Neurofibrillary Tangle Stage Research Articles

Simple Quantitative Indices for the Differentiation of Advanced-Stage Alzheimer's Disease and Other Limbic Tauopathies.

The differentiation of Alzheimer's disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. The purpose of this study is to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice.

Maturation of neuronal AD-tau pathology involves site-specific phosphorylation of cytoplasmic and synaptic tau preceding conformational change and fibril formation

In Alzheimer's disease (AD), tau-protein undergoes a multi-step process involving the transition from a natively unfolded monomer to large, aggregated structures such as neurofibrillary tangles (NFTs). However, it is not yet clear which events initiate the early preclinical phase of AD tauopathy and whether they have impact on the propagation of tau pathology in later disease stages. To address this question, we analyzed the distribution of tau species phosphorylated at T231, S396/S404 and S202/T205, conformationally modified at the MC1 epitope and fibrillary tau detected by the Gallyas method (Gallyas-tau), in the brains of 15 symptomatic and 20 asymptomatic cases with AD pathology as well as of 19 nonAD cases. As initial tau lesions, we identified phosphorylated-T231-tau diffusely distributed within the somatodendritic compartment (IC-tau) and phosphorylated-S396/pS404-tau in axonal lesions of the white matter and in the neuropil (IN-tau). The subcellular localization of pT231-tau in the cell body and pS396/pS404-tau in the presynapse was confirmed in hP301L mutant Drosophila larvae. Phosphorylated-S202/T205-tau, MC1-tau and Gallyas-tau were negative for these lesions. IC- and IN-tau were observed in all analyzed regions of the human brain, including early affected regions in nonAD cases (entorhinal cortex) and late affected regions in symptomatic AD cases (cerebellum), indicating that tau pathology initiation follows similar processes when propagating into previously unaffected regions. Furthermore, a sequence of AD-related maturation of tau-aggregates was observed, initiated by the appearance of IC- and IN-tau, followed by the formation of pretangles exhibiting pT231-tau, pS396/pS404-tau and pS202/pT205-tau, then by MC1-conformational tau, and, finally, by the formation of Gallyas-positive NFTs. Since cases classified as nonAD [Braak NFT stages < I (including a-1b)] already showed IC- and IN-tau, our findings suggest that these lesions are a prerequisite for the development of AD.

TAR DNA-Binding Protein 43 Is Associated with Rate of Memory, Functional and Global Cognitive Decline in the Decade Prior to Death.

Background:Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with memory impairment and overall cognitive decline. It is unclear how TDP-43 contributes to the rate of clinical decline.Objective:To determine whether cross-sectional and longitudinal cognitive and functional decline are associated with anatomical distribution of TDP-43 in the brain.Methods:Longitudinal clinical-neuropathologic autopsy cohort study of 385 initially cognitively normal/mildly impaired older adults prospectively followed until death. We investigated how TDP-43, amyloid-β (Aβ), tau neurofibrillary tangles (NFT), Lewy body disease (LBD), age, sex, and genetics are associated with clinical scores and rates of their longitudinal decline.Results:Of 385 participants, 260 (68%) had no TDP-43, 32 (8%) had TDP-43 limited to amygdala, and 93 (24%) had TDP-43 in the hippocampus and beyond. Higher TDP-43 and Braak NFT stages independently were associated with faster decline in global cognition, functional performance measured by Clinical Dementia Rating scale, and naming and episodic memory, whereas older age was associated with slower rate of cognitive, psychiatric, and functional decline. Cross-sectionally the following associations were found: higher TDP-43 and Braak NFT - worse performance; higher Aβ burden - worse global cognition, more behavioral changes, the latter also with higher LBD; older age - worse naming, lower frequency of behavioral changes; female sex - more impaired naming and better preserved episodic memory. There were no genetic associations.Conclusion:The association of TDP-43 distribution with decline in cognitive and functional performance suggests that TDP-43 is playing a role in the clinical progression to dementia. Further characterization of clinical features associated with TDP-43 can facilitate establishment of antemortem diagnosis.

18F]MK‐6240 depicts early and late Braak stages of neurofibrillary tangles in preclinical and symptomatic subjects

AbstractBackgroundPostmortem Braak staging provides an index of disease stage and has therefore been incorporated as a core neuropathological criterion for the diagnosis of Alzheimer’s disease (AD). Recent in vivo studies using the tau positron emission tomography agent [18F]flortaucipir have shown low sensitivity to detect tau pathology in early Braak stages. These studies report Braak I‐II or greater in ∼20% of cognitively unimpaired elderly, in contrast to the ∼70‐90% of non‐zero Braak stage reported in postmortem studies. Here, we tested whether the novel high‐affinity tau tangles tracer [18F]MK‐6240 (6 fold &gt; [18F]flortaucipir)can better identify individuals in the early stages of tau accumulation.MethodTo this end, we studied 301 individuals (30 young adults, 138 cognitively unimpaired (CU) elderly, 67 mild cognitive impairment (MCI), 54 AD dementia, and 12 frontotemporal dementia (FTD)) with amyloid‐b[18F]NAV4694, tau [18F]MK‐6240, magnetic resonance imaging, and clinical assessments.Results[18F]MK‐6240 discriminated AD from FTD dementia as well as predicted amyloid‐b positivity with the highest area under the curve in Braak I‐II region (=∼95‐100%)(Fig.1 and 2). [18F]MK‐6240 accumulation hierarchically followed the 6 Braak stages (Fig.3)in 98% of our population (Fig.4).91% of the elderly amyloid‐b positive and 46% of the elderly amyloid‐b negative displayed tau deposition, at least in the transentorhinal cortex (Braak I)(Fig.4). Cognition and amyloid‐b status explained most of the Braak stages variance (P&lt;0.0001, R2=0.75). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid‐b, neurodegeneration, and cognitive impairment (P&lt;0.0001). No single region‐of‐interest accurately segregated individuals into the 6 Braak stages (Fig.5). However, classification decision tree analysis suggested that a composite of transentorhinal, entorhinal, and hippocampal cortices(Braak I‐II) was the region‐of‐interest that best represented [18F]MK‐6240Braak stages (capacity of a region’ SUVR cutoff segregating individuals in 7 levels (Braak 0‐VI)) (accuracy=86.2%)(Fig.6).ConclusionOur results highlight that the hierarchical 6‐stage Braak model using [18F]MK‐6240 provides a robust index of early and late tau accumulation as well as disease stages in preclinical and symptomatic individuals. Tau positron emission tomography Braak staging using high‐affinity tracers has the potential to be incorporated in the diagnosis of living patients with AD.

Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy

AbstractBackgroundBeta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.MethodData were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.ResultWe identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.ConclusionThese results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.

Cognitive impairment and risk factors of LATE in the oldest old: The 90+ Study

AbstractBackgroundLimbic predominant age related TDP‐43 encephalopathy (LATE) is a newly proposed term to denote the contribution of TDP‐43 pathology to dementia at older age. The aim of this work was to study the role of LATE in cognitive impairment and its risk factors in the oldest old.Method240 participants of The 90+ Study with comprehensive clinical, neuropsychology, and neuropathology data were included. Dementia status, clinical syndrome, and impaired cognitive domains were determined at multi‐disciplinary post‐mortem case conferences blind to autopsy data. Alzheimer’s disease neuropathology (ADNP) was defined as CERAD neuritic plaque score≥2 and Braak neurofibrillary tangle stage≥5. We defined LATE as those with at least amygdala and hippocampal TDP‐43 pathology (stage&gt;2). We explored the association of LATE and ADNP with cognition measures as outcome by logistic regression analyses adjusting for age, sex, and education. We separately explored the association between medical histories (as potential risk factors) and LATE and ADNP as outcomes adjusting for the above covariates.Result52% of the participants (N=125) died with dementia and of those, 33% were LATE positive (Table 1). There was no association between LATE and sex, age at death, or education. Compared with ADNP, LATE was as important a predictor of dementia and clinical diagnosis of Alzheimer’s at death (Table 2). Both pathologies were associated with impaired memory, language, visuospatial ability, and orientation. Only ADNP, but not TDP‐43, was associated with impaired executive function. Lower likelihood of LATE was associated with histories of hypertension (but not hypertension medications), cataract, alcohol use (median 1 drink/day), and macular degeneration (trended toward significant association). History of COPD was significantly associated and history of autoimmune conditions (thyroid or rheumatological diseases) trended towards an association with a higher likelihood of LATE (Figure). None of the above relationships were seen for ADNP.ConclusionLATE is an important degenerative pathology in the oldest old comparable to ADNP in its relation to dementia and clinical diagnosis of Alzheimer’s. The intriguing associations of LATE with other health conditions warrant further investigation of the potential effect of autoimmunity, reduced brain perfusion, and chronic hypoxia in its development.

Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy.

Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.

315 - Prevalence and clinical associations of tau in Lewy body dementias: a systematic review and meta-analysis

Background:Neurofibrillary tangles (NFT) formed by tau proteins, a pathological hallmark of Alzheimer’s disease, are a common co-pathology in people with Lewy body dementias, which include dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).Aims:To investigate the prevalence of tau in Lewy body dementia, and its association with clinical outcomes.Methods:A systematic search was conducted on Medline, Embase and PubMed using the search term: (“dementia with Lewy bodies” OR “diffuse Lewy body disease”) AND (“tau protein” OR “tauopathy” OR “neurofibrillary tangle”). A total of 42 articles met the inclusion criteria for data extraction. Random-effect meta-analyses were performed to obtain pooled estimates for prevalence, and risk ratios (RR) or standardised mean difference (SMD) for clinical outcomes measures.Results:Braak NFT stage ≥III was observed in 67% (n=1399, 95%CI 59%-76%) of DLB and 52% (n=429, 95%CI 26%-78%) of PDD at autopsy. Abnormal CSF phosphorylated-tau levels were present in 27% (n=705, 95%CI 23%-30%) of DLB and 15% (n=172, 95%CI 5%-24%) of PDD cases. Higher tau burden in DLB was associated with reduced likelihood of manifesting visual hallucinations (RR 0.56; 95%CI 0.40-0.77) and motor parkinsonism (RR 0.62; 95%CI 0.40-0.98), lower diagnostic accuracy of DLB during life (RR 0.49; 95%CI 0.38-0.64) and worse cognition prior to death (SMD 0.60; 95%CI 0.44-0.76).Conclusions:Tau is more common in DLB than PDD and may negatively impact clinical diagnostic accuracy in people with DLB. Prospective longitudinal studies are needed to understand the roles of co-morbid neuropathologies in Lewy body dementias.

Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults

Quadruple misfolded proteins (tau neurofibrillary tangles, amyloid-β [Aβ], α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]) in the same brain are relatively common in aging. However, the clinical presentation, associated factors, frequency in community-based cohorts, genetic characteristics, and cognitive trajectories associated with the quadruple misfolded proteins phenotype are not well understood. To describe the quadruple misfolded proteins phenotype, including the trajectories of global cognition, in an autopsy cohort. This retrospective cohort study used brain autopsy data from the University of Kentucky Alzheimer Disease Center (UK-ADC) Brain Bank. Participants were deceased individuals who were enrolled in a longitudinal community-based cohort study of aging and dementia in central Kentucky conducted by the UK-ADC. Included participants were enrolled in the UK-ADC cohort between January 1, 1989, and December 31, 2017; aged 55 years or older at baseline; and followed up for a mean duration of 10.4 years. The participants had Alzheimer disease pathology (tau and Aβ), α-synuclein, and TDP-43 data, along with Braak neurofibrillary tangle stage I to VI. Data analysis was conducted between February 1, 2019, and September 30, 2019. Frequency of quadruple misfolded proteins was estimated, and proteinopathy group characteristics and associations with global cognition were evaluated. Multinomial logistic regression was used to estimate the association of proteinopathy group with participant characteristics, including age at death, sex, and apolipoprotein ε4 (APOE ε4) allele. Generalized estimating equations were used to estimate the probability of obtaining Mini-Mental State Examination (MMSE) scores within the normal cognition (27-30 points) and severe impairment (≤13 points) ranges during the 12 years before death. The final sample included 375 individuals (mean [SD] age at death, 86.9 [8.0] years); 232 women [61.9%]). Quadruple misfolded proteins were detected in 41 of 214 individuals with dementia (19.2%). Overall, 46 individuals (12.3%) had quadruple misfolded proteins, whereas 143 individuals (38.1%) had 3 proteinopathies. Dementia frequency was highest among those with quadruple misfolded proteins (41 [89.1%]), and participants with quadruple misfolded proteins had the lowest final mean (SD) MMSE scores of 13.4 (9.8) points. Adjusting for age at death and sex, the APOE ε4 allele was associated with higher odds of quadruple misfolded proteins (adjusted odds ratio, 2.55; 95% CI, 1.16- 5.62; P = .02). The quadruple misfolded proteins group had both the lowest probability of obtaining MMSE scores in the normal cognition range, even 12 years before death, and the highest probability of having MMSE scores in the severe impairment range. Quadruple misfolded proteins appear to be a common substrate for cognitive impairment and to be associated with an aggressive course of disease that typically ends with severe dementia. The prevalence of comorbid α-synuclein and TDP-43 with Alzheimer disease pathology (tau and Aβ) may complicate efforts to identify therapies to treat and prevent Alzheimer disease.

The histopathological staging of tau, but not amyloid, corresponds to antemortem cognitive status, dementia stage, functional abilities and neuropsychiatric symptoms

Purpose Alzheimer’s disease (AD) is characterised by two cardinal pathologies, namely the extracellular accumulation amyloid-related aggregates, and the intracellular formation of tau-related neurofibrillary tangles (NFTs). While both pathologies disrupt cognitive function, a large body of evidence suggests that tau-pathology has a stronger relationship with the clinical manifestation of the disease compared to amyloid. Given the ordinal nature of histopathological staging systems, however, it is possible that the effect of amyloid pathology has been underestimated in clinicopathological studies. Methods We investigated this possibility using data from the National Alzheimer’s Coordinating Center (NACC) database, which contains data from patients in the United States of America. Bayesian ordinal models were used to directly investigate the relative contribution of Braak NFT, diffuse plaque, and neuritic plaque staging to the severity of antemortem clinical impairment. Results Data from 144 participants were included in the final analysis. Bayesian ordinal models revealed that Braak NFT stage was the only predictor of global cognitive status, clinical dementia stage, functional abilities, and neuropsychiatric symptoms. When compared directly, Braak NFT stage was a stronger predictor than diffuse or neuritic plaques across these domains. Conclusions These findings confirm that tau-related pathology is more strongly related to clinical status than amyloid pathology. This suggests that conventional clinical markers of disease progression might be insensitive to amyloid-pathology, and hence might be inappropriate for use as outcome measures in therapeutic trials that directly target amyloid.

Association between transactive response DNA-binding protein of 43 kDa type and cognitive resilience to Alzheimer’s disease: a case-control study

Association between the transactive response DNA-binding protein of 43 kDa (TDP-43), its newly described types (type α/type β), and resilience to Alzheimer’s disease neuropathological change (ADNC) defined as preservation of normal cognitive functioning despite advanced ADNC has been evaluated in this case-control study of 63 older adults. Twenty-one resilient to ADNC individuals were matched 1:2 to nonresilient (Alzheimer’s dementia) using propensity scores, accounting for age at death, neuritic plaque density, and neurofibrillary tangle stage. Resilient and matched nonresilient participants were similar in terms of gender, apolipoprotein E ε4 carriership, education, occupation, AD, and other pathologies. Resilient participants had lower frequency of TDP-43 co-pathology compared to nonresilient (19% vs. 62%, p = 0.002). Among TDP-43-positive cases, TDP-43 type α inclusions were absent in resilient to ADNC participants and were dominant in matched nonresilient cases (65%, p = 0.03). TDP-43 and TDP-43 types appear to be one of the key pathological determinants of loss of cognitive resilience to ADNC and hence are important in the understanding of the clinical expression of ADNC.

Circle of Willis abnormalities and their clinical importance in ageing brains: A cadaveric anatomical and pathological study

The circle of Willis (CW) located at the base of the brain forms an important collateral network to maintain adequate cerebral perfusion, especially in clinical situations requiring compensatory changes in blood flow. Morphopathological changes in the CW may relate to the severity of the symptoms of certain neurodegenerative and cerebrovascular disorders. The purpose of this study was to investigate the CW abnormalities and their clinical importance in ageing brains. The CW was examined macroscopically in 73 formalin-fixed samples to determine the degree of stenosis of each CW component, atherosclerosis of the CW, hypoplasia (threshold diameter < 1 mm), anatomical variations and aneurysms. Age-related neurodegenerative and cerebrovascular pathologies were screened using immunohistopathological techniques on specific neuroanatomical regions based on standard guidelines. The majority of the elderly brains −93 % (68/73) presented at least a single hypoplastic CW component at death. Anatomical variations were mostly identified in communicating arteries, followed by proximal posterior and anterior cerebral arteries. Arterial bifurcations were found to be the predominant sites for cerebral aneurysms. More than 90 % of the elderly brains presented CW atherosclerosis at death. CW abnormalities did not show any strong associations with neurodegenerative pathologies except for an “at risk” significant association observed between Braak’s neurofibrillary tangle (NFT) stages 1-VI and CW atherosclerosis grades ≥ mild (p = 0.05). However, a significant association was observed between microscopic infarcts in deep white matter and hypoplasia in communicating arteries with Fisher’s exact test (p < 0.05). Overall, CW abnormalities were predominant in the ageing brains, however their relationships to the occurrence and severity of the symptoms of neurodegenerative pathologies were found to be low.

Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer's Disease Neuropathological Changes.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer's disease (AD), but whether the association is modified by other factors is unknown. To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E (APOE) ɛ4, Lewy bodies (LBs), amyloid-β (Aβ), or Braak neurofibrillary tangle (NFT) stage. In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (Aβ-positive) that had completed antemortem head MRI, we investigated how age, gender, APOEɛ4, presence of LBs, Aβ, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models. Older age, female gender, APOEɛ4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOEɛ4 carriers (p = 0.04). Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another.

TDP-43 is associated with a reduced likelihood of rendering a clinical diagnosis of dementia with Lewy bodies in autopsy-confirmed cases of transitional/diffuse Lewy body disease.

Trans-active response DNA-binding protein of 43kDa (TDP-43) can be detected in up to 63% of autopsy-confirmed Lewy body disease (LBD) cases. It is unclear whether TDP-43 is associated with a decreased likelihood of a clinical diagnosis of probable dementia with Lewy bodies (pDLB) during life. In an autopsy cohort of 395 cognitively impaired patients from the Mayo Clinic Alzheimer's Disease Research Center, we determined the presence of TDP-43 in the hippocampus [hTDP-43(+)] and examined associations between hTDP-43 and an antemortem pDLB clinical diagnosis with multiple regression analyses. For this study, given our specific question, we only counted transitional and diffuse Lewy body disease as LBD positive (LBD+). One-hundred forty-five cases (37%) were hTDP-43(+) and 156 (39%) were LBD+; co-pathology was noted in 63 (16%) cases. Patients with pDLB- LBD+ were more likely to be older, hTDP-43(+) and have high Braak neurofibrillary tangle (NFT) status compared to the pDLB+ LBD+ patients. After accounting for older age at death and high Braak NFT status, hTDP-43(+) status was associated with the absence of a clinical diagnosis of pDLB despite LBD+ status (p < 0.05). The absence of a diagnosis of pDLB during life in patients with LBD is associated with older age, high Braak NFT stage and hTDP-43, each feature contributing independently to a lower likelihood of a clinical diagnosis of pDLB during life.

Disruption of a RAC1-centred network is associated with Alzheimer's disease pathology and causes age-dependent neurodegeneration.

The molecular biological mechanisms of Alzheimer’s disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

18F-fluorodeoxyglucose positron emission tomography in dementia with Lewy bodies.

Among individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether 18F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these 18F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease (n = 34) and a clinically diagnosed group of dementia with Lewy bodies (n = 87). A subset of the clinically diagnosed group was followed longitudinally (n = 51). We evaluated whether 18F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher 18F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.

Amyloid and tau imaging biomarkers explain cognitive decline from late middle-age.

This study investigated differences in retrospective cognitive trajectories between amyloid and tau PET biomarker stratified groups in initially cognitively unimpaired participants sampled from the Wisconsin Registry for Alzheimer's Prevention. One hundred and sixty-seven initially unimpaired individuals (baseline age 59 ± 6 years; 115 females) were stratified by elevated amyloid-β and tau status based on 11C-Pittsburgh compound B (PiB) and 18F-MK-6240 PET imaging. Mixed effects models were used to determine if longitudinal cognitive trajectories based on a composite of cognitive tests including memory and executive function differed between biomarker groups. Secondary analyses investigated group differences for a variety of cross-sectional health and cognitive tests, and associations between 18F-MK-6240, 11C-PiB, and age. A significant group × age interaction was observed with post hoc comparisons indicating that the group with both elevated amyloid and tau pathophysiology were declining approximately three times faster in retrospective cognition compared to those with just one or no elevated biomarkers. This result was robust against various thresholds and medial temporal lobe regions defining elevated tau. Participants were relatively healthy and mostly did not differ between biomarker groups in health factors at the beginning or end of study, or most cognitive measures at study entry. Analyses investigating association between age, MK-6240 and PiB indicated weak associations between age and 18F-MK-6240 in tangle-associated regions, which were negligible after adjusting for 11C-PiB. Strong associations, particularly in entorhinal cortex, hippocampus and amygdala, were observed between 18F-MK-6240 and global 11C-PiB in regions associated with Braak neurofibrillary tangle stages I-VI. These results suggest that the combination of pathological amyloid and tau is detrimental to cognitive decline in preclinical Alzheimer's disease during late middle-age. Within the Alzheimer's disease continuum, middle-age health factors likely do not greatly influence preclinical cognitive decline. Future studies in a larger preclinical sample are needed to determine if and to what extent individual contributions of amyloid and tau affect cognitive decline. 18F-MK-6240 shows promise as a sensitive biomarker for detecting neurofibrillary tangles in preclinical Alzheimer's disease.

Epidemiological pathology of A\u03b2 deposition in the ageing brain in CFAS: addition of multiple A\u03b2-derived measures does not improve dementia assessment using logistic regression and machine learning approaches

Aβ-amyloid deposition is a key feature of Alzheimer’s disease, but Consortium to Establish a Registry for Alzheimer's Disease (CERAD) assessment, based on neuritic plaque density, shows a limited relationships to dementia. Thal phase is based on a neuroanatomical hierarchy of Aβ-deposition, and in combination with Braak neurofibrillary tangle staging also allows derivation of primary age-related tauopathy (PART). We sought to determine whether Thal Aβ phase predicts dementia better than CERAD in a population-representative cohort (n = 186) derived from the Cognitive Function and Ageing Study (CFAS). Cerebral amyloid angiopathy (CAA) was quantitied as the number of neuroanatomical areas involved and cases meeting criteria for PART were defined to determine if they are a distinct pathological group within the ageing population. Agreement with the Thal scheme was excellent. In univariate analysis Thal phase performed less well as a predictor of dementia than CERAD, Braak or CAA. Logistic regression, decision tree and linear discriminant analysis were performed for multivariable analysis, with similar results. Thal phase did not provide a better explanation of dementia than CERAD, and there was no additional benefit to including more than one assessment of Aβ in the model. Number of areas involved by CAA was highly correlated with assessment based on a severity score (p < 0.001). The presence of capillary involvement (CAA type I) was associated with higher Thal phase and Braak stage (p < 0.001). CAA was not associated with microinfarcts (p = 0.1). Cases satisfying pathological criteria for PART were present at a frequency of 10.2% but were not older and did not have a higher likelihood of dementia than a comparison group of individuals with similar Braak stage but with more Aβ. They also did not have higher hippocampal-tau stage, although PART was weakly associated with increased presence of thorn-shaped astrocytes (p = 0.048), suggesting common age-related mechanisms. Thal phase is highly applicable in a population-representative setting and allows definition of pathological subgroups, such as PART. Thal phase, plaque density, and extent and type of CAA measure different aspects of Aβ pathology, but addition of more than one Aβ measure does not improve dementia prediction, probably because these variables are highly correlated. Machine learning predictions reveal the importance of combining neuropathological measurements for the assessment of dementia.

Braak neurofibrillary tangle staging prediction from in vivo MRI metrics

IntroductionAlzheimer's disease diagnosis requires postmortem visualization of amyloid and tau deposits. As brain atrophy can provide assessment of consequent neurodegeneration, our objective was to predict postmortem neurofibrillary tangles (NFT) from in vivo MRI measurements. MethodsAll participants with neuroimaging and neuropathological data from the Alzheimer's Disease Neuroimaging Initiative, the National Alzheimer's Coordinating Center and the Rush Memory and Aging Project were selected (n = 186). Two hundred and thirty two variables were extracted from last MRI before death using FreeSurfer. Nonparametric correlation analysis and multivariable support vector machine classification were performed to provide a predictive model of Braak NFT staging. ResultsWe demonstrated that 59 of our MRI variables, mostly temporal lobe structures, were significantly associated with Braak NFT stages (P < .005). We obtained a 62.4% correct classification rate for discrimination between transentorhinal, limbic, and isocortical groups. DiscussionStructural neuroimaging may therefore be considered as a potential biomarker for early detection of Alzheimer's disease–associated neurofibrillary degeneration.

Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer's Disease in Urban Children and Young Adults.

Exposures to fine particulate matter (PM2.5) and ozone (O3) ≥US EPA standards are associated with Alzheimer's disease (AD) risk. The projection of 13.8 million AD cases in the US by the year 2050 obligate us to explore early environmental exposures as contributors to AD risk and pathogenesis. Metropolitan Mexico City children and young adults have lifetime exposures to PM2.5 and O3, and AD starting in the brainstem and olfactory bulb is relentlessly progressing in the first two decades of life. Magnetite combustion and friction-derived nanoparticles reach the brain and are associated with early and progressive damage to the neurovascular unit and to brain cells. In this review: 1) we highlight the interplay environment/genetics in the AD development in young populations; 2) comment upon ApoE ɛ4 and the rapid progression of neurofibrillary tangle stages and higher suicide risk in youth; and 3) discuss the role of combustion-derived nanoparticles and brain damage. A key aspect of this review is to show the reader that air pollution is complex and that profiles change from city to city with common denominators across countries. We explore and compare particulate matter profiles in Mexico City, Paris, and Santiago in Chile and make the point of why we should invest in decreasing PM2.5 to at least our current US EPA standard. Multidisciplinary intervention strategies are critical for prevention or amelioration of cognitive deficits and AD progression and risk of suicide in young individuals. AD pathology evolving from childhood is threating the wellbeing of future generations.