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We applied graph theory analysis on resting-state functional magnetic resonance imaging data to evaluate sex differences of brain functional topography in normal controls (NCs), early mild cognitive impairment (eMCI), and AD patients. These metrics were correlated with RAVLT verbal learning and memory scores. The results show NCs have better functional connectivity (FC) metrics than eMCI and AD, and NC women show worse FC metrics compared to men, despite performing better on the RAVLT. FC differences between men and women diminished in eMCI and disappeared in AD. Within women, better FC metrics relate to better RAVLT learning in NCs and eMCI groups.

Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer's disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD.

We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia.

We assessed Aβ proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry.

The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment.

The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.

The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.Amyloid-β (Aβ) peptides and hyperphosphorylated tau protein are the most important pathological markers of Alzheimer's disease (AD). Enitociclib purchase Neuroinflammation and oxidative stress are also involved in the development and pathological mechanism of AD. Hypoxia inducible factor-1α (HIF-1α) is a transcriptional factor responsible for cellular and tissue adaption to low oxygen tension. Emerging evidence has revealed HIF-1α as a potential medicinal target for neurodegenerative diseases. On the one hand, HIF-1α increases AβPP processing and Aβ generation by promoting β/γ-secretases and suppressing α-secretases, inactivates microglia and reduces their activity, contributes to microglia death and neuroinflammation, which promotes AD pathogenesis. On the other hand, HIF-1α could resist the toxic effect of Aβ, inhibits tau hyperphosphorylation and promotes microglial activation. In summary, this review focuses on the potential complex roles and the future perspectives of HIF-1α in AD, in order to provide references for seeking new drug targets and treatment methods for AD.Primary progressive aphasia (PPA) is mainly considered a sporadic disease and few studies have systematically analyzed its genetic basis. We here report the analyses of C9orf72 genotyping and whole-exome sequencing data in a consecutive and well-characterized cohort of 50 patients with PPA. We identified three pathogenic GRN variants, one of them unreported, and two cases with C9orf72 expansions. In addition, one likely pathogenic variant was found in the SQSTM1 gene. Overall, we found 12%of patients carrying pathogenic or likely pathogenic variants. These results support the genetic role in the pathophysiology of a proportion of patients with PPA.Alzheimer's disease (AD) is the leading cause of dementia. With aging societies, the prevalence of AD is increasing dramatically worldwide. The onset of AD is often not identified, and currently no available treatments are capable of stopping the disease process and its effect on cognitive decline. Thus, well-validated biomarkers of the preclinical stages of AD are needed. Alzheimer-associated neuronal thread protein (AD7c-NTP) is a member of the neuronal thread protein family and has a molecular weight of approximately 41 kD. AD7c-NTP has been identified as a biomarker for its specifically elevated levels in putative brain domains, cerebrospinal fluid (CSF), and the urine of AD and mild cognitive impairment (MCI) patients. Since the urine test is non-invasive, easy to perform, and patients accept it more easily than other methods, the urinary AD7c-NTP concentration has been recommended as a practical diagnostic tool for diagnosing AD and MCI. AD7c-NTP has undergone nearly 25 years of research course from its initial discovery to pathological verification, multi-center clinical evaluation, improvement of detection methods, epidemiological investigation, and combined application with other biomarkers. However, as a fluid biomarker, AD7c-NTP can be detected in urine instead of the traditional biomarker sources-CSF or blood, which has made the use of AD7c-NTP as a biomarker controversial. In this article, we review the research course of AD7c-NTP and suggest directions for future research.

Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients.

To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheralblood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice.

By real-time PCR and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence.

Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores.