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Alcohol Research : Current Reviews 2024By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a... (Review)
Review
PURPOSE
By 2040, 21.6% of Americans will be over age 65, and the population of those older than age 85 is estimated to reach 14.4 million. Although not causative, older age is a risk factor for dementia: every 5 years beyond age 65, the risk doubles; approximately one-third of those older than age 85 are diagnosed with dementia. As current alcohol consumption among older adults is significantly higher compared to previous generations, a pressing question is whether drinking alcohol increases the risk for Alzheimer's disease or other forms of dementia.
SEARCH METHODS
Databases explored included PubMed, Web of Science, and ScienceDirect. To accomplish this narrative review on the effects of alcohol consumption on dementia risk, the literature covered included clinical diagnoses, epidemiology, neuropsychology, postmortem pathology, neuroimaging and other biomarkers, and translational studies. Searches conducted between January 12 and August 1, 2023, included the following terms and combinations: "aging," "alcoholism," "alcohol use disorder (AUD)," "brain," "CNS," "dementia," "Wernicke," "Korsakoff," "Alzheimer," "vascular," "frontotemporal," "Lewy body," "clinical," "diagnosis," "epidemiology," "pathology," "autopsy," "postmortem," "histology," "cognitive," "motor," "neuropsychological," "magnetic resonance," "imaging," "PET," "ligand," "degeneration," "atrophy," "translational," "rodent," "rat," "mouse," "model," "amyloid," "neurofibrillary tangles," "α-synuclein," or "presenilin." When relevant, "species" (i.e., "humans" or "other animals") was selected as an additional filter. Review articles were avoided when possible.
SEARCH RESULTS
The two terms "alcoholism" and "aging" retrieved about 1,350 papers; adding phrases-for example, "postmortem" or "magnetic resonance"-limited the number to fewer than 100 papers. Using the traditional term, "alcoholism" with "dementia" resulted in 876 citations, but using the currently accepted term "alcohol use disorder (AUD)" with "dementia" produced only 87 papers. Similarly, whereas the terms "Alzheimer's" and "alcoholism" yielded 318 results, "Alzheimer's" and "alcohol use disorder (AUD)" returned only 40 citations. As pertinent postmortem pathology papers were published in the 1950s and recent animal models of Alzheimer's disease were created in the early 2000s, articles referenced span the years 1957 to 2024. In total, more than 5,000 articles were considered; about 400 are herein referenced.
DISCUSSION AND CONCLUSIONS
Chronic alcohol misuse accelerates brain aging and contributes to cognitive impairments, including those in the mnemonic domain. The consensus among studies from multiple disciplines, however, is that alcohol misuse can increase the risk for dementia, but not necessarily Alzheimer's disease. Key issues to consider include the reversibility of brain damage following abstinence from chronic alcohol misuse compared to the degenerative and progressive course of Alzheimer's disease, and the characteristic presence of protein inclusions in the brains of people with Alzheimer's disease, which are absent in the brains of those with AUD.
Topics: Humans; Dementia; Alcoholism; Aged; Animals; Aged, 80 and over; Alcohol Drinking; Brain; Alzheimer Disease; Risk Factors
PubMed: 38812709
DOI: 10.35946/arcr.v44.1.03 -
Translational Psychiatry May 2024Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases;...
Bidirectional two-sample Mendelian randomization analyses support causal relationships between structural and diffusion imaging-derived phenotypes and the risk of major neurodegenerative diseases.
Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer's disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.
Topics: Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Neurodegenerative Diseases; Polymorphism, Single Nucleotide; Alzheimer Disease; Phenotype; Frontotemporal Dementia; Male; Female; Diffusion Magnetic Resonance Imaging; Multiple Sclerosis; Brain; Aged; Lewy Body Disease; Middle Aged; Magnetic Resonance Imaging; United Kingdom
PubMed: 38806463
DOI: 10.1038/s41398-024-02939-3 -
MedRxiv : the Preprint Server For... May 2024Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a...
Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a standardized protocol for brain embedding, imaging, and processing, facilitating alignment between antemortem MRI, postmortem MRI, and pathology to observe brain atrophy and structural damage progression over time. Using 7T postmortem ex vivo MRI, we explore the potential correlation of amygdala and hippocampal atrophy with neuropathological burden in both Down syndrome (DS) and Alzheimer's disease (AD) cohorts. Using 7T postmortem ex vivo MRI scans from 66 cases (12 DS and 54 AD) alongside a subset of antemortem scans (n=17), we correlated manually segmented hippocampal and amygdala volumes, adjusted for age, sex, and ApoE4 status, with pathological indicators such as Thal phase, Braak stage, limbic-predominant age-related TDP-43 encephalopathy (LATE) stage, hippocampal sclerosis (HS), and Lewy body (LB) stage. A significant correlation was observed between postmortem and antemortem volumes for the hippocampus, but a similar trend observed for the amygdala did not reach statistical significance. DS individuals exhibited notably smaller hippocampal and amygdala volumes compared to AD subjects. In DS, lower hippocampal and amygdala volumes correlated with more severe Braak stage, without significant associations with Thal phase. LATE and HS pathologies were uncommon in DS cases but trended toward smaller hippocampal volumes. In AD, lower hippocampal volume associated with dementia duration, advanced Thal phase, Braak stage, LATE stage, and HS presence, whereas reduced amygdala volume correlated mainly with severe LATE stage and HS, but not with Thal or Braak stages. No significant LB correlation was detected in either DS or AD cohorts. Hippocampal volume in AD appears influenced by both AD and LATE pathologies, while amygdala volume seems primarily influenced by LATE. In DS, smaller hippocampal volume, relative to AD, appears primarily influenced by tau pathology.
PubMed: 38798514
DOI: 10.1101/2024.05.15.24307354 -
Cortico-amygdala synaptic structural abnormalities produced by templated aggregation of α-synuclein.BioRxiv : the Preprint Server For... May 2024Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in...
Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-synuclein pre-formed fibrils (PFFs) into the striatum induces robust α-synuclein aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-synuclein show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that PFF-injected mice showed reduced intervesicular distances similar to a recent study showing phospho-serine-129 α-synuclein increases synaptic vesicle clustering. Thus, pathologic α-synuclein causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.
PubMed: 38798467
DOI: 10.1101/2024.05.15.594419 -
Acta Neuropathologica Communications May 2024Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to...
Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis. The study included cases with a pathological diagnosis of Intermediate/High AD based on the National Institute on Aging- Alzheimer's Association (NIA-AA) and/or NIA-Reagan criteria. A 2:1 random comparison sample of NHWD was frequency-balanced and matched with HD by age and sex. An expert blinded to demographics and center origin evaluated arteriolosclerosis, cerebral amyloid angiopathy (CAA), and Lewy bodies/Lewy neurites (LBs/LNs) with a semi-quantitative approach using established criteria. There were many similarities and a few differences among groups. HD showed more severe Vonsattel grading of CAA in the cerebellum (p = 0.04), higher CAA density in the posterior hippocampus and cerebellum (ps = 0.01), and increased LBs/LNs density in the frontal (p = 0.01) and temporal cortices (p = 0.03), as determined by Wilcoxon's test. Ordinal logistic regression adjusting for age, sex, and center confirmed these findings except for LBs/LNs in the temporal cortex. Results indicate HD with AD exhibit greater CAA and α-synuclein burdens in select neuroanatomic regions when compared to age- and sex-matched NHWD with AD. These findings aid in the generalizability of concurrent arteriolosclerosis, CAA, and LBs/LNs topography and severity within the setting of pathologically confirmed AD, particularly in persons of Hispanic descent, showing many similarities and a few differences to those of NHW descent and providing insights into precision medicine approaches.
Topics: Humans; Alzheimer Disease; Female; Male; Aged; Hispanic or Latino; Aged, 80 and over; Cohort Studies; White People; Lewy Bodies; Cerebral Amyloid Angiopathy; alpha-Synuclein; Brain; Cerebral Small Vessel Diseases; Arteriolosclerosis
PubMed: 38790074
DOI: 10.1186/s40478-024-01773-4 -
Parkinsonism & Related Disorders May 2024Several recent studies have uncovered the presence of widespread urea elevations in multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's...
INTRODUCTION
Several recent studies have uncovered the presence of widespread urea elevations in multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease dementia (PDD), vascular dementia (VaD), and Huntington's disease (HD). However, it is currently unknown whether dementia with Lewy bodies also shows these alterations in urea. This study aimed to investigate if and where urea is perturbed in the DLB brain.
METHODS
Tissues from ten brain regions were obtained from 20 diagnosed cases of DLB and 19 controls. Urea concentrations were measured using ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Case-control differences were assessed by nonparametric Mann-Whitney U tests, and s-values, E-values, effect sizes, and risk ratios were determined for each brain region. The results were compared to those previously obtained for AD, PDD, VaD, and HD.
RESULTS
As with other previously investigated dementia diseases, DLB shows widespread urea elevations, affecting all ten regions investigated in the current study; the degree of these elevations is lower than that seen in AD or PDD, similar to that seen in HD, and higher than that observed in VaD. The highest urea fold-change was observed in the pons and the lowest in the primary visual cortex.
CONCLUSION
Urea elevations appear to be a shared alterations across at least five neurodegenerative diseases, despite their many differences in clinical and neuropathological presentation. The cause and effects of this perturbation should be the focus of future studies, for its possible contributions to the pathology of these conditions.
PubMed: 38788611
DOI: 10.1016/j.parkreldis.2024.107017 -
Aging Clinical and Experimental Research May 2024To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e.,...
OBJECTIVE
To describe the 10-year preclinical cognitive trajectories of older, non-demented individuals towards the onset of the four most prevalent types of dementia, i.e., Alzheimer's disease(AD), Lewy body(LBD), vascular(VD) and frontotemporal dementia(FTD).
METHODS
Our analysis focused on data from older (≥ 60years) NACC (National Alzheimer's Coordinating Center) participants. Four distinct presymptomatic dementia groups (AD-LBD-VD-FTD) and a comparison group of cognitively unimpaired(CU) participants were formed. Comprehensive cognitive assessments involving verbal episodic memory, semantic verbal fluency, confrontation naming, mental processing speed - attention and executive function - cognitive flexibility were conducted at baseline and on an approximately yearly basis. Descriptive analyses (adjusted general linear models) were performed to determine and compare the yearly cognitive scores of each group throughout the follow-up. Exploratory analyses were conducted to estimate the rates of cognitive decline.
RESULTS
There were 3343 participants who developed AD, 247 LBD, 108 FTD, 155 VD and 3398 composed the CU group. Participants with AD performed worse on episodic memory than those with VD and LBD for about 3 to 4 years prior to dementia onset (the FTD group documented an intermediate course). Presymptomatic verbal fluency and confrontation naming trajectories differentiated quite well between the FTD group and the remaining dementia entities. Participants with incident LBD and VD performed worse than those with AD on executive functions and mental processing speed-attention since about 5 years prior to the onset of dementia, and worse than those with FTD more proximally to the diagnosis of the disorder.
CONCLUSIONS
Heterogeneous cognitive trajectories characterize the presymptomatic courses of the most prevalent dementia entities.
Topics: Humans; Aged; Male; Female; Longitudinal Studies; Cognition; Dementia; Neuropsychological Tests; Middle Aged; Alzheimer Disease; Aged, 80 and over; Disease Progression; Databases, Factual; Frontotemporal Dementia; Lewy Body Disease; Dementia, Vascular; Memory, Episodic; Cognitive Dysfunction; Executive Function
PubMed: 38780681
DOI: 10.1007/s40520-024-02769-9 -
Molecular Brain May 2024Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates...
Broad proteomics analysis of seeding-induced aggregation of α-synuclein in M83 neurons reveals remodeling of proteostasis mechanisms that might contribute to Parkinson's disease pathogenesis.
Aggregation of misfolded α-synuclein (α-syn) is a key characteristic feature of Parkinson's disease (PD) and related synucleinopathies. The nature of these aggregates and their contribution to cellular dysfunction is still not clearly elucidated. We employed mass spectrometry-based total and phospho-proteomics to characterize the underlying molecular and biological changes due to α-syn aggregation using the M83 mouse primary neuronal model of PD. We identified gross changes in the proteome that coincided with the formation of large Lewy body-like α-syn aggregates in these neurons. We used protein-protein interaction (PPI)-based network analysis to identify key protein clusters modulating specific biological pathways that may be dysregulated and identified several mechanisms that regulate protein homeostasis (proteostasis). The observed changes in the proteome may include both homeostatic compensation and dysregulation due to α-syn aggregation and a greater understanding of both processes and their role in α-syn-related proteostasis may lead to improved therapeutic options for patients with PD and related disorders.
Topics: alpha-Synuclein; Animals; Proteostasis; Parkinson Disease; Proteomics; Neurons; Protein Aggregates; Mice; Protein Interaction Maps; Proteome
PubMed: 38778381
DOI: 10.1186/s13041-024-01099-1 -
NPJ Parkinson's Disease May 2024Alpha-synuclein (αS)-rich Lewy bodies and neurites in the cerebral cortex correlate with the presence of dementia in Parkinson disease (PD) and Dementia with Lewy...
Alpha-synuclein (αS)-rich Lewy bodies and neurites in the cerebral cortex correlate with the presence of dementia in Parkinson disease (PD) and Dementia with Lewy bodies (DLB), but whether αS influences synaptic vesicle dynamics in human cortical neurons is unknown. Using a new iPSC-based assay platform for measuring synaptic vesicle cycling, we found that in human cortical glutamatergic neurons, increased αS from either transgenic expression or triplication of the endogenous locus in patient-derived neurons reduced synaptic vesicle cycling under both stimulated and spontaneous conditions. Thus, using a robust, easily adopted assay platform, we show for the first time αS-induced synaptic dysfunction in human cortical neurons, a key cellular substrate for PD dementia and DLB.
PubMed: 38773105
DOI: 10.1038/s41531-024-00725-y -
BioRxiv : the Preprint Server For... May 2024Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and...
Spread and aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain ( in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinson's Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.
PubMed: 38765963
DOI: 10.1101/2024.05.07.593056