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Vascular disease is responsible for only a minority of cases of chronic dementia. Vascular dementia can be an end stage of a variety of mechansisms. Correct identification of the cause of the vascular disease is the key to successful treatment.
BACKGROUND: Vascular dementia (VaD) lacks well-defined genetic mechanisms. Cell-type-specific effects of GWAS loci remain unexplored. METHODS: We integrated single‑cell eQTL data (183 donors, eight cell types) with VaD GWAS (3624 cases, 475,484 controls) using Mendelian randomization and Bayesian colocalization, replicated in an independent cohort (2074 cases, 456,366 controls). Subtype, snRNA‑seq, cell‑cell communication, PheWAS, expression profiling, and drug prediction with BBB permeability assessment were performed. RESULTS: Microglial PICALM was the only robustly replicated signal (OR = 0.8334, p = 5.3 × 10⁻⁴; colocalization PP.H4 > 0.75). The effect was strongest in multiple infarctions dementia (OR = 0.7746). Exploratory snRNA-seq analysis (4 VaD vs. 4 controls; GSE282111) provided supporting evidence for microglial PICALM enrichment and downregulation (p < 0.001). PICALM‑high microglia showed enhanced neurovascular‑ and phagocytosis‑related communication (e.g., SPP1, GAS6, GRN). PheWAS revealed no pleiotropy. In silico drug repurposing prioritised three FDA-approved BBB-penetrant compounds (disopyramide, benzocaine, amantadine) as candidates warranting further mechanistic validation. CONCLUSIONS: Microglial PICALM is identified as a likely genetic determinant of VaD, especially in the multiple infarctions subtype. Upregulating PICALM may be associated with a neuroprotective microglial phenotype, highlighting PICALM as a candidate therapeutic target warranting further experimental validation.
Ischemic stroke (IS) is a major cause of disability and mortality worldwide, and vascular dementia (VaD) is a common dementia subtype associated with cerebrovascular injury. Observational studies have suggested a relationship between IS and VaD, but these studies are vulnerable to confounding and reverse causality. This protocol describes a reproducible two-sample Mendelian randomization (MR) workflow for evaluating the potential causal association between IS and VaD using publicly available genome-wide association study (GWAS) summary statistics. Genetic instruments associated with IS were extracted from a public GWAS dataset, and outcome associations for VaD were obtained from a public VaD GWAS dataset. The corresponding dataset IDs are provided in the Protocol section. After outcome matching and allele harmonization, 51 single-nucleotide polymorphisms (SNPs) were retained for the final MR analysis. The workflow includes instrumental variable selection, linkage disequilibrium clumping, allele harmonization, instrument strength assessment, inverse variance weighted (IVW) analysis, weighted median analysis, MR-Egger analysis, heterogeneity testing, horizontal pleiotropy assessment, and leave-one-out sensitivity analysis. In the representative analysis, the IVW method showed a positive association between genetically predicted IS and VaD risk, and the weighted median method yielded a directionally concordant result. The MR-Egger estimate was directionally consistent but did not reach statistical significance. Therefore, these findings should be interpreted as suggestive evidence of a possible causal effect, rather than definitive proof of causality. This protocol may help researchers apply a transparent and reproducible MR workflow to investigate cerebrovascular disease-related outcomes using public GWAS data.
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Choline acetyltransferase activity (presynaptic cholinergic system) and high affinity binding of cholinergic antagonists (postsynaptic cholinergic system) were measured in brain tissue removed after death from both mentally normal and demented old people. Muscarinic receptor binding sites in frontal cortex decreased with advancing years only in old people without appreciable morphological evidence of senile degeration. Preliminary data for temporal lobe suggested that also in Pick's disease the density of receptor binding sites is reduced. The markers are not significantly reduced in cases of mixed senile and vascular dementia. However, in non-vascular senile dementia of the Alzheimer type, there were indications that the presynaptic marker is selectively depleted. Therefore, centrally acting anticholinesterases might be beneficial, particularly in the early stages of the disease.
BACKGROUND: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis. RESULTS: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings. CONCLUSION: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.
At the Bel-Air Psychiatric Clinic, Geneva, Switzerland, the technique of ultrasonic Doppler flowmetry was used to examine the internal carotid arteries of 30 aged patients - 10 with cerebral degenerative dementia, 10 with cerebrovascular dementia, and 10 without dementia. An index of cerebrovascular resistance was calculated. Apparently this index can distinguish a group of vascular dementias from a group of degenerative dementias.
INTRODUCTION: Type 2 diabetes (T2D) significantly increases dementia risk, yet the molecular mechanisms underlying this association remain unclear. OBJECTIVES: This study aimed to identify protein signatures that distinguish dementia risk in T2D patients, develop a proteomic prediction model, and elucidate biological pathways connecting T2D and dementia. METHODS: We analyzed 2,920 plasma proteins from 52,958 participants (including 3,292 with T2D) in the UK Biobank Pharma Proteomics Project with a median follow-up of 14.6 years. Cox regression models with interaction terms identified T2D-specific protein associations with dementia risk. Machine learning models were developed to predict dementia in T2D patients. Pathway analysis and weighted gene co-expression network analysis identified biological mechanisms linking T2D and dementia. RESULTS: We identified 471 proteins with significant interaction effects between T2D and dementia risk. In non-T2D individuals, elevated levels of neuronal pentraxin receptor (NPTXR, HR = 0.74, 95 %CI:0.66-0.83) and carbonic anhydrase 14 (CA14, HR = 0.67, 95 %CI:0.60-0.75) were exclusively associated with decreased dementia risk. Conversely, in T2D patients, elevated rho guanine nucleotide exchange factor 12 (ARHGEF12, HR = 1.45, 95 %CI:1.10-1.91) was specifically associated with increased dementia risk. A 51-protein model accurately predicted 15-year dementia risk in T2D patients (AUC = 0.835, C-index = 0.829), outperforming conventional clinical risk scores and maintaining high accuracy for Alzheimer's disease and vascular dementia. Pathway analysis revealed enrichment of IL6-JAK-STAT3 signaling in T2D-related dementia, while dysregulation of fatty acid metabolism was specific to T2D-associated Alzheimer's disease. CONCLUSIONS: This large-scale proteomic analysis identifies specific molecular signatures that differentiate dementia risk in diabetic and non-diabetic populations, with potential applications for early risk stratification and targeted interventions. The identified pathways provide novel insights into the pathophysiological processes connecting T2D and dementia and suggest potential therapeutic targets.
Subcortical arteriosclerotic encephalopathy, a chronic vascular dementia with hydrocephalus, was characterized pathologically in five patients by severe thickening of small vessels and by diffuse regions of white matter loss with gliosis. Lacunar infarcts were also present. The clinical picture in 11 patients was characterized by: (1) persistent hypertension and systemic vascular disease; (2) acute strokes; (3) subacute accumulation of focal neurologic symptoms and signs over weeks to months; (4) long plateau periods; (5) lengthy clinical course; (6) dementia; (7) prominent motor signs and pseudobulbar palsy and; (8) hydrocephalus. The pathogenesis of subcortical arteriosclerotic encephalopathy is unknown; possible mechanisms include diffuse ischemia and fluid transudation with subsequent gliosis related to subacute hypertensive encephalopathy.
Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and whole-genome sequencing-based heritability at 46%. Rare coding variant analysis identified HMGCR as a gene in which rare damaging variants confer risk for postpartum psychosis (FDR < 0.05). Analyses of 240,009 participants from the All of Us Research Program and 58,990 participants from the Mount Sinai BioMe Biobank identified significant associations linking deleterious rare variants in HMGCR to vascular dementia and mental disorder, not otherwise specified, supporting the gene's broader psychiatric relevance. Additionally, among the top 200 genes ranked by association statistics, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorders exhibit a possible association with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.
IMPORTANCE: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. OBJECTIVE: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. DESIGN SETTING AND PARTICIPANTS: Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records. EXPOSURES: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). MAIN OUTCOMES AND MEASURES: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. RESULTS: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (β = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls (β = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (β = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. CONCLUSIONS AND RELEVANCE: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.
Fifty-six brains from middle-aged and elderly normal as well as demented subjects and patients with provisional clinical diagnosis of other neurological and psychiatric diseases were assessed histologically. On this basis the specimens were classified into 14 diagnostic groups. A survey of potential indices of specific neurons has been carried out on these brains in which neurotransmitter-related enzymes, gamma-GTP (a potential index of capillaries) and specific proteins have been determined in up to 20 brain regions. In addition, the agonal state has been tentatively assessed by examining the post-mortem states of the circulatory and respiratory systems. CAT and gamma-GTP activities and the concentration of a soluble neuronal-type protein (neuronin S-5) were found to be relatively unaffected by the agonal state. When cases of senile dementia were compared to controls (matched with respect to the cause of death) the activity of CAT (the potential index of cholinergic neurons) appears to be reduced in the cerebral cortex. This is a preliminary finding, although a correlation was indicated between CAT activity and 'senile' morphological changes, the activity was markedly reduced in only 3 brains. However, despite inconsistencies in the literature (Karczmar, 1975) at least one pharmacological study on humans appears to show that the cholinergic system may be involved in age-related memory degeneration (Drachman and Leavitt, 1974). Cholinergic neurons may be abnormal in the other abiotrophies examined (Huntington's chorea, motor neuron disease and mixed vascular and senile dementia). gamma-GTP and neuronin S-5 (identical in most respects to the soluble acidic neuronal protein 14-3-2 of antigen alpha) were not reduced in senile dementia. The activities of brain decarboxylase (GAD and AAD) and the concentration of another soluble acidic brain protein (neuronin S-6) appear to be affected by the agonal state. This is remarkable because GAD and, in particular, neuronin S6, are relatively unaffected by post-mortem autolysis. As judged by the state of the extraneural systems which regulated the blood and oxygen supply to the brain it appears that terminal 'cerebral hypoxia' is responsible for the depletion of these brain constituents. This effect appears to be particularly marked in deep grey matter. In non-demented patients that die of bronchopneumonia, the areas of the cortex which are depleted in neuronin S-6 are consistent with the pattern of the 'selective vulnerability' of the cortex to hypoxia, suggesting that the terminal state can also affect the neocortex. If so, then this is particularly relevant to studies on senile dementia, for the effect of the terminal bronchopneumonia that so often occurs in these patients (and in patients with other abiotrophies) may be exacerbated by a terminal reduction in cerebral blood flow...
More than 1400 necropsies performed on patients with either a nontraumatic cerebral hemorrhage (400 cases) or with dementia over the age of 55 (1010 cases), or both, have been reviewed. There were 15 cases in which a cerebral hemorrhage had occurred together with cerebral amyloid angiopathy all of whom had been demented. Eight of the 15 patients were hypertensive. The 7 non-hypertensives showing only the amyloid change included two cases of "atypical" Alzheimer's disease with acute neurological features, and 5 cases of senile dementia (aged 72 to 78 years) coupled with focal neurological disorders. In the hypertensive patients, aged 67 to 86 years, with a progressive dementing syndrome and acute neurological signs, multiple ball-like hemorrhages (7 cases) and/or cerebral hematomas (3 cases) were associated with a combination of amyloid and hyalinar (hypertensive) angiopathy, often affecting segments of the same pial and cortical vessels. From these data and recent reports on lethal cerebral hemorrhage occurring spontaneously or after neurosurgical procedures in demented old people, cerebral amyloid angiopathy, which is not necessarily associated with systemic amyloidosis or severe (pre)senile cerebral degeneration, may be considered a rare but important cause of cerebral hemorrhage in the aged. The "vascular" type of presenile dementia, occasionally complicated by focal cerebrovascular lesions or bleeds, is considered a variant of Alzheimer's disease. The mechanism leading to formation of cerebral amyloid is unknown.
Fifty-two patients presenting with dementia were divided into a group in whom clinical features suggested an ischaemic basis (multi-infarct dementia) and a group in whom a primary degenerative process seemed more likely. Focal EEG changes and angiographic evidence of ischeamic areas and atheromatous disease of intracranial vessels were more common in the "ischaemic" than in the primary degenerative group. CBF was significantly reduced in the former but the regional pattern was equally distorted in the two groups. These findings strengthen the belief that the ischaemic score can identify those patients whose dementia is associated with vascular disease.
In a study of senile degenerative lesions-including Alzheimer's neurofibrillary changes, senile plaques and amyloid angiopathy-the hippocampal area of the brain was examined by thioflavine T fluorescence microscopy in 146 consecutive autopsy patients over the age of 49. The incidence and quantity of neurofibrillary changes and senile plaques rose with age, and an approximate positive correlation in quantity was noted among the three kinds of degenerative change. The quantity of neurofibrillary lesions and senile plaques was significantly different between the demented and non-demented patients, but not between the severely and less severly demented patients. The cause of dementia was studied retrospectively, based on the extent of morphologic changes in the brain, thus classifying dementia into three types: degenerative, vascular, and mixed. Clinically, the mixed type resembled the vascular type with regard to major neurologic signs, and there was some similarity to the degenerative type with regard to mental features.
BACKGROUND: Dementia after the age of 80 years (late-life) is increasingly common due to vascular and non-vascular risk factors. Identifying individuals at higher risk of late-life dementia remains a global priority. METHODS: In prospective study of 958 ambulant community-dwelling older women (≥70 years), lateral spine images (LSI) captured in 1998 (baseline) from a bone density machine were used to assess abdominal aortic calcification (AAC). AAC was classified into established categories (low, moderate and extensive). Cardiovascular risk factors and apolipoprotein E (APOE) genotyping were evaluated. Incident 14.5-year late-life dementia was identified from linked hospital and mortality records. FINDINGS: At baseline women were 75.0 ± 2.6 years, 44.7% had low AAC, 36.4% had moderate AAC and 18.9% had extensive AAC. Over 14.5- years, 150 (15.7%) women had a late-life dementia hospitalisation (n = 132) and/or death (n = 58). Compared to those with low AAC, women with moderate and extensive AAC were more likely to suffer late-life dementia hospitalisations (9.3%, 15.5%, 18.3%, respectively) and deaths (2.8%, 8.3%, 9.4%, respectively). After adjustment for cardiovascular risk factors and APOE, women with moderate and extensive AAC had twice the relative hazards of late-life dementia (moderate, aHR 2.03 95%CI 1.38-2.97; extensive, aHR 2.10 95%CI 1.33-3.32), compared to women with low AAC. INTERPRETATION: In community-dwelling older women, those with more advanced AAC had higher risk of late-life dementia, independent of cardiovascular risk factors and APOE genotype. Given the widespread use of bone density testing, simultaneously capturing AAC information may be a novel, non-invasive, scalable approach to identify older women at risk of late-life dementia. FUNDING: Kidney Health Australia, Healthway Health Promotion Foundation of Western Australia, Sir Charles Gairdner Hospital Research Advisory Committee Grant, National Health and Medical Research Council of Australia.
The palmo-mental reflex has been described, together with other neurological signs, in senile dementia. It is, however, found in normal adults, where its frequency increases with age. In vascular hemiplegia it has a considerably higher incidence, nevertheless it is not a sign of mental deterioration.
In"cerebral arteriosclerosis" the diffuse sclerotic involvement of the cerebral vessels may produce acute softening of cerebral tissue. However this paper concentrates mainly on the clinical symptomatology which, in the absence of major vascular accidents, is characterized from the psychopathologic viewpoint by acute confusional states, aggressive behaviour, fluctuating loss of memory, disturbances of concentration and finally dementia. The chief neurologic symptoms are motor disturbance with short-stepping gait, stooped position of the body, pseudobulbar symptoms with dysarthric speech and disturbances of swallowing, and increased perioral reflexes. A complete case history and a thorough neurologic and psychopathologic examination are the most important factors in diagnosis, while ancillary methods are of value only for differential diagnosis. Prophylaxis and therapy (cardiotherapy, treatment of diabetes and hypertension, lowering of serum cholesterol and sedation) are discussed. In the differential diagnosis of dementia in the elderly patient consideration should be given to chronic vascular diseases, degenerative cerebral atrophies, brain tumors, low pressure hydrocephalus, progressive paralysis and some other rare brain conditions.