Dementia Pathology Research Articles

1,3‐Butanediol Mitigates High‐Salt Diet Induced Cognitive Impairment in Aging Mice

Vascular dementia (VaD) is the second most common form of dementia after Alzheimer’s disease (AD). Hypertension is the second leading risk factor for developing neurodegenerative disease. A recent study reported that Dietary salt promotes cognitive impairment through tau phosphorylation. However, the effect of ketone bodies or the precursor molecule (1,3‐butanediol) supplementation on cognitive impairment in aged mice or the absence of high salt has not been investigated. The study tests the hypothesis that 1,3‐butanediol attenuates the progression of vascular dementia mediated through histone acetylation mechanism in hypertensive aged mice. To test this hypothesis, we employed old male and female wild‐type (WT) mice. For three months, the mice were fed with a high salt diet (HSD) (8%). HSD mice have supplemented with ketone bodies precursor, 1,3‐Butanediol (2%), and ketone bodies compound β‐hydroxybutyrate (BHB, 0.2%) in drinking water for 12 weeks. Blood pressure was measured after 12 weeks of treatment by tail‐cuff plethysmography. After 12 weeks, urine and tissues were collected. The results show that 1,3‐Butanediol or BHB treatment reduced blood pressure and miRNA‐128‐3p in aged hypertensive mice. Further, the data analysis revealed the loss of short‐term and long‐term memory in HSD‐hypertensive mice compared to HSD+BHB or HSD+ 1,3‐Butanediol mice. This mechanistic study shows that HSD+ 1,3‐Butanediol mice display an increased mitochondrial TFAM dependent upregulation of brain‐derived neurotrophic factor (BDNF) and nuclear receptor subfamily 4A (Nr4a) in the mouse hippocampus via activation of the H3K27ac acetylation at the promoter. In addition, the anti‐miR‐128 treatment restored neuroprotective function and reduced the dementia pathology in old‐hypertensive mice. The present data demonstrate that 1,3‐Butanediol or BHB increases ketone bodies production and improves cognitive functions in aged hypertensive mice and could be a novel nutritional intervention for vascular dementia treatment.

APOE \u03b54, Alzheimer\u2019s disease neuropathology and sleep disturbance, in individuals with and without dementia

BackgroundApolipoprotein E epsilon 4 (APOE-ε4) carrier status is an established risk factor for Alzheimer’s disease (AD) dementia. It has also been linked with sleep disturbance in healthy older adults and increased insomnia risk. This association may be driven by the effect of APOE-ε4 on AD pathological change, itself associated with sleep abnormalities. To assess this relationship, we have evaluated post-mortem neuropathological findings in patients with and without cognitive impairment and AD pathology, who had extensive clinical assessment within 12 months of death.MethodsThis retrospective cohort study used UK Brain Banks Network data. Eligible subjects were aged over 50, with pre-mortem neuropsychiatry inventory scores of sleep disturbance (NPI-K), neurocognitive testing and functional cognitive status assessment (Clinical Dementia Rating scale). Neuropathological data included Thal phase, Braak stage and CERAD scores (measures of Aβ plaque distribution, tangle distribution and neuritic plaque density, respectively) combined to form the National Institute on Aging Alzheimer’s Association (NIA-AA) ABC score reflecting AD neuropathology. Participants with other significant intracerebral pathology or pathological features of non-AD dementia were excluded.Multivariate linear regression was performed with NPIK Global Score (NPIK frequency score multiplied by severity score) as the dependent variable and APOE-ε4 heterozygosity or homozygosity as independent variables. Covariates included age, gender, APOE-ε2 status and ABC NPI measures reflecting depression and anxiety. Further models stratified by ABC score and functional cognitive status were also produced.ResultsSeven hundred twenty-eight records were identified. Two hundred two participants were included in the final analysis: mean (SD) age 84.0 (9.2) and MMSE 14.0 (11.8). Mean sleep disturbance scores were highest in ε4 homozygosity (n=11), 4.55 (5.4); intermediate in ε4 heterozygosity (n=95), 2.03 (4.0); and lowest in non-ε4 carriers (n=96), 1.36 (3.3). Within the full sample, controlling for pathological status, age, gender, depression, anxiety and CDR-SOB status, APOE-ε4 homozygosity was associated with sleep disturbance (β 2.53, p=0.034). APOE-ε4 heterozygosity was similarly associated in individuals without dementia (β 1.21, p=0.048).ConclusionThese findings lend weight to the hypothesis that APOE-ε4 affects sleep by mechanisms independent of AD pathological change. Evaluation of those mechanisms would enhance understanding of sleep disturbance pathways and potentially provide treatment targets.

Cannabinoids and Psychedelics for Neuropsychiatric Symptoms of Alzheimer's: Addressing Disparities Through Clinical Trials

AD and other forms of dementia are commonly associated with neuropsychiatric symptoms, including anxiety, agitation, and depression, all of which can lead to more rapid cognitive decline and a poor quality of life for both caregivers and patients.There are currently no FDA approved medications to treat neuropsychiatric symptoms associated with dementia. Instead, current treatment options include off-label use of psychotropic medications that are associated with well-established risks. Alternative therapeutic options include cannabinoids and psychedelics. This session will focus on discussing the safety and efficacy of cannabinoids in treating anxiety and agitation associated with Alzheimer's dementia, as well as the safety and efficacy of psychedelics in treating depression in older adults with dementia.The history of medicinal cannabis use dates back as far as 4000BC. Delta-9-tetrahydrocannabinol (THC), the major psychoactive component of cannabis, activates cannabinoid receptors (mainly CB1 and CB2 receptors), producing anxiolytic and antidepressant effects while also reducing reduce brain inflammation. Cannabidiol (CBD), the major non-intoxicating component of cannabis, possesses low affinity to CB1 and CB2 receptors. CBD modulates systems outside of the endocannabinoid system, producing antioxidant and antipsychotic effects. Both THC and CBD have shown evidence of therapeutic effects on anxiety and pain. We will discuss three studies evaluating the use of cannabinoids as potential forms of treatment for agitation and anxiety in dementia.Psychedelics are also being introduced as potential mental health treatments. Past research has shown psychedelics can produce long-term anxiolytic and antidepressant effects after a single administration. A pilot trial at Johns Hopkins is examining the safety and efficacy of psilocybin treatment for participants with mild cognitive impairment (MCI) and depressive symptoms. The study hypothesizes that the psilocybin treatment will be associated with a significant reduction in depressive symptoms.Overall, these trials collectively guide research towards furthering our understanding of the pathology of Alzheimer's dementia and other forms of dementia and improving the quality of life for older adults and their caregivers.

Network Theoretical Approach to Explore Factors Affecting Signal Propagation and Stability in Dementia's Protein-Protein Interaction Network.

Dementia—a syndrome affecting human cognition—is a major public health concern given to its rising prevalence worldwide. Though multiple research studies have analyzed disorders such as Alzheimer’s disease and Frontotemporal dementia using a systems biology approach, a similar approach to dementia syndrome as a whole is required. In this study, we try to find the high-impact core regulating processes and factors involved in dementia’s protein–protein interaction network. We also explore various aspects related to its stability and signal propagation. Using gene interaction databases such as STRING and GeneMANIA, a principal dementia network (PDN) consisting of 881 genes and 59,085 interactions was achieved. It was assortative in nature with hierarchical, scale-free topology enriched in various gene ontology (GO) categories and KEGG pathways, such as negative and positive regulation of apoptotic processes, macroautophagy, aging, response to drug, protein binding, etc. Using a clustering algorithm (Louvain method of modularity maximization) iteratively, we found a number of communities at different levels of hierarchy in PDN consisting of 95 “motif-localized hubs”, out of which, 7 were present at deepest level and hence were key regulators (KRs) of PDN (HSP90AA1, HSP90AB1, EGFR, FYN, JUN, CELF2 and CTNNA3). In order to explore aspects of network’s resilience, a knockout (of motif-localized hubs) experiment was carried out. It changed the network’s topology from a hierarchal scale-free topology to scale-free, where independent clusters exhibited greater control. Additionally, network experiments on interaction of druggable genome and motif-localized hubs were carried out where UBC, EGFR, APP, CTNNB1, NTRK1, FN1, HSP90AA1, MDM2, VCP, CTNNA1 and GRB2 were identified as hubs in the resultant network (RN). We finally concluded that stability and resilience of PDN highly relies on motif-localized hubs (especially those present at deeper levels), making them important therapeutic intervention candidates. HSP90AA1, involved in heat shock response (and its master regulator, i.e., HSF1), and EGFR are most important genes in pathology of dementia apart from KRs, given their presence as KRs as well as hubs in RN.

Cortical Proteins and Individual Differences in Cognitive Resilience in Older Adults.

Background and ObjectivesCognitive resilience is a well-recognized concept, but knowledge gaps about its underlying mechanisms have made it difficult to develop instruments that identify older adults with high or low resilience. We tested whether aggregating cortical peptides associated with cognitive resilience into an index can identify adults with higher or lower cognitive resilience.MethodsWe used data from 1,192 older decedents, including annual clinical testing, indices of 10 Alzheimer disease (AD) and related dementia (ADRD) pathologies, and 226 proteotypic peptides measured in the dorsal lateral prefrontal cortex. We used linear mixed-effects models to identify peptides that were related to cognitive resilience (i.e., cognitive decline not explained by ADRD pathologies [false discovery rate <0.05]). We aggregated the expression levels of these resilience peptides into a person-specific cognitive resilience index and examined its association with AD clinical and pathologic phenotypes.ResultsWe constructed a resilience index from 52 of 226 peptides related to cognitive resilience. A higher index was associated with slower cognitive decline (estimate 0.05, SE 0.003, p < 0.001) and slower motor decline (estimate 0.005, SE 0.001, p < 0.001). Most resilience peptides (70%) were specific to cognitive decline, but 30% also provided resilience for motor decline. A higher index was also related to a lower burden of AD pathologies (odds ratio [OR] 0.41, SE 0.01, p < 0.001) and modified the association of AD pathology with cognition in that a higher index modified the negative effects of AD pathology on AD dementia proximate to death (OR 0.70, SE 0.14, p = 0.010). Up to 90% of cognitive resilience peptides were related to AD pathologic phenotypes.DiscussionCortical proteins may provide some degree of cognitive resilience. These multifunctional proteins also seem to provide resilience to other AD clinical phenotypes and have independent associations with ADRD pathologies. Resilience proteins may be high-value therapeutic targets for drug discovery of interventions that maintain brain health in aging adults via multiple pathways.

Poor pulmonary function is associated with mild cognitive impairment, its progression to dementia, and brain pathologies: A community-based cohort study.

The relationship between pulmonary function (PF) and mild cognitive impairment (MCI), dementia, and brain pathologies remains unclear. A total of 1312 dementia-free participants, including a cognitively intact group (n=985) and an MCI group (n=327), were followed for up to 21 years to detect incident MCI and dementia. PF was assessed at baseline with a composite score and tertiled. Over follow-up, 540 participants underwent autopsies for neuropathological assessment. Compared to the highest PF, the hazard ratios (95% confidence intervals [CIs]) of the lowest PF were 1.95 (1.43-2.66) for MCI in the cognitively intact group and 1.55 (1.03-2.33) for dementia in the MCI group. Low PF was further related to Alzheimer's disease pathology (odds ratio [OR] 1.32, 95% CI 1.19-1.47) and vascular pathology (OR 3.05, 95% CI 1.49-6.25). Low PF increases MCI risk and accelerates MCI progression to dementia. Both neurodegenerative and vascular mechanisms may underlie the PF-dementia association.

Psychiatric symptoms of frontotemporal dementia and subcortical (co-)pathology burden: new insights.

Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-β, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-β (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-β burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.

The vascular risk factors and vascular neuropathology in subjects with autopsy-confirmed dementia with Lewy bodies.

The frequency of vascular risk factors (VRFs) and the relationship between vascular pathology and cognitive function in neurodegenerative disease remains incompletely understood. The purpose of this study was to describe the frequency of VRFs and vascular pathology and explore the relationship between vascular pathology and cognitive function in dementia with Lewy bodies (DLB). This study included 363 autopsy-confirmed DLB and 753 Alzheimer's disease (AD) patients from the National Alzheimer's Coordinating Center (NACC) database. We used chi-squared test and analysis of variance to compare the VRFs and related factors in DLB and AD. Multinomial logistic regression and Spearman's correlation test were used to examine the relationship between vascular pathology and cognitive function. No significant differences of VRFs were identified between DLB and AD. Alzheimer's disease patients had higher rates of microinfarcts (23.5% vs. 16.3%, p=0.005) and moderate to severe amyloid angiopathy (45.9% vs. 36.1%, p=0.002). In DLB patients, only cerebral amyloid angiopathy (CAA) pathology was negatively correlated with memory domain (r=-0.263, p < 0.001) and language (r=-0.112,p=0.034). The rates of APOE ε4 allele carriers (60.0% vs. 44.9%, p=0.004) and CAA pathology (45.9% vs.23.4%, p < 0.001) were much higher in the group with an intermediate likelihood of DLB than in the group with a high likelihood. There was a negative correlation between CAA pathology and memory (logical memory) in the group with an intermediate likelihood of DLB. No difference of VRFs was identified between autopsy-confirmed DLB and AD. Cerebral amyloid angiopathy was shown to be an important pathology in DLB, which specifically correlated with memory and language. The groups with high and intermediate likelihood of DLB differed in terms of CAA pathology, and CAA pathology may play an important role in the development of DLB.

Probing sequence space to uncover molecular interactions driving FUS liquid-liquid phase separation

Fused in Sarcoma (FUS) is an essential RNA-processing protein functioning via self-assembly including through Liquid-Liquid Phase Separation (LLPS) and implicated in amyotrophic lateral sclerosis and frontotemporal dementia pathologies through aberrant subsequent neurodegeneration. However, the biomolecular interactions driving LLPS have not been thoroughly characterized. In this work, we probe in detail the role of each of the enriched residues types in FUS in LLPS. We present a number of mutagenic and biochemical-derived systems that refine our understanding of the roles of individual amino acid types beyond tyrosine and arginine in FUS phase separation.

Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain.

There is strong evidence that aging is associated with an increased presence of senescent cells in the brain. The finding that treatment with senolytic drugs improves cognitive performance of aged laboratory mice suggests that increased cellular senescence is causally linked to age-related cognitive decline. The relationship between senescent cells and their relative locations within the brain is critical to understanding the pathology of age-related cognitive decline and dementia. To assess spatial distribution of cellular senescence in the aged mouse brain, spatially resolved whole transcriptome mRNA expression was analyzed in sections of brains derived from young (3months old) and aged (28months old) C57BL/6 mice while capturing histological information in the same tissue section. Using this spatial transcriptomics (ST)-based method, microdomains containing senescent cells were identified on the basis of their senescence-related gene expression profiles (i.e., expression of the senescence marker cyclin-dependent kinase inhibitor p16INK4A encoded by the Cdkn2a gene) and were mapped to different anatomical brain regions. We confirmed that brain aging is associated with increased cellular senescence in the white matter, the hippocampi and the cortical grey matter. Transcriptional analysis of the senescent cell-containing ST spots shows that presence of senescent cells is associated with a gene expression signature suggestive of neuroinflammation. GO enrichment analysis of differentially expressed genes in the outer region of senescent cell-containing ST spots ("neighboring ST spots") also identified functions related to microglia activation and neuroinflammation. In conclusion, senescent cells accumulate with age in the white matter, the hippocampi and cortical grey matter and likely contribute to the genesis of inflammatory foci in a paracrine manner.

The prospective association between periodontal disease and brain imaging outcomes: The Atherosclerosis Risk in Communities study.

We investigate if periodontal disease is prospectively associated with cerebrovascular and neurodegenerative markers of dementia and Alzheimer's pathology. N=1306 participants (Visit 5 mean age=76.5 [standard deviation=5.4] years) in the Atherosclerosis Risk in Communities study with completed dental exams at Visit 4 underwent brain magnetic resonance imaging scans at Visit 5 while N=248 underwent positron emission tomography scans. Participants were classified as edentulous or, among the dentate, by the modified Periodontal Profile Class. Brain volumes were regressed on periodontal status in linear regressions. Cerebrovascular measures and β-amyloid positivity were regressed on periodontal status in logistic regressions. Periodontal disease was not associated with brain volumes, microhaemorrhages, or elevated β-amyloid. Compared with periodontally healthy individuals, odds ratios [95% confidence interval] for all-type infarcts were 0.37 [0.20, 0.65] for severe tooth loss and 0.56 [0.31, 0.99] for edentulous participants. Within the limitations of this study, periodontal disease was not associated with altered brain volumes, microhaemorrhages, or β-amyloid positivity. Tooth loss was associated with lower odds of cerebral infarcts.

Neighborhood greenspace exposure as a protective factor in dementia risk among U.S. adults 75\u2009years or older: a cohort study

BackgroundResearch suggests that greenspace may confer neurocognitive benefits. This study examines whether residential greenspace is associated with risk of dementia among older adults.MethodsGreenspace exposure was computed for 3047 participants aged 75 years and older enrolled in the Gingko Evaluation of Memory Study (GEMS) across four U.S. sites that prospectively evaluated dementia and its subtypes, Alzheimer’s disease (AD), vascular dementia (VaD), and mixed pathologies, using neuropsychiatric evaluations between 2000 and 2008. After geocoding participant residences at baseline, three greenspace metrics—Normalized Difference Vegetative Index, percent park overlap within a 2-km radius, and linear distance to nearest park—were combined to create a composite residential greenspace measure categorized into tertiles. Cox proportional hazards models estimated the associations between baseline greenspace and risk of incident all-cause dementia, AD, and Mixed/VaD.ResultsCompared to low residential greenspace, high residential greenspace was associated with a reduced risk of dementia (HR = 0.76 95% CI: 0.59,0.98) in models adjusted for multiple covariates. After additional adjustment for behavioral characteristics, Apolipoprotein E ɛ4 status, and other covariates, the association was slightly attenuated (HR = 0.82; 95% CI:0.63,1.06). Those exposed to medium levels of greenspace also had 28% lower risk (HR = 0.72; CI: 0.55, 0.95) of dementia compared to those with low greenspace in adjusted models. Subtype associations between high residential greenspace and AD were not statistically significant. Greenspace was not found to be significantly associated with mixed/vascular pathologies.ConclusionsThis study showed evidence for an association between residential greenspace and all-cause dementia among older adults. Future research with larger sample size, precise characterization of different dementia subtypes, and assessment of residential greenspace earlier in life may help clarify the role between exposure to greenspace and dementia risk.

Reactive astrogliosis: A friend or foe in the pathogenesis of Alzheimer's disease.

Astrocytes are highly efficient homeostatic glial cells playing a crucial role in optimal brain functioning and homeostasis. Astrocytes respond to changes in brain homoeostasis following central nervous system (CNS) injury/diseased state by a specific defence mechanism called reactive astrogliosis. Recent studies have implicated and placed reactive astrogliosis in the centre of pathophysiology of Alzheimer's disease (AD) and other neurodegenerative disorders. The AD biomarker field is evolving rapidly with new findings providing strong evidence which supports the notion that a reactive astrogliosis is an early event in the time course of AD progression which may precede other pathological hallmarks of AD. Clinical/translational in vivo PET and in vitro postmortem brain imaging studies demonstrated 'a first and second wave' of reactive astrogliosis in AD with distinct close-loop relationships with other pathological biomarkers at different stages of the disease. At the end stages, reactive astrocytes are found to be associated, or in proximity, with amyloid plaque and tau pathological deposits in postmortem AD brains. Several new PET-tracers, which are being in pipeline and validated at a very fast pace for mapping and visualising reactive astrogliosis in the brain, will provide furtherinvaluable mechanistic insights into AD and other non-AD dementia pathologies. The complementary roles of microglia and astrocyte activation in AD progression, along with the clinicalvalue ofnew fluid astrocytes biomarkers in the context of existing biomarkers, arethe latest avenue that needs further exploration.

What is New in Nuclear Medicine Imaging for Dementia.

Advances in the molecular biology, pathology and genetics of Alzheimer's disease (AD) and other degenerative dementias have led to the development of biomarkers specific to these diseases and radiotracers that are used in nuclear medicine. Imaging and non-imaging markers have enabled very early recognition of these diseases and have caused significant changes in their definitions. Amyloid positron emission tomography (PET) and tau PET, which are molecular imaging methods, [F18]fluorodeoxyglucose (FDG) PET showing the glucose metabolism pattern in the brain, dopamine transporter single photon emission computerized tomography (SPECT) that marks dopaminergic terminals are valuable tools for early recognition and differentiation of AD and its atypical variants, frontotemporal dementias and dementia with Lewy bodies. These imaging methods, which have different advantages over each other, have different indications for use and sometimes provide complementary information. In addition, research on radiotracers targeting neuroinflammation, astrocytes, synaptic density, and cholinergic terminals is ongoing. In this review, routinely used and newly developed nuclear imaging methods in AD and other neurodegenerative dementias, the agents used and their diagnostic features will be presented together with case examples.

Small Vessel Cerebrovascular Pathology is a Major Feature in the Pathogenesis of Alzheimer’s Disease or Age-Related Dementia

Historically, cerebrovascular abnormalities were recognized as prominent in the pathology of age-related dementia. In more recent decades, however, research and funding for development of therapeutics has almost entirely been focused on ß-amyloid and tau deposits (as described by Alzheimer in pre-senile dementia), despite a lack of conclusive evidence of a causal relationship or efficacy of targeted treatment on cognitive decline or dementia. Here we present a brief history of the evidence for a dominant vascular component of Alzheimer’s Disease and highlight a potential target for slowing the functional progression of the disease.

Vascular pathology and pathogenesis of cognitive impairment and dementia in older adults.

It is well recognized that brains of older people often harbor cerebrovascular disease pathology including vessel disease and vascular-related tissue injuries and that this is associated with vascular cognitive impairment and contributes to dementia. Here we review vascular pathologies, cognitive impairment, and dementia. We highlight the importance of mixed co-morbid AD/non-AD neurodegenerative and vascular pathology that has been collected in multiple clinical pathologic studies, especially in community-based studies. We also provide an update of vascular pathologies from the Rush Memory and Aging Project and Religious Orders Study cohorts with special emphasis on the differences across age in persons with and without dementia. Finally, we discuss neuropathological perspectives on the interpretation of clinical-pathological studies and emerging data in community-based studies.

Relationship of fasting glucose and longitudinal Alzheimer's disease imaging markers.

IntroductionFasting glucose increases with age and is linked to modifiable Alzheimer's disease risk factors such as cardiovascular disease and Type 2 diabetes (T2D).MethodsWe leveraged available biospecimens and neuroimaging measures collected during the Alzheimer's Prevention Through Exercise (APEx) trial (n = 105) to examine the longitudinal relationship between change in blood glucose metabolism and change in regional cerebral amyloid deposition and gray and white matter (WM) neurodegeneration in older adults over 1 year of follow‐up.ResultsIndividuals with improving fasting glucose (n = 61) exhibited less atrophy and regional amyloid accumulation compared to those whose fasting glucose worsened over 1 year (n = 44). Specifically, while individuals with increasing fasting glucose did not yet show cognitive decline, they did have regional atrophy in the hippocampus and inferior parietal cortex, and increased amyloid accumulation in the precuneus cortex. Signs of early dementia pathology occurred in the absence of significant group differences in insulin or body composition, and was not modified by apolipoprotein E ε4 carrier status.DiscussionDysregulation of glucose in late life may signal preclinical brain change prior to clinically relevant cognitive decline. Additional work is needed to determine whether treatments specifically targeting fasting glucose levels may impact change in brain structure or cerebral amyloid in older adults.

Derivation and Validation of an Algorithmic Classification of Early Cognitive Impairment

The long prodromal period for dementia pathology demands valid and reliable approaches to detect cases before clinically recognizable symptoms emerge, by which time it may be too late to effectively intervene. We derived and compared several algorithms for early cognitive impairment (ECI) using longitudinal data on 1704 BLSA participants. Algorithms were based on cognitive impairment in various combinations of memory and non-memory tests, and the CDR. The best-performing algorithm was defined based on 1SD below age-and race-specific means in Card Rotations or California Verbal Learning Test immediate recall, two tests that in prior work show the earliest declines prior to dementia onset. While this ECI algorithm showed low concordance with concurrent adjudicated MCI/dementia (AUC: 0.63, sensitivity: 0.54, specificity: 0.73), it was among the best predictors of progression to MCI/dementia (HR: 3.65, 95% CI: 1.69,7.87). This algorithm may be useful in epidemiologic work to evaluate risk factors for early cognitive impairment.

Yi-Zhi-Fang-Dai Formula Exerts Neuroprotective Effects Against Pyroptosis and Blood-Brain Barrier-Glymphatic Dysfunctions to Prevent Amyloid-Beta Acute Accumulation After Cerebral Ischemia and Reperfusion in Rats.

Background: The dysfunctional blood–brain barrier (BBB)–glymphatic system is responsible for triggering intracerebral amyloid-beta peptide (Aβ) accumulation and acts as the key link between ischemic stroke and dementia dominated by Alzheimer’s disease (AD). Recently, pyroptosis in cerebral ischemia and reperfusion (I/R) injury is demonstrated as a considerable mechanism causing BBB–glymphatic dysfunctions and Aβ acute accumulation in the brain. Targeting glial pyroptosis to protect BBB–glymphatic functions after cerebral I/R could offer a new viewpoint to prevent Aβ accumulation and poststroke dementia. Yi-Zhi-Fang-Dai formula (YZFDF) is an herbal prescription used to cure dementia with multiple effects of regulating inflammatory responses and protecting the BBB against toxic Aβ-induced damage. Hence, YZFDF potentially possesses neuroprotective effects against cerebral I/R injury and the early pathology of poststroke dementia, which evokes our current study. Objectives: The present study was designed to confirm the potential efficacy of YZFDF against cerebral I/R injury and explore the possible mechanism associated with alleviating Aβ acute accumulation. Methods: The models of cerebral I/R injury in rats were built by the method of middle cerebral artery occlusion/reperfusion (MCAO/R). First, neurological function assessment and cerebral infarct measurement were used for confirming the efficacy of YZFDF on cerebral I/R injury, and the optimal dosage (YZFDF-H) was selected to conduct the experiments, which included Western blotting detections of pyroptosis, Aβ1-42 oligomers, and NeuN, immunofluorescence observations of glial pyroptosis, aquaporin-4 (AQP-4), and Aβ locations, brain water content measurement, SMI 71 (a specific marker for BBB)/AQP-4 immunohistochemistry, and Nissl staining to further evaluate BBB–glymphatic functions and neuronal damage. Results: YZFDF obviously alleviated neurological deficits and cerebral infarct after cerebral I/R in rats. Furthermore, YZFDF could inactivate pyroptosis signaling via inhibiting caspase-1/11 activation and gasdermin D cleavage, ameliorate glial pyroptosis and neuroinflammation, protect against BBB collapse and AQP-4 depolarization, prevent Aβ acute accumulation and Aβ1-42 oligomers formation, and reduce neuronal damage and increase neurons survival after reperfusion. Conclusion: Our study indicated that YZFDF could exert neuroprotective effects on cerebral I/R injury and prevent Aβ acute accumulation in the brain after cerebral I/R associated with inhibiting neuroinflammation-related pyroptosis and BBB–glymphatic dysfunctions.

Are age-related biomarkers of dementia risk accelerated by low educational attainment?

Background: Low education significantly elevates dementia risk but it is not clear whether this is through chronic systemic inflammation, early-onset dementia pathology, or other factors. This project compares biomarkers of inflammation and dementia pathology in a young-old and older cohort. Due to significantly lower education in the young-old cohort, we hypothesized evidence of similar or higher biomarker levels in the young-old cohort compared to the older cohort. &#x0D; Methods: Blood samples were used to measure pro-inflammatory cytokines (C-reactive protein (CRP), tumor necrosis factor (TNF interleukin (IL)-6, and IL-1 anti-inflammatory cytokines (IL-10 and IL-1RA), and the brain biomarkers phosphorylated tau (p-tau) and neurofilament light (NfL). Inflammatory markers were measured at the Considine Lab at the Indiana University School of Medicine using ELISA assays while p-tau and NfL were measured with Simoa assays at the Quanterix lab in Massachusetts. We used the natural logarithm of all biomarker variables to address skewed data. Linear regression was used to investigate race- and gender-adjusted differences in the biomarkers. &#x0D; Results: The young-old cohort (N=42) has a mean age of 62.4, 69.1% are female, and 78.6% are non-Hispanic black (NHB), while the older cohort (N=60) has a mean age of 80.3, 60% are female, and 20% are NHB. Median education in the young-old cohort is 12 vs 16 in the older cohort. Adjusted models showed higher mean CRP (p=0.004) and lower mean IL-10 (p&lt;0.001) in the young-old cohort. TNF- (p &lt;0.001), IL-6 (p=0.021), and IL-1(p=0.017), P-tau (p=0.003), and NfL (p&lt;0.001) were all higher in the older cohort. &#x0D; Conclusion: We found partial support of our hypothesis in that the younger, low education cohort had higher mean CRP and lower mean IL-10 (anti-inflammatory). However, brain biomarkers were higher in the older cohort. More research will be needed to determine if and how low education elevates ADRD risk through systemic inflammation. &#x0D;