Self-Reported Late-Life Hypertension Is Associated with a Healthy Cognitive Status and Reduced Alzheimer's Disease Pathology Burden.

Background: While mid-life hypertension represents a risk factor for the development of Alzheimer's disease (AD), the risk after the age of 65 is less certain. Establishing relationships between late life hypertension and the pathological changes of AD could be crucial in understanding the relevance of blood pressure as a risk factor for this disorder. Objective: We investigated associations between self-reported late-life hypertension, cognitive status and AD pathology at death. The impact of antihypertensive medication was also examined. Methods: Using the Cornell Medical Index questionnaire, we ascertained whether participants had ever reported hypertension. We also noted use of antihypertensive medication. The donated brains of 108 individuals were assessed for AD pathology using consensus guidelines. Statistical analysis aimed to elucidate relationships between hypertension and AD pathology. Results: We found no associations between self-reported hypertension and cognitive impairment at death. However, those with hypertension were significantly more likely to exhibit lower levels of AD pathology as measured by Thal phase, Braak stage, CERAD score, and NIA-AA criteria-even after controlling for sex, level of education and presence of APOEɛ4 allele(s). No significant associations could be found when examining use of antihypertensive medications. Conclusions: Our findings suggest that late-life hypertension is associated with less severe AD pathology. We postulate that AD pathology may be promoted by reduced cerebral blood flow.

Distinct tau folds initiate templated seeding and alter the post-translational modification profile.

Pathological tau accumulates in the brain in tauopathies such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration, and forms amyloid-like filaments incorporating various post-translational modifications (PTMs). Cryo-electron microscopic (cryo-EM) studies have demonstrated that tau filaments extracted from tauopathy brains are characteristic of the disease and share a common fold(s) in the same disease group. Furthermore, the tau PTM profile changes during tau pathology formation and disease progression, and disease-specific PTMs are detected in and around the filament core. In addition, templated seeding has been suggested to trigger pathological tau amplification and spreading in vitro and in vivo, although the molecular mechanisms are not fully understood. Recently, we reported that the cryo-EM structures of tau protofilaments in SH-SY5Y cells seeded with patient-derived tau filaments show a core structure(s) resembling that of the original seeds. Here, we investigated PTMs of tau filaments accumulated in the seeded cells by liquid chromatography/tandem mass spectrometry and compared them with the PTMs of patient-derived tau filaments. Examination of insoluble tau extracted from SH-SY5Y cells showed that numerous phosphorylation, deamidation and oxidation sites detected in the fuzzy coat in the original seeds were well reproduced in SH-SY5Y cells. Moreover, templated tau filament formation preceded both truncation of the N-/C-terminals of tau and PTMs in and around the filament core, indicating these PTMs may predominantly be introduced after the degradation of the fuzzy coat.

Cryo-EM structures of tau filaments from SH-SY5Y cells seeded with brain extracts from cases of Alzheimer's disease and corticobasal degeneration.

The formation of amyloid filaments through templated seeding is believed to underlie the propagation of pathology in most human neurodegenerative diseases. A widely used model system to study this process is to seed amyloid filament formation in cultured cells using human brain extracts. Here, we report the electron cryo-microscopy structures of tau filaments from  undifferentiated seeded SH-SY5Y cells that transiently expressed N-terminally HA-tagged 1N3R or 1N4R human tau, using brain extracts from individuals with Alzheimer's disease or corticobasal degeneration. Although the resulting filament structures differed from those of the brain seeds, some degrees of structural templating were observed. Studying templated seeding in cultured cells, and determining the structures of the resulting filaments, can thus provide insights into the cellular aspects underlying neurodegenerative diseases.

Alzheimer's disease diagnosis by blood plasma molecular fluorescence spectroscopy (EEM).

Despite tremendous research advances in detecting Alzheimer's disease (AD), traditional diagnostic tests remain expensive, time-consuming or invasive. The search for a low-cost, rapid, and minimally invasive test has marked a new era of research and technological developments toward establishing blood-based AD biomarkers. The current study has employed excitation-emission matrices (EEM) of fluorescence spectroscopy combined with machine learning to diagnose AD using blood plasma samples from 230 individuals (83 AD patients from 147 healthy controls). To evaluate the performance of the classification algorithms, we calculated the commonly used figures of merit (accuracy, sensitivity and specificity) and figures of merit that take into account the samples unbalance and the discrimination power of the models, as F2-score (F2), Matthews correlation coefficient (MCC) and test effectiveness ([Formula: see text]). The classification models achieved satisfactory results: Parallel Factor Analysis with Quadratic Discriminant Analysis (PARAFAC-QDA) with 83.33% sensitivity, 100% specificity, 86.21% F2; and Tucker3-QDA with 91.67% sensitivity, 95.45% specificity and 91.67% F2. In addition, the classifiers show high overall performance with 94.12% accuracy and 0.87 MCC. Regarding the discrimination power between healthy and AD patients, the classification algorithms showed high effectiveness with the mean scores separated by three or more standard deviations. The PARAFAC's spectral profiles and the wavelength values from both models loading profiles can be used in future research to relate this information to plasma AD biomarkers. Our results point to a rapid, low-cost and minimally invasive blood-based method for AD diagnosis.

Erratum: Evaluation of 18F-IAM6067 as a sigma-1 receptor PET tracer for neurodegeneration in vivo in rodents and in human tissue: Erratum.

[This corrects the article DOI: 10.7150/thno.47585.].

Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43.

Intracellular accumulation of abnormal proteins with conformational changes is the defining neuropathological feature of neurodegenerative diseases. The pathogenic proteins that accumulate in patients' brains adopt an amyloid-like fibrous structure and exhibit various ultrastructural features. The biochemical analysis of pathogenic proteins in sarkosyl-insoluble fractions extracted from patients' brains also shows disease-specific features. Intriguingly, these ultrastructural and biochemical features are common within the same disease group. These differences among the pathogenic proteins extracted from patients' brains have important implications for definitive diagnosis of the disease, and also suggest the existence of pathogenic protein strains that contribute to the heterogeneity of pathogenesis in neurodegenerative diseases. Recent experimental evidence has shown that prion-like propagation of these pathogenic proteins from host cells to recipient cells underlies the onset and progression of neurodegenerative diseases. The reproduction of the pathological features that characterize each disease in cellular and animal models of prion-like propagation also implies that the structural differences in the pathogenic proteins are inherited in a prion-like manner. In this review, we summarize the ultrastructural and biochemical features of pathogenic proteins extracted from the brains of patients with neurodegenerative diseases that accumulate abnormal forms of tau, α-synuclein, and TDP-43, and we discuss how these disease-specific properties are maintained in the brain, based on recent experimental insights.

Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer's Disease Pathology at Death.

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown. OBJECTIVE: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage). METHODS: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants. RESULTS: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found. CONCLUSION: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, 'at risk' individuals could be targeted for early interventions which could attenuate the progression of the disease.

Structure-based classification of tauopathies.

The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease1,2, Pick's disease3, chronic traumatic encephalopathy4 and corticobasal degeneration5 are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer's disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.