The mechanisms, hallmarks, and therapies for brain aging and age-related dementia.

Age-related cognitive decline and dementia are significant manifestations of brain aging. As the elderly population grows rapidly, the health and socio-economic impacts of cognitive dysfunction have become increasingly significant. Although clinical treatment of dementia has faced considerable challenges over the past few decades, with limited breakthroughs in slowing its progression, there has been substantial progress in understanding the molecular mechanisms and hallmarks of age-related dementia (ARD). This progress brings new hope for the intervention and treatment of this disease. In this review, we categorize the latest findings in ARD biomarkers into four stages based on disease progression: healthy brain, pre-clinical, mild cognitive impairment, and dementia. We then systematically summarize the most promising therapeutic approaches to prevent or slow ARD at four levels: genome and epigenome, organelle, cell, and organ and organism. We emphasize the importance of early prevention and detection, along with the implementation of combined treatments as multimodal intervention strategies, to address brain aging and ARD in the future.

Subjective Difficulty with Higher-Level Functional Capacity in Community-Dwelling Older People withMild Cognitive Impairment.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a predictor of future age-related dementia.　We herein investigated associations of MCI with higher-level functional capacities, as well as with subjective difficulty regarding these functions, in community-dwelling older people, to identify a simple method for early MCI detection. METHOD: We administered a test battery to 118 community-dwelling older people living in an urban area.　The battery consisted of three tests;the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC), the Touch Panel-type Dementia Assessment Scale (TDAS), and the Geriatric Depression Scale-15.　We then excluded participants with possible dementia or depression symptoms, and divided the remainder (n = 67) into an MCI group (n = 16) and a non-MCI group (n = 51), according to TDAS performance. RESULTS: Logistic regression analysis with the MCI and non-MCI groups as dependent variables indicated that TMIG-IC was a significant variable.　Male sex and the perception that preparing meals and filling out pension forms had become more difficult were significantly associated with MCI, each independently increasing the probability of MCI. CONCLUSIONS: Subjective difficulty with higher-level functions and impairment in higher-level functional capacity may serve as indices for mass screening for MCI.

Remote Self-Administration of Cognitive Screeners for Older Adults Prior to a Primary Care Visit: Pilot Cross-Sectional Study of the Reliability and Usability of the MyCog Mobile Screening App.

BACKGROUND: Routine cognitive screening is essential in the early detection of dementia, but time constraints in primary care settings often limit clinicians' ability to conduct screenings. MyCog Mobile is a newly developed cognitive screening system that patients can self-administer on their smartphones before a primary care visit, which can help save clinics' time, encourage broader screening practices, and increase early detection of cognitive decline. OBJECTIVE: The goal of this pilot study was to examine the feasibility, acceptability, and initial psychometric properties of MyCog Mobile. Research questions included (1) Can older adults complete MyCog Mobile remotely without staff support? (2) Are the internal consistency and test-retest reliability of the measures acceptable? and (3) How do participants rate the user experience of MyCog Mobile? METHODS: A sample of adults aged 65 years and older (N=51) self-administered the MyCog Mobile measures remotely on their smartphones twice within a 2- to 3-week interval. The pilot version of MyCog Mobile includes 4 activities: MyFaces measures facial memory, MySorting measures executive functioning, MySequences measures working memory, and MyPictures measures episodic memory. After their first administration, participants also completed a modified version of the Simplified System Usability Scale (S-SUS) and 2 custom survey items. RESULTS: All participants in the sample passed the practice items and completed each measure. Findings indicate that the Mobile Toolbox assessments measure the constructs well (internal consistency 0.73 to 0.91) and are stable over an approximately 2-week delay (test-retest reliability 0.61 to 0.71). Participants' rating of the user experience (mean S-SUS score 73.17, SD 19.27) indicated that older adults found the usability of MyCog Mobile to be above average. On free-response feedback items, most participants provided positive feedback or no feedback at all, but some indicated a need for clarity in certain task instructions, concerns about participants' abilities, desire to be able to contact a support person or use in-app technical support, and desire for additional practice items. CONCLUSIONS: Pilot evidence suggests that the MyCog Mobile cognitive screener can be reliably self-administered by older adults on their smartphones. Participants in our study generally provided positive feedback about the MyCog Mobile experience and rated the usability of the app highly. Based on participant feedback, we will conduct further usability research to improve support functionality, optimize task instructions and practice opportunities, and ensure that patients feel comfortable using MyCog Mobile. The next steps include a clinical validation study that compares MyCog Mobile to gold-standard assessments and tests the sensitivity and specificity of the measures for identifying dementia.

Proteome Profiling of Brain Vessels in a Mouse Model of Cerebrovascular Pathology.

Cerebrovascular pathology that involves altered protein levels (or signaling) of the transforming growth factor beta (TGFß) family has been associated with various forms of age-related dementias, including Alzheimer disease (AD) and vascular cognitive impairment and dementia (VCID). Transgenic mice overexpressing TGFß1 in the brain (TGF mice) recapitulate VCID-associated cerebrovascular pathology and develop cognitive deficits in old age or when submitted to comorbid cardiovascular risk factors for dementia. We characterized the cerebrovascular proteome of TGF mice using mass spectrometry (MS)-based quantitative proteomics. Cerebral arteries were surgically removed from 6-month-old-TGF and wild-type mice, and proteins were extracted and analyzed by gel-free nanoLC-MS/MS. We identified 3602 proteins in brain vessels, with 20 demonstrating significantly altered levels in TGF mice. For total and/or differentially expressed proteins (p ≤ 0.01, ≥ 2-fold change), using multiple databases, we (a) performed protein characterization, (b) demonstrated the presence of their RNA transcripts in both mouse and human cerebrovascular cells, and (c) demonstrated that several of these proteins were present in human extracellular vesicles (EVs) circulating in blood. Finally, using human plasma, we demonstrated the presence of several of these proteins in plasma and plasma EVs. Dysregulated proteins point to perturbed brain vessel vasomotricity, remodeling, and inflammation. Given that blood-isolated EVs are novel, attractive, and a minimally invasive biomarker discovery platform for age-related dementias, several proteins identified in this study can potentially serve as VCID markers in humans.

Practical Experience with Age-related Dementia: Implementation and Outcomes of a Semester-long Service Learning Project in Neuropsychology.

Most neuroscience faculty share the common goal of maximizing student understanding of course material and increasing student excitement for the discipline. There is evidence that educational practices such as service learning, which is characterized by the fact that it both addresses a need in the community and meets key learning objectives in a course, can help accomplish these goals in an impactful way. This article describes the implementation of a service learning project at an assisted-living facility in an upper-level neuropsychology course. In addition, results of student self-evaluations indicate that students self-report higher understanding of course content and skills associated with working with people with disabilities. Lastly, a discussion of some benefits of implementation is provided along with advice to others wishing to implement a similar service learning project. This advice will help ensure a positive experience for students in the course as well as for residents at the assisted-living facility.

Investigation of CD26, a potential SARS-CoV-2 receptor, as a biomarker of age and pathology.

OBJECTIVE: In some individuals, coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leads to a variety of serious inflammatory symptoms, including blood clotting and acute respiratory distress. Death due to COVID-19 shows a steep rise in relation to age. Comorbidities such as type 2 diabetes mellitus (T2DM), hypertension, and cardiovascular disease also increase susceptibility. It has been reported that T-cell regulatory dipeptidyl peptidase 4 (DPP4; cluster of differentiation 26 (CD26)) binds to the external spike (S) glycoprotein of SARS-CoV-2 as a receptor, for the viral entry into the host cell. CD26 is expressed on many cells, including T and natural killer (NK) cells of the immune system, as a membrane-anchored form. A soluble form (sCD26) is also found in the blood plasma and cerebrospinal fluid (CSF). Approach and results: To investigate a possible relationship between sCD26 levels, age and pathology, serum samples were collected from control, T2DM and age-related dementia (ARD) subjects. A significant reduction in serum sCD26 levels was seen in relation to age. ARD and T2DM were also associated with lower levels of sCD26. The analysis of blood smears revealed different cellular morphologies: in controls, CD26 was expressed around the neutrophil membrane, whereas in T2DM, excessive sCD26 was found around the mononucleated cells (MNCs). ARD subjects had abnormal fragmented platelets and haemolysis due to low levels of sCD26. CONCLUSIONS: These findings may help to explain the heterogeneity of SARS-CoV-2 infection. High serum sCD26 levels could protect from viral infection by competively inhibiting the virus binding to cellular CD26, whereas low sCD26 levels could increase the risk of infection. If so measuring serum sCD26 level may help to identify individuals at high risk for the COVID-19 infection.