Neurobiology of Aging

Cerebral microbleeds (CMB) are often associated with vascular risk factors and/or cerebral amyloid angiopathy and are frequently identified in people with dementia. The present study therefore aimed to estimate the pooled prevalence and associations of CMB in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), using meta-analytic methods. Sixty-five MRI studies were included after a systematic search on major electronic databases. We found that the prevalence of CMB was comparable across the three dementia subtypes (31-36%) and was highly influenced by the MRI techniques used...

We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins...

Parkinson's disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson's Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative...

At autopsy, African American decedents often have mixed Alzheimer's and cerebrovascular brain pathologies including arteriolosclerosis. We applied a novel in-vivo classifier of ARTerioloSclerosis (ARTS) in 167 older African Americans (∼75y of age) with > 2 biennial 3 T MRI scans and > 3 years of associated cognitive follow-up to determine if ARTS scores (higher score=higher likelihood of arteriolosclerosis) changed over time and if this change associated with changes in cognition in the same individuals...

There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0...

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal β-amyloid (Aβ) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition...

In 36 normal controls (NC), 37 patients with Alzheimer's disease (AD) without parkinsonism (ADP- ), 31 AD with parkinsonism (ADP+ ), and 40 AD with dementia with Lewy bodies (ADDLB ), dual-phase dopamine transporter (DAT) positron emission tomography (PET) were performed to evaluate the diagnostic performance of DAT and early-to-delayed uptake ratios (E/Ds) in the anterior caudate (AC), posterior caudate (PC), anterior putamen (AP), posterior putamen (PP), and substantia nigra (SN) to differentiate ADP+ /ADDLB from NC, and their effects on parkinsonism and cognition...

While capacity for motor skill acquisition changes with healthy aging, there has been little consideration of how age-related changes in brain function or baseline brain structure support motor skill acquisition. We examined: (1) age-dependent changes in functional reorganization related to frontoparietal regions during motor skill acquisition, and (2) whether capacity for motor skill acquisition relates to baseline white matter microstructure in frontoparietal tracts. Healthy older and younger adults engaged in 4 weeks of skilled motor practice...

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory and functional impairments. Two of 3 patients with AD are biologically female; therefore, the biological underpinnings of this diagnosis disparity may inform interventions slowing the AD progression. To bridge this gap, we conducted analyses of 1078 male and female participants from the Alzheimer's Disease Neuroimaging Initiative to examine associations between levels of cerebral spinal fluid (CSF)/neuroimaging biomarkers and cognitive/functional outcomes...

In the present study we investigated whether hippocampal subfield (cornu ammonis 1-3, dentate gyrus, and subiculum) and anteroposterior hippocampal subregion (head,body, and tail) volumes can predict episodic memory function using high-field high resolution structural magnetic resonance imaging (MRI). We recruited 126 healthy participants (18-85 years). MRI datasets were collected on a 4.7 T system. Participants were administered the Wechsler Memory Scale (WMS-IV) to evaluate episodic memory function. Structural equation modeling was used to test the relationship between studied variables...

The objective of this study was to evaluate the relation of metformin with change in cognition and brain pathology. During a mean of 8 years (SD = 5.5) of annual follow-up visits, 262/3029 participants were using metformin at any time during the study. Using a linear-mixed effect model adjusted for age, sex, and education, metformin users had slower decline on a score of global cognition compared to non-users (estimate = 0.017, SE = 0.007, p = 0.027). Analyses of cognitive domains showed a slower decline in episodic memory and semantic memory specifically...

Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's disease are needed. We previously demonstrated that higher amyloid-beta (Aβ) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluid biomarkers (Aβ42/40 , phosphorylated tau181 [pTau181 ], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention...

Current genome-wide association studies of frontotemporal dementia (FTD) are underpowered due to limited samples. Further, common genetic etiologies between FTD and amyotrophic lateral sclerosis (ALS) remain unknown. Using the largest summary statistics of FTD (3526 cases and 9402 controls) and ALS (27,205 cases and 110,881 controls), we found a significant genetic correlation between them (rˆg  = 0.637, P = 0.032) and identified 190 FTD-related variants within 5 loci (3p22...

Although there is increasing evidence for the involvement of Hippo signaling in Alzheimer's disease (AD), the detailed functions and regulatory mechanisms are not fully understood, given the diverse biological effects of this pathway. In the present work, we used Caenorhabditis elegans and mammalian cell models to investigate changes in the Hippo signaling pathway in response to Aβ and the downstream effects on AD development. Aβ1-42 production in the AD models decreased phosphorylation of the upstream CST-1/WTS-1 kinase cascade and promoted an interaction between LIN-10 and YAP-1, leading to the nuclear translocation of YAP-1 and inducing gene transcription in conjunction with the transcription factor EGL-44...

The underlying neural mechanisms underpinning the association between age-related hearing loss (ARHL) and dementia remain unclear. A limitation has been the lack of functional neuroimaging studies in ARHL cohorts to help clarify this relationship. In the present study, we investigated the neural correlates of feature binding in visual working memory with ARHL (controls = 14, mild HL = 21, and moderate or greater HL = 23). Participants completed a visual change detection task assessing feature binding while their neural activity was synchronously recorded via high-density electroencephalography...

Studies have shown that multimorbidity may be associated with the Alzheimer's disease (AD) stages, but it has not been fully characterized in patients without dementia. A total of 1402 Han Chinese older adults without dementia from Chinese Alzheimer's Biomarker and LifestylE (CABLE) study were included and grouped according to their multimorbidity patterns, defined by the number of chronic disorders and cluster analysis. Multivariable linear regression models were used to detect the associations with AD-related cerebrospinal fluid (CSF) biomarkers...

Old male rhesus macaques often show cognitive impairment, and also have attenuated circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEAS). However, it is unclear if these age-associated decreases in circulating androgen levels are casually related to mechanisms that support cognition. To test this possibility, old male rhesus macaques were given daily supplements of testosterone and DHEA for ∼7 months, using a paradigm designed to mimic the 24-hour circulating hormone patterns of young adults...

The application of the selective allosteric M1 muscarinic and sigma-1 receptor agonist, AF710B (aka ANAVEX3-71), has shown to attenuate Alzheimer's disease-like hallmarks in McGill-R-Thy1-APP transgenic rats when administered at advanced pathological stages. It remains unknown whether preventive treatment strategies applying this compound may be equally effective. We tested whether daily oral administration of AF710B (10 µg/kg) in 7-month-old, preplaque, McGill-R-Thy1-APP rats for 7 months, followed by a 4-week washout period, could prevent Alzheimer's disease-like pathological hallmarks...

We evaluated alterations in the nucleus basalis of Meynert (NBM) volume and integrity of cholinergic white matter pathways in objective subtle cognitive impairment (Obj-SCI) individuals. NBM segmentation and cholinergic pathways tracking were conducted at baseline, 12-, 24-, and 48-month follow-ups in 41 Obj-SCI individuals and 61 healthy controls (HC). The baseline and 4-year rate of change in NBM volume and cholinergic pathways mean diffusivity were compared. Associations between cholinergic index changes and pathological processes and cognitive performance were evaluated...

After overexposure to loud music, we experience a decrease in our ability to hear (robustness), which usually recovers (resilience). Here, we exploited the amenable auditory system of the desert locust, Schistocerca gregaria, to measure how robustness and resilience depend on age. We found that gene expression changes are dominated by age as opposed to noise exposure. We measured sound-evoked nerve activity for young and aged locusts directly, after 24 hours and 48 hours after noise exposure...