Neurofibrillary Pathology Research Articles

Anatomic survey of seeding in Alzheimer’s disease brains reveals unexpected patterns

Tauopathies are heterogeneous neurodegenerative diseases defined by progressive brain accumulation of tau aggregates. The most common tauopathy, sporadic Alzheimer’s disease (AD), involves progressive tau deposition that can be divided into specific stages of neurofibrillary tangle pathology. This classification is consistent with experimental data which suggests that network-based propagation is mediated by cell–cell transfer of tau “seeds”, or assemblies, that serve as templates for their own replication. Until now, seeding assays of AD brain have largely been limited to areas previously defined by NFT pathology. We now expand this work to additional regions. We selected 20 individuals with AD pathology of NFT stages I, III, and V. We stained and classified 25 brain regions in each using the anti-phospho-tau monoclonal antibody AT8. We measured tau seeding in each of the 500 samples using a cell-based tau “biosensor” assay in which induction of intracellular tau aggregation is mediated by exogenous tau assemblies. We observed a progressive increase in tau seeding according to NFT stage. Seeding frequently preceded NFT pathology, e.g., in the basolateral subnucleus of the amygdala and the substantia nigra, pars compacta. We observed seeding in brain regions not previously known to develop tau pathology, e.g., the globus pallidus and internal capsule, where AT8 staining revealed mainly axonal accumulation of tau. AT8 staining in brain regions identified because of tau seeding also revealed pathology in a previously undescribed cell type: Bergmann glia of the cerebellar cortex. We also detected tau seeding in brain regions not previously examined, e.g., the intermediate reticular zone, dorsal raphe nucleus, amygdala, basal nucleus of Meynert, and olfactory bulb. In conclusion, tau histopathology and seeding are complementary analytical tools. Tau seeding assays reveal pathology in the absence of AT8 signal in some instances, and previously unrecognized sites of tau deposition. The variation in sites of seeding between individuals could underlie differences in the clinical presentation and course of AD.

Tau pathology mediates age effects on medial temporal lobe structure

Hippocampal atrophy is endemic in ‘normal aging’ but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n = 191) and longitudinal (n = 164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral β-amyloid and assessed whether white matter hyperintensities (WMHs) and cerebrospinal fluid (CSF) phospho tau (p-tau) levels can explain age-related changes in the MTL. Age was significantly associated with hippocampal volumes and Brodmann Area (BA) 35 thickness, regions affected early by neurofibrillary tangle pathology, in the cross-sectional analysis and with anterior and/or posterior hippocampus, entorhinal cortex and BA35 in the longitudinal analysis. CSF p-tau was significantly associated with hippocampal volumes and atrophy rates. Mediation analyses showed that CSF p-tau levels partially mediated age effects on hippocampal atrophy rates. No significant associations were observed for WMHs. These findings point toward a role of tau pathology, potentially reflecting Primary Age-Related Tauopathy, in age-related MTL structural changes and suggests a potential role for tau-targeted interventions in age-associated neurodegeneration and memory decline.

Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

Sensitive Measures of Cognition in Mild Cognitive Impairment.

Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer's disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention.

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Cellular investigations to uncover curative potentials of polyphenols- An in vitro study of Apple Cider Vinegar (ACV) and Chrysin against Alzheimer's like pathology via down-regulation of AChE activity

Amyloid aggregation and neurofibrillary pathology is the characteristic feature of Alzheimer's disease (AD). Streptozotocin (STZ) is a glucosamine nitrosourea compound that is toxic to the cells, impairs insulin signaling in the brain. STZ induces DNA damage and oxidative stress, which leads to cognitive impairments. In this experimental study, STZ treatment induces Alzheimer's pathology in mouse neuroblastoma (N2A) cells. The study also explored the protection of cellular damage by pre-treatment with test drugs Apple cider vinegar (ACV), chrysin and rivastigmine. This study had been concentrated mainly on the cellular mechanism of neuromodulation and anti –oxidant potency of test drugs to attenuate cellular toxicity induced by STZ treatment. The 100 μM concentration of STZ was used for treatment in N2A cells for 24 h and 48 h and multiple studies were performed. The STZ causes tau phosphorylation, amyloid aggregation and increased acetyl cholinesterase (AChE) activity. Along with STZ at a concentration of 100 μM, the cells were pre-treated with ACV, chrysin and rivastigmine at a concentration of 2, 10, 50 μM each. The results show that 2 μM test drug concentration presented considerable protection, against STZ generated neurocytotoxicity via. restoration of anti-oxidant enzymes, MDA and AChE level, compared to the other two concentrations.

Visit-to-Visit Blood Pressure Variability, Neuropathology, and Cognitive Decline.

Large systolic blood pressure (SBP) variability has been proposed as a novel risk factor for dementia above and beyond SBP levels, but the underlying neuropathology is largely unknown. We investigated the relationship among visit-to-visit SBP variability, cognitive deterioration, and underlying neuropathologic changes. We used longitudinal data (between 2005 and 2019) from the National Alzheimer's Coordinating Center. A total of 13,284 dementia-free participants ≥50 years of age were followed up over a median of 5.0 (interquartile range 3.1-7.6) years. Neuropathology data were available in 1,400 autopsied participants. Visit-to-visit SBP variability was quantified from repeated annual SBP measurements. Cognitive deterioration was defined as conversion from normal cognition to mild cognitive impairment (MCI) or dementia or from MCI to dementia. Larger visit-to-visit SBP variability was associated with cognitive deterioration (adjusted odds ratio comparing extreme quintiles 2.64, 95% confidence interval 2.29-3.04, p < 0.001). It was also associated with a higher burden of vascular pathology (including microinfarcts, white matter lesions, atherosclerosis of the circle of Willis, and arteriolosclerosis) and with neurofibrillary tangle pathology assessed by Braak staging (all p < 0.05). The association with cognitive deterioration and vascular pathology appeared stronger among those with normal cognition vs those with MCI at baseline. These findings were observed after adjustment for age, sex, mean SBP, and other confounding variables. Similar results were observed for diastolic blood pressure variability. Larger visit-to-visit SBP variability was associated with cognitive deterioration. It was also associated with cerebrovascular pathology and neurofibrillary tangles. These results suggest the intertwined role of vascular and Alzheimer disease pathology in the etiology of dementia.

MECP2 Increases the Pro-Inflammatory Response of Microglial Cells and Phosphorylation at Serine 423 Regulates Neuronal Gene Expression upon Neuroinflammation.

Methyl-CpG-binding protein 2 (MECP2) is a critical transcriptional regulator for synaptic function. Dysfunction of synapses, as well as microglia-mediated neuroinflammation, represent the earliest pathological events in Alzheimer’s disease (AD). Here, expression, protein levels, and activity-related phosphorylation changes of MECP2 were analyzed in post-mortem human temporal cortex. The effects of wild type and phosphorylation-deficient MECP2 variants at serine 423 (S423) or S80 on microglial and neuronal function were assessed utilizing BV2 microglial monocultures and co-cultures with mouse cortical neurons under inflammatory stress conditions. MECP2 phosphorylation at the functionally relevant S423 site nominally decreased in the early stages of AD-related neurofibrillary pathology in the human temporal cortex. Overexpression of wild type MECP2 enhanced the pro-inflammatory response in BV2 cells upon treatment with lipopolysaccharide (LPS) and interferon-γ (IFNγ) and decreased BV2 cell phagocytic activity. The expression of the phosphorylation-deficient MECP2-S423A variant, but not S80A, further increased the pro-inflammatory response of BV2 cells. In neurons co-cultured with BV2 cells, the MECP2-S423A variant increased the expression of several genes, which are important for the maintenance and protection of neurons and synapses upon inflammatory stress. Collectively, functional analyses in different cellular models suggest that MECP2 may influence the inflammatory response in microglia independently of S423 and S80 phosphorylation, while the S423 phosphorylation might play a role in the activation of neuronal gene expression, which conveys neuroprotection under neuroinflammation-related stress.

Candidate Alzheimer's Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression.

MicroRNAs have been demonstrated as key regulators of gene expression in the etiology of a range of diseases including Alzheimer’s disease (AD). Recently, we identified miR-483-5p as the most upregulated miRNA amongst a panel of miRNAs in blood plasma specific to prodromal, early-stage Alzheimer’s disease patients. Here, we investigated the functional role of miR-483-5p in AD pathology. Using TargetScan and miRTarBase, we identified the microtubule-associated protein MAPT, often referred to as TAU, and the extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), known to phosphorylate TAU, as predicted direct targets of miR-483-5p. Employing several functional assays, we found that miR-483-5p regulates ERK1 and ERK2 at both mRNA and protein levels, resulting in lower levels of phosphorylated forms of both kinases. Moreover, miR-483-5p-mediated repression of ERK1/2 resulted in reduced phosphorylation of TAU protein at epitopes associated with TAU neurofibrillary pathology in AD. These results indicate that upregulation of miR-483-5p can decrease phosphorylation of TAU via ERK pathway, representing a compensatory neuroprotective mechanism in AD pathology. This miR-483-5p/ERK1/TAU axis thus represents a novel target for intervention in AD.

Utility of animal models of Alzheimer's disease in food bioactive research

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by globally impaired cognition. AD research in animals has shown a substantial deficit in translational relevance. The most extensively used transgenic mouse models overexpress human genes associated with rare familial early-onset AD, which results in the formation of amyloid plaques. However, the most common form of AD (late-onset sporadic AD) is a multifactorial disorder involving different cytotoxic factors, including neurofibrillary pathology. Transgenic mice studies have been valuable in elucidating pathogenetic mechanisms that may be relevant to human AD. However, their utility in the development of novel treatment strategies and as preclinical testbeds of new drugs has been unsatisfactory. Animal models have so far failed to demonstrate predictive value in regard to novel therapies of AD, including the use of bioactive food components. While many therapeutic approaches assessed in animals have shown promising results, attempts to translate these findings to people with AD have been disappointing. Food scientists should be aware that the available animal models appear to be unable to predict clinical success in humans. Therefore, food bioactive research should focus on human-centric preventive approaches to AD in clinically meaningful settings rather than on highly questionable preclinical research in animals.

Brain DNA Methylation Patterns in CLDN5 Associated With Cognitive Decline

BackgroundCognitive trajectory varies widely and can distinguish people who develop dementia from people who remain cognitively normal. Variation in cognitive trajectory is only partially explained by traditional neuropathologies. We sought to identify novel genes associated with cognitive trajectory using DNA methylation profiles from human postmortem brain. MethodsWe performed a brain epigenome-wide association study of cognitive trajectory in 636 participants from the ROS (Religious Orders Study) and MAP (Rush Memory and Aging Project) using DNA methylation profiles of the dorsolateral prefrontal cortex. To maximize our power to detect epigenetic associations, we used the recently developed Gene Association with Multiple Traits test to analyze the 5 measured cognitive domains simultaneously. ResultsWe found an epigenome-wide association for differential methylation of sites in the CLDN5 locus and cognitive trajectory (p = 9.96 × 10−7) that was robust to adjustment for cell type proportions (p = 8.52 × 10−7). This association was primarily driven by association with declines in episodic (p = 4.65 × 10−6) and working (p = 2.54 × 10−7) memory. This association between methylation in CLDN5 and cognitive decline was significant even in participants with no or little signs of amyloid-β and neurofibrillary tangle pathology. ConclusionsDifferential methylation of CLDN5, a gene that encodes an important protein of the blood-brain barrier, is associated with cognitive trajectory beyond traditional Alzheimer’s disease pathologies. The association between CLDN5 methylation and cognitive trajectory in people with low pathology suggests an early role for CLDN5 and blood-brain barrier dysfunction in cognitive decline and Alzheimer’s disease.

Three-dimensional analysis of synaptic organization in the hippocampal CA1field in Alzheimer's disease.

Alzheimer’s disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer’s disease is typically associated with extracellular deposits of amyloid-β peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-β and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer’s disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer’s disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer’s disease cases with different stages of the disease, using focused ion beam/scanning electron microscopy (FIB/SEM). In cases with early stages of Alzheimer’s disease, the synapse morphology looks normal and we observed no significant differences between control and Alzheimer’s disease cases regarding the synaptic density, the ratio of excitatory and inhibitory synapses, or the spatial distribution of synapses. However, differences in the distribution of postsynaptic targets and synaptic shapes were found. Furthermore, a lower proportion of larger excitatory synapses in both strata were found in Alzheimer’s disease cases. Individuals in late stages of the disease suffered the most severe synaptic alterations, including a decrease in synaptic density and morphological alterations of the remaining synapses. Since Alzheimer’s disease cases show cortical atrophy, our data indicate a reduction in the total number (but not the density) of synapses at early stages of the disease, with this reduction being much more accentuated in subjects with late stages of Alzheimer’s disease. The observed synaptic alterations may represent a structural basis for the progressive learning and memory dysfunctions seen in Alzheimer’s disease cases.

Molecular characterization of selectively vulnerable neurons in Alzheimer's disease.

Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus – brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively – from postmortem brains spanning the progression of AD-type tau neurofibrillary pathology. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience.

Hypertension does not alter disturbances in leptin signalling observed in experimental model of tauopathy

Neurodegeneration is associated with hypertension and disturbance in fat metabolism. The complex interaction of neurodegenerative processes with both metabolic changes and blood pressure is still not fully elucidated. Here we demonstrate that the experimentally induced tauopathy in hypertensive transgenic animals causes significant downregulation of plasma leptin (53% of control), reduction of body weight by 11%, a 1.2-fold drop of adiposity index, and decrease in HDL cholesterol level, while the fasting glucose and insulin concentration remain unchanged. Despite of these alterations we found the leptin projection circuit including the arcuate nucleus, paraventricular nucleus in hypothalamus, and nucleus tractus solitarius in the brainstem not affected by neurofibrillary pathology. Furthermore, hypertension does not alter disturbances in leptin signalling. The presented data provide further insight into neurodegeneration-induced metabolic alterations relevant for human tauopathies.

Periodontal dysbiosis associates with reduced CSF Aβ42 in cognitively normal elderly.

IntroductionPeriodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer's disease (AD) and Down syndrome.MethodsA total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect‐size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups.ResultsAt genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 (P = 0.02 and 0.01) but not with P‐tau.DiscussionWe show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ.

Seeding-Competent Tau in Gray Matter Versus White Matter of Alzheimer's Disease Brain.

Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer's disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. To determine the seeding activity of tau in cerebral gray and white matters of AD. Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol-resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity was quantitatively assessed by measuring RIPA buffer-insoluble tau in HEK-293FT/tau151-391 cells treated with brain extracts. We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151-391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter.

Transcriptomic signature of Alzheimer's disease tau seed-induced pathology.

Spreading of tau pathology to anatomical distinct regions in Alzheimer's disease (AD) is associated with progression of the disease. Studies in recent decade have strived to understand the processes involved in this characteristic spread. We recently showed that AD-derived insoluble tau seeds are able to initiate neurofibrillary pathology in transgenic rodent model of tauopathy. In the present study, we pursued to identify the molecular changes that govern the induction and propagation of tau pathology on the transcriptomic level. We first show that microglia in vicinity to AD-Tau-induced pathology has phagocytic morphology when compared to PBS-injected group. On transcriptomic level, we observed deregulation of 15 genes 3-month post AD-Tau seeds inoculation. Integrated bioinformatic analysis identified 31 significantly enriched pathways. Amongst these, the inflammatory signalling pathway mediated by cytokine and chemokine networks, along with, toll-like receptor and JAK-STAT signalling were the most dominant. Furthermore, the enriched signalling also involved the regulation of autophagy, mitophagy and endoplasmic reticulum stress pathways. To our best of knowledge, the study is the first to investigate the transcriptomic profile of AD-Tau seed-induced pathology in hippocampus of transgenic model of tauopathy.

Blood pressure is associated with tau pathology independent of beta‐amyloid

AbstractBackgroundHigh blood pressure is a risk factor of Alzheimer’s disease (AD) but it is unclear whether it plays a direct role in disease pathogenesis. Recent animal work indicates that induced ischemic disease promotes tau hyperphosphorylation, suggesting that vascular risk factors may directly contribute to AD via neurofibrillary tangle pathology. We examined the relationship between blood pressure indicators and tau pathology, measured with Flortaucipir PET, in early Braak regions among older adults with mild cognitive impairment (MCI) or no cognitive impairment (NC) in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).MethodA total of 141 ADNI 2 participants (75.6 + 6.72 years old, 53.2% women, 92% White, 33.3% MCI) who underwent Florbetapir (AV‐45) amyloid and Flortaucipir (AV‐1451) tau PET imaging were included in the analyses. Diastolic (DBP) and systolic blood (SBP) pressure measurements from screening visits were considered. We derived mean arterial pressure (MAP; SBP+2(DBP)), pulse pressure (SBP–DBP), and characterized participants as Stage 2 hypertensive (systolic BP &gt; 140 and/or diastolic BP &gt; 90). We examined the association of each blood pressure indicator with tau standardized uptake value ratios (SUVR) in the entorhinal cortex (EC), adjusting for age, sex/gender, MCI diagnosis, time interval between the screening visit and PET visit (4.5 + 1.17 SD years prior to the PET scan), and a cortical amyloid summary measure. We tested interactions between MCI diagnosis and blood pressure.ResultIndependent of amyloid pathology, higher systolic pressure (β=0.217, p=0.009), higher MAP (β=0.186, p=0.021), and hypertension (β=0.165, p=0.044) were associated with increased tau deposition in the entorhinal cortex. Of the covariates, amyloid SUVR (βs=0.301‐0.303, p&lt;0.001), and MCI diagnosis (βs=0.165‐0.189, p=0.031–0.049) were also associated with entorhinal cortex tau. The association between MAP and entorhinal cortex tau was stronger in MCI relative to controls (MCI: β=0.330, p=0.037, NC: β=0.086, p=0.321).ConclusionHigh blood pressure is associated with future neurofibrillary tangle pathology in early Braak regions, independently of amyloid. Our results are consistent with reports of earlier life hypertension as risk for later life AD. Together with results from recent animal studies, they highlight a potential pathway in which vascular factors promote AD pathogenesis via tau.

Using seeding models to understand strain differences from Alzheimer’s disease and pathological aging brains

AbstractBackgroundPathological aging (PA) patients are individuals that are cognitively normal prior to death but have abundant and widespread amyloid‐β (Aβ) deposits. These individuals typically have few cored amyloid deposits with variable levels of diffuse parenchymal deposits and/or vascular deposits. There is little or no inflammatory reaction, neuritic pathology or neurofibrillary tangles in the cortex. Previously, we have shown that total Aβ levels in PA brain lysates were similar to the levels in Alzheimer’s disease (AD) brain lysates, with overlap in the length of the Aβ peptides that were deposited and no major differences in SDS‐stable Aβ oligomeric assemblies. Despite these similarities, it is unclear whether PA represents a prodromal phase of AD or if the amyloid pathology of PA patients represents a less pathogenic variant. To explore this idea, we examined the seeding capacity of AD and PA brain homogenates to induce Aβ deposition and to secondarily induce tau pathology.MethodWe determined the seeding capacity of two AD, four PA and two control brain homogenates in transgenic mice expressing APPswe/ind with and without Tau‐P301L by intracerebral injection at neonatal day 0. At either 6, 9, 12 or 18 months, we assessed Aβ deposition and neurofibrillary pathology in all 4 genotypes by immunohistochemical and biochemical methods. Furthermore we examined the seeding activity of human AD brain lysates in brain slice cultures from APP/Tau transgenic mice.ResultIn our newborn mouse injections, we observed widespread Aβ seeding as evidenced by accelerated onset of diffuse parenchymal Aβ deposition that was largely proportional to the burden of parenchyma deposits in patient brains. In all cases, high levels of pial deposition were observed and Aβ42 was the predominant peptide deposited. Tau pathology was not induced in any animal, and with the absence of neuritic plaques there was no induction of tau positive neurites.ConclusionThis study provides evidence that the Aβ conformers associated with diffuse Aβ deposits in the brains of cognitively normal individuals possess seeding activities similar to those found in the brains of AD patients. The findings are consistent with the idea that pathological aging is on a continuum with AD.

Multiple pathologies in an amateur soccer player with severe chronic traumatic encephalopathy

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a tauopathy associated with repeated brain injuries. The presence of co‐pathologies is not uncommon in individuals with CTE. Here, we described clinical and neuropathological findings of amateur soccer with a history of progressive parkinsonism and dementia.Method63‐years old male with no family history of neurodegenerative disease or alcohol abuse. He played amateur soccer as a goalkeeper for 42 years. Episode of concussion with loss of conciseness at age of 20, without symptoms afterward. He denied any non‐soccer related episodes of brain trauma. At the age of 65, he started with REM behavior disorder, followed by apathy. At age 67, he developed asymmetric bradykinesia, limb rigidity, and complete anosmia. At the age of 73, a neurological examination demonstrated asymmetric parkinsonism, worse in the left. He denied motor fluctuations or hallucinations. At age 75, cognitive impairment was observed and his MMSE score was 22/30 with temporal disorientation, executive and delayed recall impairments. The working diagnosis was Parkinson's disease dementia. He died at age of 81.ResultNeuropathological examination showed prominent frontal and temporal atrophy, hippocampal asymmetry and moderate depigmentation of substantia nigra, and locus coeruleus. Hematoxylin and eosin staining showed left hippocampal sclerosis and white matter arteriolosclerosis. Immunohistochemistry evaluation showed aggregates of hyperphosphorylated tau in neurons, astrocytes and cell processes in a patch distribution around vessels, with deep sulcal accentuation in several cortical regions fulfilling criteria for CTE stage III. Additionally, neurofibrillary pathology was found in subcortical and cortical areas (BRAAK stage V) and Aß plaques were distributed in cortical, limbic and diencephalon areas (Thal 4), altogether meeting criteria for an intermediated ADNC. Also, phosphorylated TDP‐43 immunoreactive dot‐like and neuronal cytoplasmatic inclusions were found in entorhinal cortex, amygdala and hippocampus (LATE stage 3). Moreover, diffuse Lewy pathology was observed (Braak 5 of Parkinson´s disease).ConclusionDespite showing multiple co‐pathologies, former soccer players may develop CTE changes. This case adds to the increased number of former soccer players showing dementia due to multiple pathologies and CTE. If soccer‐related brain trauma triggers multiple neuropathological processes or if they develop independently remains an open question.