Biology subjects

Breitner, J.

Publications and source records attributed to Breitner, J..

4 recordsLinked to original sources

bioRxiv2025

Locus coeruleus degeneration is associated with cortical tau deposition and cognitive decline in older adults at familial risk of Alzheimer's disease

INTRODUCTIONThe locus coeruleus (LC) is among the first sites of tau pathology in Alzheimers disease (AD) and may seed neocortical tau. METHODSWe used longitudinal neuromelanin-sensitive MRI to assess LC integrity in vivo in a cohort of cognitively unimpaired older adults with familial risk of AD in relation to tau and amyloid PET and long-term cognitive trajectories. RESULTSWe showed that both LC integrity at baseline and its rate of degeneration over time independently predicted a neocortical pattern of tau deposition. In keeping with the known function of the LC, neuropsychological tests showed that LC integrity at baseline predicted changes in attention. Finally, we found that longitudinal LC degeneration correlated with memory decline in people with elevated neocortical amyloid burden. DISCUSSIONOur findings underscore the importance of LC in AD pathogenesis. Longitudinal measurement of LC degeneration may help distinguish trajectories of age-related cognitive decline and early AD.

neuroscience↗

bioRxiv2019

APOE4 status is related to differences in memory-related brain function in asymptomatic older adults: Baseline analysis of the PREVENT-AD task fMRI dataset

Episodic memory decline is one of the earliest symptoms of late-onset Alzheimers Disease (AD) and older adults with the apolipoprotein E e4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. In the current study we report the baseline episodic memory task fMRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimers Disease (PREVENT-AD) study in Montreal, Canada, in which 327 healthy older adults, within 15 years of the parents conversion to AD, were scanned. During the task fMRI protocol volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to successful spatial source recollection and failures in spatial source recollection, with memory for only item (object) memory. Multivariate task-related partial least squares (task PLS) was used to test the hypothesis that +APOE4 adults with a family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also tested for group differences in the correlation between event-related brain activity and memory performance in +APOE4 compared to -APOE4 adults using behavioral-PLS (B-PLS). We found group similarities in memory performance and in task-related brain activity in the recollection network. However, the B-PLS results indicated there were group differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with parental history of AD. Future research should further investigate the potential to distinguish risk of AD development based on memory performance and associated patterns of brain activity.

neuroscience↗

bioRxiv2018

A signature of cognitive deficits and brain atrophy that is highly predictive of progression to Alzheimer’s dementia

Patients with mild cognitive impairment (MCI) are at risk of progressing to Alzheimers dementia, yet only a fraction of them do. We explore here whether a very high-risk MCI subgroup can be identified using cognitive assessments and structural neuroimaging. A multimodal signature of Alzheimers dementia was first extracted using machine learning tools in the ADNI1 sample, and was comprised of cognitive deficits across multiple domains as well as atrophy in temporal, parietal and occipital regions. We then validated the predictive value of this signature on two MCI cohorts. In ADNI1 (N=235), the presence of the signature predicted progression to dementia over three years with 80.4% positive predictive value, adjusted for a \"typical\" MCI baseline rate of 33% (95.6% specificity, 55.1% sensitivity). These results were replicated in ADNI2 (N=235), with 87.8% adjusted positive predictive value (96.7% specificity, 47.3% sensitivity). Our results demonstrate that, even for widely used markers, marked improvement in positive predictive value over the literature can be achieved by focusing on a subgroup of individuals with similar brain characteristics. The signature can be readily applied for the enrichment of clinical trials.

neuroscience↗

bioRxiv2017

Subtypes of functional brain connectivity as early markers of neurodegeneration in Alzheimer’s disease

HighlightsO_LIReliable functional brain network subtypes accompany cognitive impairment in AD\nC_LIO_LISymptom-related subtypes exist in the default-mode, limbic and salience networks\nC_LIO_LIA limbic subtype is associated with a familial risk of AD in healthy older adults\nC_LIO_LILimbic subtypes also associate with beta amyloid deposition and ApoE4\nC_LI\n\nIn BriefWe found reliable subtypes of functional brain connectivity networks in older adults, associated with AD-related clinical symptoms in patients as well as several AD risk factors/biomarkers in asymptomatic individuals.\n\nSummaryThe heterogeneity of brain degeneration has not been investigated yet for functional brain network connectivity, a promising biomarker of Alzheimers disease. We coupled cluster analysis with resting-state functional magnetic resonance imaging to discover connectivity subtypes in healthy older adults and patients with cognitive disorders related to Alzheimers disease, noting associations between subtypes and cognitive symptoms in the default-mode, limbic and salience networks. In an independent asymptomatic cohort with a family history of Alzheimers dementia, the connectivity subtypes had good test-retest reliability across all tested networks. We found that a limbic subtype was overrepresented in these individuals, which was previously associated with symptoms. Other limbic subtypes showed associations with cerebrospinal fluid A{beta}1-42 levels and ApoE4 genotype. Our results demonstrate the existence of reliable subtypes of functional brain networks in older adults and support future investigations in limbic connectivity subtypes as early biomarkers of Alzheimers degeneration.

neuroscience↗