Density Of Neurofibrillary Tangles Research Articles

Reduced PIN1 expression in neocortical and limbic brain regions in female Alzheimer’s patients correlates with cognitive and neuropathological phenotypes

Women have a higher incidence of Alzheimer’s disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.

Profiles of Lifestyle Health Behaviors and Postmortem Dementia-Related Neuropathology.

High engagement in lifestyle health behaviors appears to be protective against cognitive decline in aging. We investigated the association between patterns of modifiable lifestyle health behaviors and common brain neuropathologies of dementia as a possible mechanism. We examined 555 decedents from the Rush Memory and Aging Project, free of dementia at their initial concurrent report of lifestyle health behaviors of interest (physical, social, and cognitive activities, and healthy diet), and who underwent a postmortem neuropathology evaluation. First, we used latent profile analysis to group participants based on baseline behavior patterns. Second, we assessed the associations of profile membership with each neurodegenerative (global Alzheimer's disease [AD] pathology, amyloid-beta load, density of neurofibrillary tangles, and presence of cortical Lewy bodies and TAR DNA-binding protein 43 cytoplasmic inclusions) and neurovascular pathologies (presence of chronic gross or microscopic infarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy), using separate linear or logistic regression models, adjusted for age at death, sex (core model), vascular disease risk factors, and vascular conditions (fully adjusted model). Participants had either consistently lower (N = 224) or consistently higher (N = 331) engagement across 4 lifestyle health behaviors. We generally found no differences in neuropathologies between higher and lower engagement groups in core or fully adjusted models; for example, higher engagement in lifestyle health behaviors was not associated with global AD pathology after core or full adjustment (both p > .8). In conclusion, we found no evidence of associations between patterns of lifestyle health behaviors and neuropathology. Other mechanisms may underlie protective effects of health behaviors against dementia.

Correlation of Presynaptic and Postsynaptic Proteins with Pathology in Alzheimer's Disease.

Synaptic transmission is essential for nervous system function and the loss of synapses is a known major contributor to dementia. Alzheimer's disease dementia (ADD) is characterized by synaptic loss in the mesial temporal lobe and cerebral neocortex, both of which are brain areas associated with memory and cognition. The association of synaptic loss and ADD was established in the late 1980s, and it has been estimated that 30-50% of neocortical synaptic protein is lost in ADD, but there has not yet been a quantitative profiling of different synaptic proteins in different brain regions in ADD from the same individuals. Very recently, positron emission tomography (PET) imaging of synapses is being developed, accelerating the focus on the role of synaptic loss in ADD and other conditions. In this study, we quantified the densities of two synaptic proteins, the presynaptic protein Synaptosome Associated Protein 25 (SNAP25) and the postsynaptic protein postsynaptic density protein 95 (PSD95) in the human brain, using enzyme-linked immunosorbent assays (ELISA). Protein was extracted from the cingulate gyrus, hippocampus, frontal, primary visual, and entorhinal cortex from cognitively unimpaired controls, subjects with mild cognitive impairment (MCI), and subjects with dementia that have different levels of Alzheimer's pathology. SNAP25 is significantly reduced in ADD when compared to controls in the frontal cortex, visual cortex, and cingulate, while the hippocampus showed a smaller, non-significant reduction, and entorhinal cortex concentrations were not different. In contrast, all brain areas showed lower PSD95 concentrations in ADD when compared to controls without dementia, although in the hippocampus, this failed to reach significance. Interestingly, cognitively unimpaired cases with high levels of AD pathology had higher levels of both synaptic proteins in all brain regions. SNAP25 and PSD95 concentrations significantly correlated with densities of neurofibrillary tangles, amyloid plaques, and Mini Mental State Examination (MMSE) scores. Our results suggest that synaptic transmission is affected by ADD in multiple brain regions. The differences were less marked in the entorhinal cortex and the hippocampus, most likely due to a ceiling effect imposed by the very early development of neurofibrillary tangles in older people in these brain regions.

Neurofibrillary tangle distribution in posterior cortical atrophy and early‐onset Alzheimer disease

AbstractBackgroundEarly onset sporadic Alzheimer’s disease (AD) sometimes presents with non‐memory symptoms attributed to relatively greater neocortical than hippocampal tau neurofibrillary tangle (NFT) density. Posterior cortical atrophy (PCA) is a variant of AD presenting with visuospatial deficits and atrophy of the occipital cortex, yet the pathologic underpinning is poorly understood.MethodWe examined brains of 50 patients with early onset (age<65 y.), autopsy‐confirmed AD from the UCSD Alzheimer’s Disease Research Center, 12 of whom were clinically diagnosed with PCA. Immunohistochemistry for tau was performed in the hippocampus (HP), midfrontal cortex (MF), and occipital cortex (OC), and the density of NFTs was measured.ResultPCA and non‐PCA patients did not significantly differ in age (63.35±4.59 y. at death) or sex (40% female). The APOE ε4 allele was much less frequent in PCA (p = 0.002). While the PCA group was less impaired on the MMSE (p = 0.01), they performed comparably on the CDR sum‐of‐boxes. The OC NFT density did not differ between the groups; however, the OC/HP (p = 0.04) and OC/MF (p = 0.008) ratios demonstrate that PCA cases had relatively greater OC pathology than non‐PCA patients. Across the groups, age at symptom onset was inversely associated with OC NFT density (p = 0.01) and the OC/HP NFT ratio (p = 0.008), such that earlier onset was associated with greater OC NFT burden. Visuospatial performance, measured by the Block Design test, was associated with the OC NFT density (p = 0.006), as well as the OC/HP (p = 0.007) and OC/MF NFT ratios (p = 0.03), with the effects remaining significant when restricting to non‐PCA participants. In contrast, memory performance measured by the Logical Memory Immediate Recall measure was only associated with HP NFT density (p = 0.02).ConclusionDespite differences in the predominance of early visuospatial symptoms, PCA and non‐PCA patients did not differ in OC tangle density, with some of the highest densities in non‐PCA patients. However, the degree of visuospatial impairment was associated with the OC/HP NFT ratio across both groups. Results suggest that greater memory impairment in the non‐PCA patients associated with a higher HP tangle density may moderate the predominance of visuospatial impairment so that they do not receive a formal PCA diagnosis.

Genetic Drivers of Atypical Alzheimer’s Disease Neuropathologic Change

AbstractBackgroundQuantitative differences in neurofibrillary tangle density are not well captured by more global measures such as Braak staging. Indeed, amongst cases with high Alzheimer’s disease neuropathologic change (ADNC), quantitative differences in the distribution of neurofibrillary tangle density is associated with atypical, non‐amnestic clinical presentations. We sought here to study the effect of TREM2 and APOE risk genotypes on neuropathologically and clinically defined atypical Alzheimer’s disease.MethodsTREM2 variant versus wild‐type autopsy cases with an intermediate to high level of ADNC were identified from the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Archived clinical records were used to classify cases into typical versus atypical AD. Neuropathologic classification of cases into typical versus atypical AD was based on quantification of neurofibrillary tangle density using PHF1 stained sections from neocortical and hippocampal regions. Morphology from Iba1 stained sections was used to quantify microglial reactivity.Results31 AD cases with TREM2 risk genotypes were compared to wild‐type TREM2 AD cases (n = 119). TREM2 variants were associated with a significantly higher proportion of atypical AD clinical phenotypes including behavioral/dysexecutive variants, primary progressive aphasias, posterior cortical atrophy, and others (19.33% versus 48.39%, Fisher’s exact test p = 0.002). These clinical phenotypes were associated with a significantly higher proportion of TREM2 variant cases with neuropathologically defined atypical AD, namely hippocampal sparing AD (8.7% versus 28.57%, Fisher’s exact test p = 0.046). Moreover, the proportion of microglia with a dystrophic morphology correlated with neurofibrillary tangle density and not amyloid burden. Finally, to get a sense of the magnitude of this TREM2 association relative to other genetic risk factors, we observed a non‐significant trend towards the absence of the APOE E4 risk genotype being associated with hippocampal sparing AD.ConclusionsThis clinicopathologic correlation study suggests that TREM2 risk variants are associated with clinically and neuropathologically defined atypical AD. Given that both TREM2 and APOE affect microglial reactivity to amyloid, the observed tendency towards TREM2 variant cases exhibiting hippocampal sparing AD suggests that altered microglial reactivity to amyloid may change downstream tauopathy patterns leading to atypical AD clinical phenotypes.

In‐vivo and post‐mortem retinal and brain pathological findings in a homozygote for the A431E PSEN1 mutation

AbstractBackgroundThe neuropathology associated with PSEN1 mutations shares many features with late‐onset Alzheimer’s disease although atypical features are also seen. An important question is whether the manifestations of PSEN1 mutations are dose‐dependent. We present the neuropathological findings of a homozygote for the pathogenic A431E mutation in PSEN1 relative to heterozygotes and the finding of retinal Aβ lesions consistent with those that were topographically detected in vivo by retinal fluorescence imaging.MethodsA homozygote for the A431E PSEN1 mutation began having symptoms at age 33 and underwent a comprehensive ophthalmic and neurologic evaluation at age 37 before passing away at age 39. Brain and eyes were collected and brain sections and retinal flatmounts and cross‐sections were processed and immunostained with 4G8 or 12F4 (anti‐Aβ), AT8 or pS396 (anti‐phosphoTau) antibodies. Retinal vascular and astrocytic markers were also assessed.ResultsBrain weight of the homozygote was 1180 grams relative to 840 and 860 grams in two heterozygotes with only mild to moderate gross atrophy appreciable relative to moderate to severe atrophy in the heterozygotes. More abundant 4G8 (Aβ) staining was appreciable in widespread brain areas in the homozygote relative to the heterozygotes with some having a “cotton wool” morphology. Conversely, neurofibrillary tangle density was markedly lower in the homozygote relative to heterozygotes in all areas assessed. Retinal in vivo imaging revealed very small, yellow deposits in the macula in both eyes that were atypical for a 37‐year‐old. These lesions correlated topographically with areas of Aβ deposits stained in post‐mortem flatmounts. In retinal cross‐section, Aβ accumulation, including vascular Aβ40 and Aβ42 deposits, pS396‐positive staining and NFTs are clearly detected, along with enhanced GFAP‐positive gliosis.ConclusionThe neuropathological changes seen in a person homozygous for the A431E PSEN1 mutation showed an increased degree of Aβ pathology and evidence of a lesser degree of downstream pathology, possibly representing a more rapidly evolving disease with progressive disability despite a relative lack of neurodegeneration. We also demonstrated that Aβ and tau pathology occurs in the retina in this form of AD and that it can be visualized on clinical examination during life.Funded by: P30AG066530, U01AG051218, R01AG062007

Alzheimer Plasma Biomarkers Distinguish SuperAgers from their Cognitively Average Peers

AbstractBackgroundSuperAgers are individuals ≥80 years old who were selected for having episodic memory performance that is at least as good as individuals 20‐30 years their junior. We have previously shown that on average SuperAgers show lower neurofibrillary tangle density in the entorhinal cortex than cognitively average controls, which may be one biological factor contributing to superior memory beyond the 8th decade. This preliminary study investigated whether plasma concentrations of Alzheimer and related neurodegenerative biomarkers differ between SuperAgers and their cognitively average peers.MethodSuperAgers (N = 61) and Cognitively Average Controls (N = 28) were enrolled through the SuperAging Research Program. The plasma biomarkers amyloid β peptide 40 (Aβ40), amyloid β peptide 42 (Aβ42), neurofilament light (NFL), phosphorylated tau‐181 (pTau‐181), and glial fibrillary acidic protein (GFAP) were measured in SuperAgers and Cognitively Average participants using the Quanterix single molecule protein detection (SIMOA) platform. Independent samples t‐tests were used for statistical analyses (significance was set at p<0.05, uncorrected).ResultThere were no significant differences in mean age between SuperAgers and Cognitively Average Controls. Concentrations of Aβ42, Aβ40, the ratio of Aβ42/Aβ40, NFL or GFAP did not significantly differ between groups. On average, SuperAgers and Controls showed pTau‐181 levels that were <16.5 pg/mL, falling within the “Unlikely Alzheimer’s” designation according to Quanterix guidelines. SuperAgers showed significantly lower pTau‐181 levels compared to Cognitively Average Controls [M = 5.42 pg/mL (SD = 2.60) vs M = 7.10 pg/mL (SD = 3.14), respectively].ConclusionPlasma phosphotau biomarkers are promising for the assessment of brain integrity versus degeneration across the age‐Alzheimer continuum. The current results provide preliminary support for the contention that the SuperAger brain may be even more removed from the Alzheimer side of the continuum than neurotypical controls.Emily Rogalski and Changiz Geula contributed equally to this study.

Accurate digital quantification of tau pathology in progressive supranuclear palsy

The development of novel treatments for Progressive Supranuclear Palsy (PSP) is hindered by a knowledge gap of the impact of neurodegenerative neuropathology on brain structure and function. The current standard practice for measuring postmortem tau histology is semi-quantitative assessment, which is prone to inter-rater variability, time-consuming and difficult to scale. We developed and optimized a tau aggregate type-specific quantification pipeline for cortical and subcortical regions, in human brain donors with PSP. We quantified 4 tau objects (‘neurofibrillary tangles’, ‘coiled bodies’, ‘tufted astrocytes’, and ‘tau fragments’) using a probabilistic random forest machine learning classifier. The tau pipeline achieved high classification performance (F1-score > 0.90), comparable to neuropathologist inter-rater reliability in the held-out test set. Using 240 AT8 slides from 32 postmortem brains, the tau burden was correlated against the PSP pathology staging scheme using Spearman’s rank correlation. We assessed whether clinical severity (PSP rating scale, PSPRS) score reflects neuropathological severity inferred from PSP stage and tau burden using Bayesian linear mixed regression. Tufted astrocyte density in cortical regions and coiled body density in subcortical regions showed the highest correlation to PSP stage (r = 0.62 and r = 0.38, respectively). Using traditional manual staging, only PSP patients in stage 6, not earlier stages, had significantly higher clinical severity than stage 2. Cortical tau density and neurofibrillary tangle density in subcortical regions correlated with clinical severity. Overall, our data indicate the potential for highly accurate digital tau aggregate type-specific quantification for neurodegenerative tauopathies; and the importance of studying tau aggregate type-specific burden in different brain regions as opposed to overall tau, to gain insights into the pathogenesis and progression of tauopathies.

Protective Association of HLA-DRB1*04 Subtypes in Neurodegenerative Diseases Implicates Acetylated Tau PHF6 Sequences

Objective To explore genetic association between human leukocyte antigen (HLA) and neurodegenerative diseases and investigate mechanisms behind the association. Background Pathophysiology of Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) involves accumulation of tau (neurofibrillary tangles) and amyloid-ß-rich (amyloid plaques) aggregates in AD, a-synuclein-rich aggregates (Lewy bodies) in PD and TDP-43 aggregates in ALS, although these aggregates may also co-occur. Likewise, consensus is growing that tau may play a key role in PD and ALS as well. Design/Methods We analyzed HLA associations in ∼176,000 individuals with PD or AD versus controls across ancestry groups. Pursuing this, we also compared postmortem brain density of neurofibrillary tangles and amyloid plaques in brain, tau and Aß42 levels in cerebrospinal fluid (CSF) of ∼8,000 individuals (controls and AD), and examined association of HLA in ∼2,500 patient with pathologically demonstrated Lewy Body Dementia. This was followed by HLA binding and tetramer T cell studies. Results A shared genetic association was observed across AD and PD at rs601945 (PD: odds ratio (OR) = 0.84; 95% confidence interval, [0.80; 0.88]; p = 2.2 x 10-13; AD: OR = 0.91[0.89; 0.93]; p = 1.8 x 10-22) and with a protective HLA association recently reported in ALS. Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03 and absent for HLA-DRB1*04:05. The same signal was associated with decreased neurofibrillary tangle (but not neuritic plaque) density postmortem and was more associated with lower tau levels than Aß42 level changes in CSF. Furthermore, protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. T cells recognizing this epitope were identified, showing relevance of this immune response in patients with neurodegenerative disorders. Conclusions An HLA-DRB1*04-mediated adaptive immune response, potentially against tau, decreases PD, AD and ALS risk, offering the possibility of new therapeutic avenues.

Age‐at‐Onset and APOE Related Heterogeneity in the Clinical, Plasma Biomarker, and Neuropathologic Presentation of Alzheimer’s Disease (AD)

AbstractBackgroundPatients with sporadic early‐onset AD (EOAD) show less pronounced memory impairment, faster cognitive decline, and greater likelihood of focal cortical syndromes than those with later onset (LOAD), while often lacking the APOE ε4 allele classically associated with younger onset. This heterogeneity could arise from differences in the distribution of AD pathology or presence of concomitant pathologies.MethodWe examined clinical and cognitive heterogeneity in relation to age‐at‐onset, APOE genotype, and concomitant neuropathology (Lewy body, TDP‐43, and vascular) in patients with autopsy‐confirmed severe AD from the National Alzheimer’s Coordinating Center database (N=1750). In patients from the UCSD Alzheimer’s Disease Research Center (N=121) we examined how age‐related heterogeneity relates to differences in distribution of neurofibrillary tangle (NFT) pathology and plasma biomarkers of AD.ResultAge‐at‐onset distribution in APOE ε4‐ patients was bimodal with best separation at age 63. Patients with EOAD (age ≤63) had faster cognitive and functional decline than LOAD regardless of APOE genotype; and were more likely to present with nonmemory cognitive complaints (OR=5.56, 99%CI: 3.32‐9.39), show greater executive dysfunction (β=2.59 SD, 99%CI: 2.10‐3.09), and receive a non‐AD clinical diagnosis (OR=1.54, 99%CI: 1.19‐1.97), particularly for ε4‐ EOAD (p’s<0.01, APOE × age‐at‐onset interactions). Despite this atypicality, groups did not differ in their high rates of AD biomarker positivity, and ε4‐ EOAD patients were most likely to have pure AD without concomitant pathology. TDP‐43 (OR=0.37; 99%CI: 0.18–0.72) and microvascular (OR=0.65; 99%CI: 0.47–0.88) pathology were less common in EOAD, while Lewy pathology was more common in ε4+ (OR=1.48; 99% CI, 1.02–2.17). Midfrontal NFT density was higher in EOAD than LOAD (β= 0.87 SD, 99%CI: 0.44‐1.29). Greater hippocampal NFT density was associated with APOE ε4+ (β=0.49 SD, 99%CI: 0.02‐0.96). Mediation analyses suggest that differences in midfrontal/hippocampal NFT ratio, rather than concomitant neuropathology, mediate the atypical cognitive profiles and decline of EOAD (p<0.01).ConclusionA relatively more neocortical NFT distribution, rather than concomitant non‐AD pathology, accounts for the atypical, non‐memory dominant clinical presentation and rapid progression in EOAD. This suggests that selective cortical vulnerability may explain the earlier‐than‐expected onset and atypical profile in these individuals without the APOE ε4 risk allele.

TREM2 risk variants are associated with atypical Alzheimer's disease.

Alzheimer's disease (AD) has multiple clinically and pathologically defined subtypes where the underlying causes of such heterogeneity are not well established. Rare TREM2 variants confer significantly increased risk for clinical AD in addition to other neurodegenerative disease clinical phenotypes. Whether TREM2 variants are associated with atypical clinical or pathologically defined subtypes of AD is not known. We studied here the clinical and pathological features associated with TREM2 risk variants in an autopsy-confirmed cohort. TREM2 variant cases were more frequently associated with non-amnestic clinical syndromes. Pathologically, TREM2 variant cases were associated with an atypical distribution of neurofibrillary tangle density with significantly lower hippocampal NFT burden relative to neocortical NFT accumulation. In addition, NFT density but not amyloid burden was associated with an increase of dystrophic microglia. TREM2 variant cases were not associated with an increased prevalence, extent, or severity of co-pathologies. These clinicopathological features suggest that TREM2 variants contribute to clinical and pathologic AD heterogeneity by altering the distribution of neurofibrillary degeneration and tau-dependent microglial dystrophy, resulting in hippocampal-sparing and non-amnestic AD phenotypes.

Longitudinal change in serial position scores in older adults with entorhinal and hippocampal neuropathologies.

Serial position scores on verbal memory tests are sensitive to early Alzheimer's disease (AD)-related neuropathological changes that occur in the entorhinal cortex and hippocampus. The current study examines longitudinal change in serial position scores as markers of subtle cognitive decline in older adults who may be in preclinical or at-risk states for AD. This study uses longitudinal data from the Religious Orders Study and the Rush Memory and Aging Project. Participants (n = 141) were included if they did not have dementia at enrollment, completed follow-up assessments, and died and were classified as Braak stage I or II. Memory tests were used to calculate serial position (primacy, recency), total recall, and episodic memory composite scores. A neuropathological evaluation quantified AD, vascular, and Lewy body pathologies. Mixed effects models were used to examine change in memory scores. Neuropathologies and covariates (age, sex, education, APOE e4) were examined as moderators. Primacy scores declined (β = -.032, p < .001), whereas recency scores increased (β = .021, p = .012). No change was observed in standard memory measures. Greater neurofibrillary tangle density and atherosclerosis explained 10.4% of the variance in primacy decline. Neuropathologies were not associated with recency change. In older adults with hippocampal neuropathologies, primacy score decline may be a sensitive marker of early AD-related changes. Tangle density and atherosclerosis had additive effects on decline. Recency improvement may reflect a compensatory mechanism. Monitoring for changes in serial position scores may be a useful in vivo method of tracking incipient AD.

Brain ethanolamine phospholipids, neuropathology and cognition: A comparative post-mortem analysis of structurally specific plasmalogen and phosphatidyl species.

Reduced cognition in the elderly is associated with low levels of plasmalogens and high levels of lipid rafts, amyloid plaques, and neurofibrillary tangles in the temporal cortex. A systematic integrative analysis of key indices of these pathologies to determine their collective and independent contributions to cognition was performed. Levels of four phosphatidylethanolamines (PE) and four ethanolamine plasmalogens (PL) of identical sn-1 carbon length and desaturation (stearic, 18:0) and identical sn-2 fatty acid compositions of varying side chain lengths and degrees of unsaturation (oleic, 18:1; linoleic, 18:2; arachidonic, 20:4; docosahexaenoic, 22:6), flotillin-1 expression and amyloid plaque and neurofibrillary tangle densities were measured in inferior temporal cortex tissue from 100 elderly subjects (Rush University Memory and Aging Project, 88.5 ± 5.8 years old). Subjects were evenly distributed with respect to gender (52/48, F/M) and cognitive status (38/24/38, no cognitive impairment/mild cognitive impairment/Alzheimer’s dementia) proximate to death. Multivariate logistic regression analyses were used to determine the relative and collective associations of the neuropathological indices with cognition. Higher levels of tangles, amyloid, or flotillin and lower levels of PL 18:0/22:6 were significantly associated with lower cognition in the base model (adjusted for age, sex, education). Multivariate analysis revealed that only PL 18:0/22:6 (β = 0.506; p < 0.00001), tangles (−0.307; p < 0.01), and flotillin (−0.2027; p < 0.05) were independently associated with reduced cognition. PL 18:0/22:6 and PE 18:0/22:6 levels were independently associated with cognition in the presence of tangles, amyloid, and flotillin, but only PL 18:0/22:6 retained its association with cognition when both PL and PE 18:0/22:6 were included in the model indicating that PE 18:0/22:6 levels were associated with PL 18:0/22:6, not cognition. Only high brain levels of PL 18:0/22:6 (>mean+1SD) was predictive of normal cognition (coef = 1.67, p < 0.05) and non-demented state (coef = −2.73, p < 0.001), whereas low levels of PL 18:0/22:6 and high levels of tangles or flotillin were predictive of dementia. The association of high brain polyunsaturated (PUFA)-PL levels with better cognition was independent of amyloid plaque, neurofibrillary tangle, PE, and flotillin-1 expression. Maintenance or augmentation of brain docosahexaenoic (DHA)-PL levels warrants further investigation as a target for preventing cognitive decline or improving cognition in the elderly, respectively.

Focal amyloid and asymmetric tau in an imaging-to-autopsy case of clinical primary progressive aphasia with Alzheimer disease neuropathology

Quantification of in vivo amyloid and tau PET imaging relationships with postmortem measurements are critical for validating the sensitivity and specificity imaging biomarkers across clinical phenotypes with Alzheimer disease neuropathologic change (ADNC). This study examined the quantitative relationship between regional binding of in vivo 18F-florbetapir amyloid PET and 18F-flortaucipir tau PET with postmortem stereological counts of amyloid plaques and neurofibrillary tangles (NFT) in a case of primary progressive aphasia (PPA) with ADNC, where neurodegeneration asymmetrically targets the left hemisphere. Beginning 2 years prior to death, a 63-year-old right-handed man presenting with agrammatic variant PPA underwent a florbetapir and flortaucpir PET scan, and neuropsychological assessments and magnetic resonance imaging sessions every 6 months. Florbetapir and flortaucpir PET standard uptake value ratios (SUVRs) were quantified from 8 left and right hemisphere brain regions with stereological quantification of amyloid plaques and NFTs from corresponding postmortem sections. Pearson’s correlations and measures of asymmetry were used to examine relationships between imaging and autopsy measurements. The three visits prior to death revealed decline of language measures, with marked progression of atrophy. Florbetapir PET presented with an atypical focal pattern of uptake and showed a significant positive correlation with postmortem amyloid plaque density across the 8 regions (r = 0.92; p = 0.001). Flortaucipir PET had a left-lateralized distribution and showed a significant positive correlation with NFT density (r = 0.78; p = 0.023). Flortaucipir PET and NFT density indicated a medial temporal lobe sparing presentation of ADNC, demonstrating that AD does not always target the medial temporal lobe. This study adds additional evidence, in a non-amnestic phenotype of ADNC, that there is a strong correlation between AD PET biomarkers, florbetapir and flortaucipir, with quantitative neuropathology. The atypical and focal presentation of plaque density and florbetapir PET uptake suggests not all amyloid pathology presents as diffuse across neocortex.

Pelargonidin and Berry Intake Association with Alzheimer's Disease Neuropathology: A Community-Based Study.

An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer's dementia risk. This study investigated if pelargonidin or berry intake is associated with Alzheimer's disease (AD) neuropathology in human brains. The study was conducted among 575 deceased participants (age at death = 91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed. In a linear regression model adjusted for age at death, sex, education, APOE ɛ4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE) = -0.293 (0.14), p = 0.038), and fewer phosphorylated tau tangles (β (SE) = -0.310, p = 0.051). Among APOE ɛ4 non-carriers, higher strawberry (β (SE) = -0.227 (0.11), p = 0.037) and pelargonidin (Q4 versus Q1: β (SE) = -0.401 (0.16), p = 0.011; p trend = 0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ɛ4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p = 0.004) and pelargonidin (ptrend = 0.007) intake were associated with fewer phosphorylated tau tangles. Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.

Entorhinal Subfield Vulnerability to Neurofibrillary Tangles in Aging and the Preclinical Stage of Alzheimer's Disease.

Background:Neurofibrillary tangle (NFT) accumulation in the entorhinal cortex (EC) precedes the transformation from cognitive controls to mild cognitive impairment and Alzheimer’s disease (AD). While tauopathy has been described in the EC before, the order and degree to which the individual subfields within the EC are engulfed by NFTs in aging and the preclinical AD stage is unknown.Objective:We aimed to investigate substructures within the EC to map the populations of cortical neurons most vulnerable to tau pathology in aging and the preclinical AD stage.Methods:We characterized phosphorylated tau (CP13) in 10 cases at eight well-defined anterior-posterior levels and assessed NFT density within the eight entorhinal subfields (described by Insausti and colleagues) at the preclinical stages of AD. We validated with immunohistochemistry and labeled the NFT density ratings on ex vivo MRIs. We measured subfield cortical thickness and reconstructed the labels as three-dimensional isosurfaces, resulting in anatomically comprehensive, histopathologically validated tau “heat maps.”Results:We found the lateral EC subfields ELc, ECL, and ECs (lateral portion) to have the highest tau density in semi-quantitative scores and quantitative measurements. We observed significant stepwise higher tau from anterior to posterior levels (p < 0.001). We report an age-dependent anatomically-specific vulnerability, with all cases showing posterior tau pathology, yet older individuals displaying an additional anterior tau burden. Finally, cortical thickness of each subfield negatively correlated with respective tau scores (p < 0.05).Conclusion:Our findings indicate that posterior-lateral subfields within the EC are the most vulnerable to early NFTs and atrophy in aging and preclinical AD.

Substrate-selective positive allosteric modulation of PTPRD’s phosphatase by flavonols

The receptor type protein tyrosine phosphatase D (PTPRD) is expressed by neurons and implicated in interesting phenotypes that include reward from addictive substances, restless leg syndrome and neurofibrillary tangle densities in Alzheimer’s disease (AD-NFTs). However, the brain phosphotyrosine phosphoprotein (PTPP) substrates for PTPRD’s phosphatase have not been clearly defined. Although we have identified small molecule inhibitors of PTPRD’s phosphatase that are candidates for reducing reward from addictive substances, no positive allosteric modulators of this phosphatase that might be candidates for reducing AD-NFTs have been reported.We now report identification of candidate brain substrates for PTPRD based on their increased phosphorylation in knockout vs wildtype animals, coexpression with PTPRD in neuronal subtypes and brisk dephosphorylation by recombinant human PTPRD phosphatase. We also report discovery that quercetin and other flavonols, though not closely-related flavones, enhance rates of PTPRD’s dephosphorylation of a group of these candidate substrate PTPPs but not others. This substrate-selective positive allosteric modulation provides a novel pharmacological action. Flavonol-mediated increases in PTPRD’s dephosphorylation of the GSK3 β and α kinases that hyperphosphorylate tau, the major component of AD-NFTs, could help to explain recent data concerning genetic and dietary impacts on Alzheimer’s disease.

Frontotemporal neurofibrillary tangles and cerebrovascular lesions are associated with autism spectrum behaviors in late-life dementia.

The pathologic substrates or neuroanatomic regions responsible for similarities in behavioral features seen in autism spectrum disorder and late-life dementia remain unknown. The present study examined the neuropathologic features of late-life dementia in research volunteers with and without antemortem behaviors characteristic of autism spectrum disorders. Antemortem cross-sectional assessment of autistic spectrum behaviors proximal to death in persons with diagnosis of mild cognitive impairment or dementia was completed using the Gilliam Autism Rating Scale, 2nd edition (GARS-2), followed by postmortem quantitative and semiquantitative neuropathologic assessment. All individuals who completed the GARS-2 prior to autopsy were included (n = 56) and we note that no participants had known diagnosis of autism spectrum disorder. The GARS-2 was used as an antemortem screening tool to stratify participants into two groups: "Autism Possible/Very Likely" or "Autism Unlikely." Data were analyzed using nonparametric statistics comparing location and scale to evaluate between-group differences in pathologic features. Neurofibrillary tangles (NFT; p = 0.028) density and tau burden (p = 0.032) in the frontal region, the NFT density (p = 0.048) and neuritic plaque burden (p = 0.042), and the tau burden (p = 0.032) of the temporal region, were significantly different in scale between groups. For measures with significant group differences, the medians of the Autism Possible/Very Likely group were roughly equal to the 75th percentile of the Autism Unlikely group (i.e., the distributions were shifted to the right). This study links behaviors characteristic of autism to increased pathologic tau burden in the frontal and temporal lobes in persons with late-life dementia. Additional studies are needed to determine causal factors and treatment options for behaviors characteristic of autism behaviors in late-life dementias.

Molecular Subgroup Classification in Alzheimer's Disease by Transcriptomic Profiles.

Alzheimer's disease (AD) is a progressive cognitive disorder that occurs worldwide, and the lack of disease-modifying targets and pathways is a pressing issue. This study aimed to provide new targets and pathways by performing molecular subgroup classification. After normalizing the collected data, the subgroup number was confirmed with consensus clustering. Comparisons of clinical features among subgroups were conducted to clarify the clinical traits of each subgroup. Subgroup-specific genes were identified to perform weighted gene coexpression analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out. Next, gene set enrichment analysis (GSEA) was performed. Protein-protein interaction networks were built to screen core genes and in each subgroup to perform Spearman correlation analysis with clinical traits. Sequencing profiles of 1068 AD samples collected from 2 datasets were classified into 3 subgroups. Clinical comparisons revealed that patients in subgroup III tended to be younger, while their pathological grades were the most severe. WGCNA detected four gene modules, and the turquoise module, where the dopaminergic synapse pathway was enriched, was related to subgroup I. The neurotrophin signaling pathway and TGF-beta signaling pathway were robustly enriched in the blue and brown modules, respectively, in subgroup III. Moreover, 3 hub genes in subgroup I were negatively correlated with the sum of neurofibrillary tangle (Nft) density. Conversely, hub genes in subgroups II and III exhibited positive correlations with the sum of Nft density. These results provide new pathways and targets for AD treatment.

Extracranial carotid atherosclerosis is associated with increased neurofibrillary tangle accumulation.

We sought to determine whether extracranial carotid atherosclerotic disease (ECAD) is associated with increased key neurodegenerative pathology such as neurofibrillary tangle (NFT), beta-amyloid plaque, or cerebral amyloid angiopathy (CAA) accumulation, findings associated with Alzheimer's disease (AD) and other dementias. Our prospective, longitudinal, clinicopathologic study, the AZSAND (Arizona study of aging and neurodegenerative disorders) and Brain and Body Donation Program, recorded the presence or absence of clinically diagnosed ECAD and performed semiquantitative density estimates of NFT, beta-amyloid plaque, and CAA at death. After adjusting for potential confounding factors determined by logistic regression analysis, histopathology density scores were evaluated in individuals with ECAD (n= 66) and those without ECAD (n= 125). We found that the presence of ECAD was associated with a 21% greater NFT burden at death compared with no ECAD (P= .02). Anatomically, an increased NFT burden was seen throughout the brain regions evaluated but was significant in the temporal lobe (P< .05) and entorhinal cortex (P= .02). In addition, we found that subjects who had undergone carotid endarterectomy (CEA), the surgical treatment of ECAD (n= 32), had decreased NFT densities compared with those with ECAD who had not undergone CEA (n= 66; P= .04). In contrast to NFT, ECAD was not associated with beta-amyloid plaques or CAA density. These findings indicate that ECAD is associated with the NFT burden in the temporal lobe and entorhinal cortex, which has clinical significance for AD and non-AD dementias and cognitive dysfunction. Further understanding of whether ECAD increases the risk of neurodegenerative brain changes is highly relevant because ECAD is a treatable disease that has not, otherwise, been evaluated for nor specifically treated as a dementia risk factor.