RESUMEN
Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased ß-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/metabolismo , Barrera Hematoencefálica/metabolismo , Células Endoteliales/metabolismo , Angiogénesis , Encéfalo/metabolismo , Péptidos beta-Amiloides/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Breakdown of the neurovascular unit is associated with blood-brain barrier (BBB) leakiness contributing to cognitive decline and disease pathology in the early stages of Alzheimer's disease (AD). Vascular stability depends on angiopoietin-1 (ANGPT-1) signalling, antagonised by angiopoietin-2 (ANGPT-2) expressed upon endothelial injury. We examined the relationship between CSF ANGPT-2 and CSF markers of BBB leakiness and core AD biomarkers across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aß42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 20 participants with mild cognitive impairment (MCI), and 17 with AD); (iii) a neurologically normal cohort aged 23-78 years with paired CSF and serum samples. CSF ANGPT-2, sPDGFRß, albumin and fibrinogen levels were measured by sandwich ELISA. In cohort (i), CSF ANGPT-2 was elevated in AD and correlated with CSF t-tau and p-tau181 but not Aß42. ANGPT-2 also correlated positively with CSF sPDGFRß and fibrinogen - markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT-2 was highest in MCI and correlated with CSF albumin in the CU and MCI cohorts but not in AD. CSF ANGPT-2 also correlated with CSF t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT-2 correlated strongly with the CSF/serum albumin ratio. Serum ANGPT-2 showed non-significant positive associations with CSF ANGPT-2 and the CSF/serum albumin ratio. Together, these data indicate that CSF and possibly serum ANGPT-2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT-2 as a biomarker of BBB damage in AD requires further study.
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Enfermedad de Alzheimer , Angiopoyetina 2 , Barrera Hematoencefálica , Humanos , Angiopoyetina 2/líquido cefalorraquídeo , Biomarcadores , Fibrinógeno , Albúmina SéricaRESUMEN
BACKGROUND: Depression and dementia are both common diseases. Although new cases of depression are more common in younger adults, there is a second peak at the age of 50 years suggesting a different pathological process. Late-life depression (LLD) is associated with dementia. However, it remains unclear whether depression represents a dementia prodrome or is a true risk factor for its development. LLD is thought to have a vascular component and this may be a possible link between depression and dementia. We hypothesised that later-life depression is a prodromal manifestation of dementia and would therefore be associated with more AD, and/or ischaemic brain abnormalities that are present in earlier-life depression or in age- and sex-matched controls. METHODS: We assessed post-mortem orbitofrontal cortex and dorsolateral pre-frontal cortex from 145 individuals in 4 groups: 28 18-50-year-olds with depression, 30 older individuals (ages 51-90) with depression, 28 with early AD (Braak tangle stages III-IV) and 57 matched controls (17 early-life, 42 later-life). Levels of Aß, phospho-tau and α-synuclein were assessed by immunohistochemistry and ELISA. To quantify chronic ischaemia, VEGF, MAG and PLP1 were measured by ELISA. To assess pericyte damage, PDGFRB was measured by ELISA. For blood-brain barrier leakiness, JAM-A, claudin 5 and fibrinogen were measured by ELISA. To quantity endothelial activation, the ratio of ICAM1:collagen IV was assessed by immunohistochemistry. RESULTS: There was no evidence of chronic cerebral hypoperfusion or increased Aß/tau in either depression group. There was also no indication of pericyte damage, increased blood-brain barrier leakiness or endothelial activation in the OFC or DLPFC in the depression groups. CONCLUSIONS: Contrary to some previous findings, we have not found evidence of impaired vascular function or increased Aß in LLD. Our study had a relatively small sample size and limitations in the availability of clinical data. These results suggest that depression is a risk factor for dementia rather than an early manifestation of AD or a consequence of cerebral vascular insufficiency.
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Enfermedad de Alzheimer , Adulto , Humanos , Persona de Mediana Edad , Síntomas Prodrómicos , Depresión , Encéfalo , Barrera HematoencefálicaRESUMEN
Breakdown of the neurovascular unit in early Alzheimer's disease (AD) leads to leakiness of the blood-brain barrier (BBB), contributing to cognitive decline and disease pathology. Vascular stability depends on angiopoietin-1 (ANGPT1) signalling, antagonised by angiopoietin-2 (ANGPT2) upon endothelial injury. We have examined the relationship between CSF ANGPT2 and CSF markers of BBB leakiness and disease pathology, across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aß42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 19 participants with mild cognitive impairment (MCI), and 21 with AD); (iii) a neurologically normal cohort aged 23-78 years with paired CSF and serum samples. CSF ANGPT2 level was measured by sandwich ELISA. In cohort (i), CSF ANGPT2 was elevated in AD, correlating with CSF t-tau and p-tau181 but not Aß42. ANGPT2 also correlated positively with CSF sPDGFRß and fibrinogen - markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT2 was highest in MCI. CSF ANGT2 correlated with CSF albumin in the CU and MCI cohorts but not in AD. ANGPT2 also correlated with t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT2 correlated strongly with the CSF:serum albumin ratio. Increased CSF ANGPT2 and the CSF:serum albumin ratio showed non-significant associations with elevated serum ANGPT2 in this small cohort. Together, these data indicate that CSF ANGPT2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT2 as a biomarker of BBB damage in AD requires further study.
RESUMEN
Hypertension in midlife contributes to cognitive decline and is a modifiable risk factor for dementia. The relationship between late-life hypertension and dementia is less clear. We have investigated the relationship of blood pressure and hypertensive status during late life (after 65 years) to post-mortem markers of Alzheimer's disease (amyloid-ß and tau loads); arteriolosclerosis and cerebral amyloid angiopathy; and to biochemical measures of ante-mortem cerebral oxygenation (the myelin-associated glycoprotein:proteolipid protein-1 ratio, which is reduced in chronically hypoperfused brain tissue, and the level of vascular endothelial growth factor-A, which is upregulated by tissue hypoxia); blood-brain barrier damage (indicated by an increase in parenchymal fibrinogen); and pericyte content (platelet-derived growth factor receptor ß, which declines with pericyte loss), in Alzheimer's disease (n = 75), vascular (n = 20) and mixed dementia (n = 31) cohorts. Systolic and diastolic blood pressure measurements were obtained retrospectively from clinical records. Non-amyloid small vessel disease and cerebral amyloid angiopathy were scored semiquantitatively. Amyloid-ß and tau loads were assessed by field fraction measurement in immunolabelled sections of frontal and parietal lobes. Homogenates of frozen tissue from the contralateral frontal and parietal lobes (cortex and white matter) were used to measure markers of vascular function by enzyme-linked immunosorbent assay. Diastolic (but not systolic) blood pressure was associated with the preservation of cerebral oxygenation, correlating positively with the ratio of myelin-associated glycoprotein to proteolipid protein-1 and negatively with vascular endothelial growth factor-A in both the frontal and parietal cortices. Diastolic blood pressure correlated negatively with parenchymal amyloid-ß in the parietal cortex. In dementia cases, elevated late-life diastolic blood pressure was associated with more severe arteriolosclerosis and cerebral amyloid angiopathy, and diastolic blood pressure correlated positively with parenchymal fibrinogen, indicating blood-brain barrier breakdown in both regions of the cortex. Systolic blood pressure was related to lower platelet-derived growth factor receptor ß in controls in the frontal cortex and in dementia cases in the superficial white matter. We found no association between blood pressure and tau. Our findings demonstrate a complex relationship between late-life blood pressure, disease pathology and vascular function in dementia. We suggest that hypertension helps to reduce cerebral ischaemia (and may slow amyloid-ß accumulation) in the face of increasing cerebral vascular resistance, but exacerbates vascular pathology.
RESUMEN
Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN-/SOX10- (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in 'bulk' cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Enfermedad de Alzheimer/metabolismo , Metilación de ADN/genética , Epigénesis Genética , Humanos , Enfermedades Neurodegenerativas/genética , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/metabolismoRESUMEN
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.
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Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Epigenoma , Lóbulo Frontal/patología , Humanos , Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/genética , Metilación , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Cerebrovascular disease underpins vascular dementia (VaD), but structural and functional changes to the cerebral vasculature contribute to disease pathology and cognitive decline in Alzheimer's disease (AD). In this review, we discuss the contribution of cerebral amyloid angiopathy and non-amyloid small vessel disease in AD, and the accompanying changes to the density, maintenance and remodelling of vessels (including alterations to the composition and function of the cerebrovascular basement membrane). We consider how abnormalities of the constituent cells of the neurovascular unit - particularly of endothelial cells and pericytes - and impairment of the blood-brain barrier (BBB) impact on the pathogenesis of AD. We also discuss how changes to the cerebral vasculature are likely to impair Aß clearance - both intra-periarteriolar drainage (IPAD) and transport of Aß peptides across the BBB, and how impaired neurovascular coupling and reduced blood flow in relation to metabolic demand increase amyloidogenic processing of APP and the production of Aß. We review the vasoactive properties of Aß peptides themselves, and the probable bi-directional relationship between vascular dysfunction and Aß accumulation in AD. Lastly, we discuss recent methodological advances in transcriptomics and imaging that have provided novel insights into vascular changes in AD, and recent advances in assessment of the retina that allow in vivo detection of vascular changes in the early stages of AD.
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Enfermedad de Alzheimer , Angiopatía Amiloide Cerebral , Humanos , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Células Endoteliales/patología , Angiopatía Amiloide Cerebral/patología , Barrera Hematoencefálica/patología , Encéfalo/patologíaRESUMEN
BACKGROUND: Apolipoprotein 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. METHODS: This 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 Aß 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. RESULTS: Seven 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 (ß 2.53, p=0.034). APOE-ε4 heterozygosity was similarly associated in individuals without dementia (ß 1.21, p=0.048). CONCLUSION: These 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.
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Enfermedad de Alzheimer , Trastornos del Sueño-Vigilia , Sueño , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Apolipoproteínas E , Humanos , Estudios Retrospectivos , Trastornos del Sueño-Vigilia/complicaciones , Trastornos del Sueño-Vigilia/genéticaRESUMEN
BACKGROUND: After aneurysmal subarachnoid hemorrhage (SAH), thrombus forms over the cerebral cortex and releases hemoglobin. When extracellular, hemoglobin is toxic to neurones. High local hemoglobin concentration overwhelms the clearance capacity of macrophages expressing the hemoglobin-haptoglobin scavenger receptor CD163. We hypothesized that iron is deposited in the cortex after SAH and would associate with outcome. METHODS: Two complementary cross-sectional studies were conducted. Postmortem brain tissue from 39 SAH (mean postictal interval of 9 days) and 22 control cases was studied with Perls' staining for iron and immunolabeling for CD163, ADAM17 (a disintegrin and metallopeptidase domain 17), CD68, and Iba1 (ionized calcium binding adaptor molecule 1). In parallel, to study the persistence of cortical iron and its relationship to clinical outcome, we conducted a susceptibility-weighted imaging study of 21 SAH patients 6 months postictus and 10 control individuals. RESULTS: In brain tissue from patients dying soon after SAH, the distribution of iron deposition followed a gradient that diminished with distance from the brain surface. Iron was located intracellularly (mainly in macrophages, and occasionally in microglia, neurones, and glial cells) and extracellularly. Microglial activation and motility markers were increased after SAH, with a similar inward diminishing gradient. In controls, there was a positive correlation between CD163 and iron, which was lost after SAH. In SAH survivors, iron-sensitive imaging 6 months post-SAH confirmed persistence of cortical iron, related to the size and location of the blood clot immediately after SAH, and associated with cognitive outcome. CONCLUSIONS: After SAH, iron deposits in the cortical gray matter in a pattern that reflects proximity to the brain surface and thrombus and is related to cognitive outcome. These observations support therapeutic manoeuvres which prevent the permeation of hemoglobin into the cortex after SAH.
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Hemorragia Subaracnoidea , Trombosis , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios Transversales , Hemoglobinas/metabolismo , Humanos , Hierro/metabolismo , Hemorragia Subaracnoidea/complicaciones , Trombosis/complicacionesRESUMEN
OBJECTIVE: Up to one-third of patients with Parkinson's disease (PD) experience visual hallucinations (VHs). Lewy bodies are sparse in the visual cortices and seem unlikely to explain the hallucinations. Some neuroimaging studies have found that perfusion is reduced in the occipital lobe in individuals with VHs. Recent work has suggested that decreased cholinergic input may directly lead to the decreased perfusion. The investigators hypothesized that individuals with PD and VHs would have biochemical evidence of reduced microvascular perfusion and reduced cholinergic activity in areas of the brain that process visual images. METHODS: Tissue from Brodmann's area (BA) 18 and BA 19 was obtained from a well-characterized cohort matched for age, gender, and postmortem interval in 69 individuals (PD without VHs, N=11; PD without dementia plus VHs N=10, N=10; PD with dementia plus VHs, N=16; and control subjects, N=32). Von Willebrand factor, vascular endothelial growth factor A, and myelin-associated glycoprotein:proteolipid protein-1 (MAG:PLP1) ratio-a measure of tissue oxygenation relative to metabolic demand, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), choline acetyltransferase, and α-synuclein-were quantified by enzyme-linked immunosorbent assay. The primary outcome was the MAG:PLP1 ratio. RESULTS: There was no biochemical evidence of chronic hypoperfusion in PD, although microvessel density was decreased in ventral BA 18 and BA 19. There was no between-group difference in BChE in either dorsal BA 18 or BA 19. AChE concentration was reduced in individuals with PD compared with control subjects in dorsal and ventral BA 18 and dorsal BA 19, and it was increased in ventral BA 19. These changes were most marked in the PD plus VHs group. CONCLUSIONS: These results suggest that changes in cholinergic activity rather than chronic hypoperfusion may underlie VHs in PD.
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Demencia , Enfermedad de Parkinson , Corteza Visual , Acetilcolinesterasa/metabolismo , Butirilcolinesterasa/metabolismo , Colinérgicos/metabolismo , Alucinaciones/etiología , Alucinaciones/metabolismo , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Corteza Visual/diagnóstico por imagen , Corteza Visual/metabolismoRESUMEN
Pericytes are vascular mural cells that contract and relax in response to vasoactive stimuli to regulate neurovascular coupling and cerebral blood flow. Pericytes are damaged and degenerate in Alzheimer's disease (AD). We previously showed that the level of the regulatory vasoconstrictor, endothelin-1 (EDN1), is elevated in AD cerebral cortex and upregulated by amyloid-beta (Aß). We have used electrical impedance analysis to monitor the contractile and proliferative response of cultured human fetal and adult brain-derived pericytes to EDN1 in real-time. EDN1 caused transient, dose-dependent contraction of fetal and adult brain pericytes that was mediated by EDN1 type A receptors and increased the subsequent proliferation of fetal but not adult cells. The contractile responses to EDN1 were weaker in the adult pericytes. The EDN1-mediated contractile response of fetal pericytes was unchanged after exposure to Aß1 - 40 or Aß1 - 42 (0.1-10 µM) for 1 h but both contraction and subsequent relaxation were significantly impaired upon exposure to Aß for 24 h. These data suggest that chronic exposure to Aß interferes with EDN1-mediated pericyte contractility, potentially contributing to neurovascular uncoupling and reduced cerebral blood flow in AD.
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Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).
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Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Metilación de ADN , Corteza Entorrinal/metabolismo , Epigenoma , Corteza Prefrontal/metabolismo , Lóbulo Temporal/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Estudios de Cohortes , Islas de CpG , Corteza Entorrinal/patología , Epigénesis Genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal/patología , Curva ROC , Lóbulo Temporal/patologíaRESUMEN
We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer's disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer's disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer's disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer's disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease. Several cytokines (IL-1ß, IL-6, TNF-α, IL-8 and IL-15) were further raised in Alzheimer's disease with systemic infection. Cerebral hypoperfusion-indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)-and blood-brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer's disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-ß42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of Alzheimer's disease, and with infection (even in Braak stage 0-II brains). Cortical platelet-derived growth factor receptor-ß (PDGFRß), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer's disease; these were related to amyloid-ß level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood-brain barrier leakiness associated with Alzheimer's disease and vascular dementia, independently of the level of insoluble amyloid-ß, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.
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Enfermedad de Alzheimer/complicaciones , Encéfalo/irrigación sanguínea , Encéfalo/inmunología , Sepsis/complicaciones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Barrera Hematoencefálica/patología , Encéfalo/patología , Circulación Cerebrovascular , Citocinas/inmunología , Demencia Vascular/complicaciones , Femenino , Humanos , Masculino , Sepsis/inmunologíaRESUMEN
INTRODUCTION: The aged brain frequently exhibits multiple pathologies, rather than a single hallmark pathology (pure pathology [PurP]), ranging from low/intermediate levels of additional pathology (LowP) to mixed severe pathology (mixed SevP). We investigated the frequency of PurP, LowP, and mixed SevP, and the impact of additional LowP on cognition. METHODS: Data came from 670 cases from the Brains for Dementia research program. Cases were categorized into PurP, mixed SevP, or a main disease with additional LowP; 508 cases had a clinical dementia rating. RESULTS: 69.9% of cases had LowP, 22.7% had PurP, and 7.5% had mixed SevP. Additional LowP increased the likelihood of having mild dementia versus mild cognitive impairment (MCI) by almost 20-fold (odds ratio = 19.5). DISCUSSION: Most aged individuals have multiple brain pathologies. The presence of one additional LowP can significantly worsen cognitive decline, increasing the risk of transitioning from MCI to dementia 20-fold. Multimorbidity should be considered in dementia research and clinical studies.
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Autopsia , Encéfalo/patología , Disfunción Cognitiva/patología , Demencia/patología , Multimorbilidad , Anciano de 80 o más Años , Péptidos beta-Amiloides , Femenino , Humanos , Masculino , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Tauopatías/patologíaRESUMEN
In vascular dementia (VaD) and Alzheimer's disease (AD), cerebral hypoperfusion and blood-brain barrier (BBB) leakiness contribute to brain damage. In this study, we have measured biochemical markers and mediators of cerebral hypoperfusion and BBB in the frontal (BA6) and parietal (BA7) cortex and underlying white matter, to investigate the pathophysiology of vascular dysfunction in AD, VaD and mixed dementia. The ratio of myelin-associated glycoprotein to proteolipid protein-1 (MAG:PLP1), a post-mortem biochemical indicator of the adequacy of ante-mortem cerebral perfusion; the concentration of fibrinogen adjusted for haemoglobin level, a marker of blood-brain barrier (BBB) leakiness; the level of vascular endothelial growth factor-A (VEGF), a marker of tissue hypoxia; and endothelin-1 (EDN1), a potent vasoconstrictor, were measured by ELISA in the frontal and parietal cortex and underlying white matter in 94 AD, 20 VaD, 33 mixed dementia cases and 58 age-matched controls. All cases were assessed neuropathologically for small vessel disease (SVD), cerebral amyloid angiopathy (CAA) severity, Aß and phospho-tau parenchymal load, and Braak tangle stage. Aß40 and Aß42 were measured by ELISA in guanidine-HCl tissue extracts. We found biochemical evidence of cerebral hypoperfusion in AD, VaD and mixed dementia to be associated with SVD, Aß level, plaque load, EDN1 level and Braak tangle stage, and to be most widespread in mixed dementia. There was evidence of BBB leakiness in AD-limited to the cerebral cortex and related to EDN1 level. In conclusion, abnormalities of cerebral perfusion and BBB function in common types of dementia can largely be explained by a combination of arteriolosclerosis, and Aß-, tau- and endothelin-related vascular dysfunction. The relative contributions of these processes vary considerably both between and within the diseases.
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Barrera Hematoencefálica/patología , Angiopatía Amiloide Cerebral/patología , Trastornos Cerebrovasculares/patología , Demencia Vascular/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Angiopatía Amiloide Cerebral/complicaciones , Trastornos Cerebrovasculares/complicaciones , Femenino , Humanos , Masculino , Placa Amiloide/complicaciones , Placa Amiloide/patologíaRESUMEN
Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.