Aging brain最新文献

Cognitive decline as part of mental ageing is typically assessed with standardized tests; below-average performance in such tests is used as an indicator for pathological cognitive aging. In addition, morphological and functional changes in the brain are used as parameters for age-related pathological decline in cognitive abilities. However, there is no simple link between the trajectories of changes in cognition and morphological or functional changes in the brain. Furthermore, below-average test performance does not necessarily mean a significant impairment in everyday activities. It therefore appears crucial to record individual everyday tasks and their cognitive (and other) requirements in functional terms. This would also allow reliable assessment of the ecological validity of existing and insufficient cognitive skills. Understanding and dealing with the phenomena and consequences of mental aging does of course not only depend on cognition. Motivation and emotions as well personal meaning of life and life satisfaction play an equally important role. This means, however, that cognition represents only one, albeit important, aspect of mental aging. Furthermore, creating and development of proper assessment tools for functional cognition is important. In this contribution we would like to discuss some aspects that we consider relevant for a holistic view of the aging mind and promote a strengthening of a multidisciplinary approach with close cooperation between all basic and applied sciences involved in aging research, a quick translation of the research results into practice, and a close cooperation between all disciplines and professions who advise and support older people.

Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer’s disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.

Blood pressure variability (BPV), independent of mean blood pressure levels, is associated with cerebrovascular disease burden on MRI and postmortem evaluation. However, less is known about relationships with markers of cerebrovascular dysfunction, such as diminished spontaneous brain activity as measured by the amplitude of low frequency fluctuations (ALFF), especially in brain regions with vascular and neuronal vulnerability in aging. We investigated the relationship between short-term BPV and concurrent regional ALFF from resting state fMRI in a sample of community-dwelling older adults (n = 44) and healthy younger adults (n = 49). In older adults, elevated systolic BPV was associated with lower ALFF in widespread medial temporal regions and the anterior cingulate cortex. Higher systolic BPV in younger adults was also related to lower ALFF in the medial temporal lobe, albeit in fewer subregions, and the amygdala. There were no significant associations between systolic BPV and ALFF across the right/left whole brain or in the insular cortex in either group. Findings suggest a possible regional vulnerability to cerebrovascular dysfunction and short-term fluctuations in blood pressure. BPV may be an understudied risk factor for cerebrovascular changes in aging.

Extant research suggest aging-related losses of different dopaminergic markers, including presynaptic dopamine transporters as well as post-synaptic DA receptors. Given the central role of DA in neurocognitive functions, maintenance of a healthy DA system may be a key to mitigate age-related cognitive decline. Mechanisms behind DA losses in aging are however largely uncharted. Past research documented an association between dopaminergic integrity and cerebrovascular health (via white matter lesion volumes). However, it remains unclear whether proximity to lesions affected the spatial patterns of age-related D1DR differences within the striatum, and whether such differences are related to mnemonic function. Here, a large cohort of middle-aged to older healthy participants (age = 40–80 years, n = 119, 50 % women) was assessed for D1-receptor (D1DR) availability with positron emission tomography using [¹¹C]SCH23390, and for white matter lesions using FLAIR-MRI. We found evidence for variations in degree of age-related differences along the ventro-dorsal axis, with more pronounced differences in the dorsal caudate. Further analyses revealed an association between distance to lesions and extent of D1DR losses in the caudate. Furthermore, D1DR differences in dorsal caudate (proximal to lesions) was more strongly associated with memory performance. In conclusion, the present findings suggest that maintenance of cerebrovascular health may be a key factor in promoting successful dopaminergic and memory aging.

Background

Though the exact mechanisms regarding brain aging and its relation to neurodegenerative disorders are not precise, oxidative stress, the key regulators of apoptosis and autophagy, such as bcl-2 and beclin 1, seem to be the potential players in the aging of the cerebral cortex and hippocampus. As a type of nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylases, sirtuin 2 (SIRT2) has been associated to age-related diseases. However, the exact role of SIRT2 in brain aging is not well studied. The objective of the current study was to study the role of SIRT2 inhibition on brain aging through the neuroprotective mechanisms.

Methods

We tested the effects of AGK-2, a SIRT2 inhibitor, on oxidative stress parameters, apoptosis and autophagy regulators including bcl-2, bax, beclin1 in young and old rats. 24 Wistar albino rats (3 months-old and 22 months-old) were divided into four groups; Young-Control (4% DMSO+PBS), Young-AGK-2 (10 µM/bw, ip), Aged-Control, and Aged-AGK-2. Following the 30 days of drug administration period the rats were sacrificed and the cerebral cortex, hippocampus, and cerebellum were isolated. Total antioxidant status (TAS) and total oxidant status (TOS) were measured as oxidative stress parameters in all three brain regions. SIRT2, bcl-2, and bax protein expression levels were measured by western blot and gene expression level of beclin 1, Atg5, and SIRT2 by real-time PCR.

Results

The bcl-2, bcl-2/bax ratio, beclin 1, and TAS in the cerebral cortex of the aged group were significantly decreased; however, the TOS, oxidative stress index (OSI), and SIRT2 expression in the cerebral cortex and hippocampus increased. SIRT2 inhibition by AGK-2 reduced TOS and OSI levels in all brain regions and increased bcl-2, bcl-2/bax ratio. In aged animals, AGK-2 also increased the beclin 1 levels in the cortex and hippocampus.

Conclusion

Our results indicate that SIRT2 has an essential role in brain aging. The inhibition of SIRT2 by AGK-2 may increase cell survival and decrease aging related processes in the cerebral cortex and hippocampus via decreasing oxidative stress, and increasing bcl-2 and beclin 1 expression.

Alzheimer’s disease (AD), the most common form of dementia, is a progressive and debilitating neurodegenerative condition which robs people of their memory, their independence, their relationships and, ultimately, their lives. It affects close to 7 million people in the European Union (EU) alone.

The detection and diagnosis of AD relies on a system that remains focused on the late stage of the disease, despite a better understanding of the disease progression. Clinical practice and healthcare systems’ readiness to detect, diagnose and treat the disease effectively are still lagging. The use of biomarkers (cerebrospinal fluid tests (CSF) and positron emission tomography scans (PET)), which are central to a diagnostic assessment for people with AD symptoms, as well as relevant diagnostic facilities are under-utilised. PET imaging is expensive and of limited availability, and CSF sampling may be considered invasive.

The European Brain Council’s ‘Rethinking Alzheimer’s disease: Detection and diagnosis’ White Paper has looked at the barriers to early diagnosis and how the healthcare systems infrastructure for detection and diagnosis of AD need to be transformed in order for people with AD to benefit from innovative solutions once they become approved for use.

Human neural cell models derived from induced pluripotent stem cells (iPSCs) have been widely accepted to model various neurodegenerative diseases such as Alzheimer’s disease (AD) in vitro. Although the most common sources of iPSCs are fibroblasts and peripheral blood mononuclear cells, the collection of these cells is invasive. To reduce the donor’s burden, we propose the use of urine-derived cells (UDCs), which can be obtained non-invasively from a urine sample. However, the collection of UDCs from elderly donors suffering from age-related diseases such as AD has not been reported, and it is unknown whether these UDCs from the donor aged over 80 years old can be converted into iPSCs and differentiated into neural cells. In this study, we reported a case of using the UDCs from the urine sample of an 89-year-old AD patient, and the UDCs were successfully reprogrammed into iPSCs and differentiated into neural cells in four different ways: (i) the dual SMAD inhibition with small-molecules via the neural progenitor precursor stage, (ii) the rapid induction method using transient expression of Ngn2 and microRNAs without going through the neural progenitor stage, (iii) the cortical brain organoids for 3D culture, and (iv) the human astrocytes. The accumulation of phosphorylated Tau proteins, which is a pathological hallmark of AD, was examined in the neuronal models generated from the UDCs of the aged donor. The application of this cell source will broaden the target population for disease modeling using iPS technology.

Human apolipoprotein E (APOE) is the greatest determinant of genetic risk for memory deficits and Alzheimer’s disease (AD). While APOE4 drives memory loss and high AD risk, APOE2 leads to healthy brain aging and reduced AD risk compared to the common APOE3 variant. We examined brain APOE protein levels in humanized mice homozygous for these alleles and found baseline levels to be age- and isoform-dependent: APOE2 levels were greater than APOE3, which were greater than APOE4. Despite the understanding that APOE lipoparticles do not traverse the blood–brain barrier, we show that brain APOE levels are responsive to dietary fat intake. Challenging mice for 6 months on a Western diet high in fat and cholesterol increased APOE protein levels in an allele-dependent fashion with a much greater increase within blood plasma than within the brain. In the brain, APOE2 levels responded most to the Western diet challenge, increasing by 20 % to 30 %. While increased lipoparticles are generally deleterious in the periphery, we propose that higher brain APOE2 levels may represent a readily available pool of beneficial lipid particles for neurons.