygenic risk discriminates Lewy body dementia from Alzheimer's disease.

Introduction: Lewy body dementia (LBD) shares genetic risk factors with Alzheimer's disease (AD), including apolipoprotein E (APOE), but is distinguishable at the genome-wide level. Polygenic risk scores (PRS) may therefore improve diagnostic classification.

Methods: We assessed diagnostic classification using AD-PRS excluding APOE (AD-PRS ), APOE risk score (APOE-RS), and plasma phosphorylated tau 181 (p-tau181), in 83 participants with LBD, 27 with positron emission tomography amyloid beta (Aβ)positive mild cognitive impairment or AD (MCI+/AD), and 57 controls.

A systematic review of diffusion tensor imaging and tractography in dementia with Lewy bodies and Parkinson's disease dementia.

We reviewed studies using diffusion tensor imaging (DTI) and tractography to characterise white matter changes in Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD). The search included MEDLINE and EMBASE, and we used a narrative strategy to synthesise the evidence. Data was extracted from 57 studies, of which the majority were considered 'good quality'.

Deconstructing Delay Discounting in Human Cocaine Addiction Using Computational Modeling and Neuroimaging.

Background: A preference for sooner-smaller over later-larger rewards, known as delay discounting, is a candidate transdiagnostic marker of waiting impulsivity and a research domain criterion. While abnormal discounting rates have been associated with many psychiatric diagnoses and abnormal brain structure, the underlying neuropsychological processes remain largely unknown. Here, we deconstruct delay discounting into choice and rate processes by testing different computational models and investigate their associations with white matter tracts.

Texture-based morphometry in relation to apolipoprotein ε4 genotype, ageing and sex in a midlife population.

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification.

The PREVENT dementia programme: baseline demographic, lifestyle, imaging and cognitive data from a midlife cohort study investigating risk factors for dementia.

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort.

Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models.

ɛ4 exacerbates age-dependent deficits in cortical microstructure.

The apolipoprotein E ɛ4 allele is the primary genetic risk factor for the sporadic type of Alzheimer's disease. However, the mechanisms by which apolipoprotein E ɛ4 are associated with neurodegeneration are still poorly understood. We applied the Neurite Orientation Dispersion Model to characterize the effects of apolipoprotein ɛ4 and its interactions with age and education on cortical microstructure in cognitively normal individuals.

In vivo imaging of synaptic density in neurodegenerative disorders with positron emission tomography: A systematic review.

Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2 A (SV2A) enables quantification of synaptic density in the living human brain. Assessing the regional distribution and severity of synaptic density loss will contribute to our understanding of the pathological processes that precede atrophy in neurodegeneration. In this systematic review, we provide a discussion of in vivo SV2A PET imaging research for quantitative assessment of synaptic density in various dementia conditions: amnestic Mild Cognitive Impairment and Alzheimer's disease, Frontotemporal dementia, Progressive supranuclear palsy and Corticobasal degeneration, Parkinson's disease and Dementia with Lewy bodies, Huntington's disease, and Spinocerebellar Ataxia.

Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration.

There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls.

Longitudinal associations between β-amyloid and cortical thickness in mild cognitive impairment.

How beta-amyloid accumulation influences brain atrophy in Alzheimer's disease remains contentious with conflicting findings. We aimed to elucidate the correlations of regional longitudinal atrophy with cross-sectional regional and global amyloid in individuals with mild cognitive impairment and no cognitive impairment. We hypothesized that greater cortical thinning over time correlated with greater amyloid deposition, particularly within Alzheimer's disease characteristic regions in mild cognitive impairment, and weaker or no correlations in those with no cognitive impairment.

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife.

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width - RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed.

Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy.

Amyloid- β and tau deposition influences cognitive and functional decline in Down syndrome.

This study investigates whether tau has (i) an independent effect from amyloid-β on changes in cognitive and functional performance and (ii) a synergistic relationship with amyloid-β in the exacerbation of decline in aging Down syndrome (DS). 105 participants with DS underwent baseline PET [F]-AV1451 and PET [C]PiB scans to quantify tau deposition in Braak regions II-VI and the Striatum and amyloid-β status respectively. Linear Mixed Effects models were implemented to assess how tau and amyloid-β deposition are related to change over three time points.

Fractal dimension of the brain in neurodegenerative disease and dementia: A systematic review.

Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset.

Support vector machine learning and diffusion-derived structural networks predict amyloid quantity and cognition in adults with Down's syndrome.

Down's syndrome results from trisomy of chromosome 21, a genetic change which also confers a probable 100% risk for the development of Alzheimer's disease neuropathology (amyloid plaque and neurofibrillary tangle formation) in later life. We aimed to assess the effectiveness of diffusion-weighted imaging and connectomic modelling for predicting brain amyloid plaque burden, baseline cognition and longitudinal cognitive change using support vector regression. Ninety-five participants with Down's syndrome successfully completed a full Pittsburgh Compound B (PiB) PET-MR protocol and memory assessment at two timepoints.

Macrostructural brain alterations at midlife are connected to cardiovascular and not inherited risk of future dementia: the PREVENT-Dementia study.

Background: Macrostructural brain alterations in the form of brain atrophy or cortical thinning typically occur during the prodromal Alzheimer's disease stage. Mixed findings largely dependent on the age of the examined cohorts have been reported during the preclinical, asymptomatic disease stage. In the present study, our aim was to examine the association of midlife dementia risk with brain macrostructural alterations.

Detecting Small Vessel Pathology in Cocaine Use Disorder.

Background: Cocaine use is associated with an increased risk of cerebrovascular accidents. Small vessel pathology has been linked to the risk of stroke in cocaine users, but can be challenging to detect on conventional magnetic resonance (MR) scans. Fluid-attenuated inversion recovery (FLAIR) scans permit better resolution of small vessel lesions.

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study.

Background: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD.

Differential levels of plasma biomarkers of neurodegeneration in Lewy body dementia, Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy.

Objectives: This longitudinal study compared emerging plasma biomarkers for neurodegenerative disease between controls, patients with Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP).

Methods: Plasma phosphorylated tau at threonine-181 (p-tau181), amyloid beta (Αβ)42, Aβ40, neurofilament light (NfL) and glial fibrillar acidic protein (GFAP) were measured using highly sensitive single molecule immunoassays (Simoa) in a multicentre cohort of 300 participants (controls=73, amyloid positive mild cognitive impairment (MCI+) and AD dementia=63, LBD=117, FTD=28, PSP=19). LBD participants had known positron emission tomography (PET)-Aβ status.

In Vivo F-Flortaucipir PET Does Not Accurately Support the Staging of Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuroglial tau pathology. A new staging system for PSP pathology postmortem has been described and validated. We used a data-driven approach to test whether postmortem pathologic staging in PSP can be reproduced in vivo with F-flortaucipir PET.

[F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

While [F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of 'off-target' [F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson's disease ( = 35), dementia with Lewy bodies ( = 10) and separate control groups ( = 37; = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models.