Journal of Alzheimer's Disease最新文献

Background: The rising number of older people, including those living with Alzheimer's disease and related dementias (AD/ADRD) in sub-Saharan Africa (SSA) highlights the need for an improved clinical diagnosis and management of the diseases.

Objective: To understand and describe healthcare providers' perceptions and practices regarding AD/ADRD diagnosis and care in Kenya, not previously reported.

Methods: This was an ethnographic study involving observations and semi-structured interviews with healthcare providers working at the Aga Khan University Hospital, Nairobi (AKUHN) Kenya. Twenty-one healthcare providers were purposively recruited and interviewed in English, with the data transcribed verbatim and thematically analysed using Nvivo version 14.

Results: Our findings reveal that AKUHN's dementia diagnostic pathway aligns with universal best practice models and involves multidisciplinary care. Yet, healthcare providers noted that this level of care is not representative of most public hospitals in Kenya, where a lack of diagnostic equipment and trained staff severely limits patient access to timely dementia care. In addition, new medications that can slow AD/ADRD progression, are not readily available in Africa, including Kenya. We also identified barriers to timely diagnosis and care such as: lack of dementia policy and guidelines, limited expertise of healthcare providers, high cost of care, and sociocultural factors, including stigma.

Conclusions: We emphasize the need for the Kenyan government and relevant stakeholders to develop social and healthcare policies and allocate resources to raise awareness about dementia and combat stigma; train healthcare providers; improve early detection and service delivery through access to diagnostic tools, and establish clear guidelines/protocols for AD/ADRD care.

Background: Individuals with type 2 diabetes have an increased risk of developing both vascular and Alzheimer's dementia.

Objective: This prospective cross-sectional study assessed the screening ability of the standard Montreal Cognitive Assessment (MoCA) score suggestive of mild cognitive impairment (<26) in a European cohort of individuals ≥65 of age with type 2 diabetes.

Methods: Participants of RECOGNISED, a European prospective EU-funded cohort study, were screened using MoCA. In addition, a 13-item Neuropsychological Test Battery (NTB) with the Clinical Dementia Rating was undertaken to categorize participants as normocognitive (NC, n = 128) or mild cognitive impaired (MCI, n = 185). Receiver operating characteristic (ROC) analysis was used to evaluate the ability of MoCA cut-off scores to categorize patients as having MCI or not.

Results: The standard MoCA cut-off of 25/26 demonstrated a sensitivity of 88% and a specificity of 51%, resulting in a false positive rate of 20%. ROC analysis showed that a MoCA cut-off of 24/25 has a better balance between sensitivity (81%) and specificity (62%), with a lower false positive rate of 16%. NTB results showed that the MCI group had the lowest norm-referenced percentile scores in the visuo-construction domain, a known early feature of Alzheimer's disease and a significant predictor of a rapid rate of disease progression.

Conclusions: MoCA as a screening tool in individuals ≥65 with type 2 diabetes, overestimates the prevalence of MCI, even when applying lower cut-offs. More specific screening strategies are necessary, particularly targeting the visuo-construction domain, to effectively identify cognitive impairment in individuals with type 2 diabetes.

To our knowledge, no reports have described nonhuman primate (NHP) models of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) that do not depend on an overexpression paradigm. Based on our recent success in generating single human MAPT knock-in mouse models of FTDP-17, we describe the experimental basis for generating knock-in marmoset models of FTDP-17. In addition, successful generation of mutant PSEN1 knock-in marmoset models lacking exon 9 (PSEN1-Δ9) of Alzheimer's disease (AD) indicates that we will be able to reconstitute two major pathological features of AD, i.e., amyloid plaques and neurofibrillary tangles, in an accelerated manner by combining these models.

Background: Diabetes is a risk factor for dementia, but we do not know whether specific diabetes medications ameliorate this risk. Objective: To systematically review and meta-analyze such medication's effect on the risk of developing dementia, mild cognitive impairment (MCI), or cognitive decline. Methods: We searched three databases until 21 November 2023. We included randomized controlled trials (RCT), cohort, and case-control studies assessing association between antidiabetic medication and future dementia, MCI, or cognitive decline. We meta-analyzed studies separately for individual drug classes and their comparators (no medication, placebo, or another drug). We appraised study quality using the Newcastle-Ottawa Scale and Physiotherapy Evidence Database Scale. Results: 42 studies fulfilled inclusion criteria. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) versus placebo reduced dementia risk by 53% in three RCTs (n = 15,820, RR = 0.47[0.25, 0.86]) and 27% in three case-control studies (n = 312,856, RR = 0.73[0.54, 0.99], I²= 96%). Repaglinide was superior to glibenclamide by 0.8 points on the Mini-Mental State Examination scale in another RCT. Meta-analysis of seven longitudinal studies showed glitazones (n = 1,081,519, RR = 0.78[0.76, 0.81], I²= 0%) were associated with reduced dementia risk. Metformin (n = 999,349, RR = 0.94[0.79, 1.13], I²= 98.4%), sulfonylureas (RR = 0.98[0.78, 1.22], I²= 83.3%), dipeptidyl peptidase-IV inhibitors (DPP-1V) (n = 192,802, RR = 0.86[0.65, 1.15], I²= 92.9%) and insulin (n = 571,274, RR = 1.09[0.95, 1.25], I²= 94.8%) were not. Most studies were observational and limited by confounding by indication. Conclusions: In people with diabetes, RCTs consistently showed GLP-RAs reduce future dementia risk. Glitazones consistently showed protective effects, without heterogeneity, suggesting potential generalizability of these results. Metformin, sulfonylureas, insulin, and DPP-1V studies had inconsistent findings. If information is available future studies should consider dosage, severity, and duration.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly, leading to severe cognitive decline and loss of autonomy. The accumulation of amyloid-β peptides and tau proteins in the brain is considered the central pathogenic mechanism, which results in neuronal dysfunction and cell death. Various metabolic disruptions, such as chronic oxidative stress and inflammatory processes, further exacerbate the progression of AD. This review, based on literature from PubMed, SciELO, MDPI, and ScienceDirect, evaluates the role of bioactive compounds and dietary patterns, specifically the Mediterranean and MIND diets, in mitigating the progression of AD. These diets, rich in vitamins, flavonoids, carotenoids, and omega-3 fatty acids, have shown potential in reducing oxidative damage and inflammation in the brain, offering neuroprotective benefits. The findings suggest that bioactive compounds such as vitamin E isomers and polyphenols may delay cognitive decline, presenting a promising avenue for future dietary interventions aimed at optimizing the consumption of these compounds to prevent or slow the onset of AD. Further research is needed to determine the optimal doses and combinations of these bioactive compounds to maximize their protective effects.

Background: Most common forms of dementia, including Alzheimer's disease, are associated with alterations in spoken language.

Objective: This study explores the potential of a speech-based machine learning (ML) approach in estimating cognitive impairment, using inputs of speech audio recordings.

Methods: We develop an automatic ML pipeline that ingests multimodal inputs of audio and transcribed text, mapping speech and language to domain-specific biomarkers optimized for high explainability and predictive ability. The resulting features are fed through a multi-stage pipeline to determine efficient classification configurations.

Results: We evaluated the system on large real-world datasets, achieving above 90% and 70% weighted average F1 scores for two-class (AD versus normal controls) and three-class (AD versus mild cognitive impairment versus normal controls) classification tasks, respectively. Model performance remains stable across different population characteristics.

Conclusions: The study introduces a robust, non-invasive method for gauging the cognitive status of AD and MCI patients from speech samples, with the potential of generalizing effectively to multiple types of diseases/disorders which may burden language.

Background: Research suggests that modifying risk factors may prevent or delay up to 40% of dementia cases, including Alzheimer's disease (AD). Thus, understanding the potential of healthful dietary patterns, like the Mediterranean diet (MD), in AD prevention is crucial. While supplementation of individual Mediterranean foods has demonstrated efficacy in reducing AD biomarkers and cognitive impairment in rodents, the effects of a comprehensive MD warrant further investigation. Additionally, while rodent studies often use a "Western diet" as a model for the typical American diet (TAD), these diets generally exceed the macronutrient densities of typical American consumption, particularly in fats and carbohydrates.

Objective: To better reflect human diets, we developed two diets for mice that more closely mirrored the macronutrient composition of the traditional MD or the TAD, each with matched macronutrient profiles (50% kcal from carbohydrates, 35% kcal from fat, 15% kcal from protein), and distinct food sources from Mediterranean regions or the U.S., respectively.

Methods: Male C57BL/6J mice were randomly assigned to one diet (MD or TAD) at weaning (21 days of age), which they consumed for six months.

Results: Compared to the TAD, MD animals had lower body weight, abdominal and hepatic fat, serum TNF-α, and central Aβ_1-42, while also exhibiting enhanced exploratory behavior, reduced anxiety-like behavior, and preserved spatial memory. The MD also protected against LPS-induced central inflammation and BDNF loss.

Conclusions: These findings suggest that a comprehensive MD provides protection against metabolic and AD-related markers in wildtype mice, despite matched caloric availability to the TAD.

Background: Metabolic syndrome (MetS) was associated with an increased incidence of mild cognitive impairment (MCI) and progression to dementia.

Objective: To study the associations between MetS indicators and cerebrospinal fluid (CSF) biomarkers in the participants.

Methods: 61 normal cognition, 66 mild MCI, and 135 dementia participants were included in our study, with the results of lumbar puncture and peripheral blood biochemistry. The CSF levels of amyloid-β (Aβ)₄₂ protein, total tau protein, phosphorylated tau protein, and Aβ_42/40 ratio, were selected as the biomarkers. The body mass index, the plasma high density lipoprotein cholesterol, uric acid, low density lipoprotein cholesterol, triglyceride, and homocysteine levels were selected as indicators of MetS. Linear regression model was used to analyze the correlation in all participants and different cognitive stages, controlling for age, gender, and APOE genotype.

Results: Our study showed that MetS indicators were associated with CSF biomarkers in participants after adjusting for possible confounding factors, including age, gender, and APOE genotype. The results of our grouping analysis further supported the potential association between plasma MetS indicators and CSF biomarkers in three group. We found that the dementia group showed the greatest correlation coefficient.

Conclusions: The CSF pathological proteins concentrations were associated with MetS indicators, and the correlation coefficient were greater in the dementia stage. These findings suggest that regulating peripheral metabolism may affect the level of pathological proteins in the brain to improve cognitive impairment.

Background: While cerebrovascular hemodynamics exhibits critical interplay with the pathogenesis of dementia, limited articles have examined the impact of vertebrobasilar (VB) hemodynamics on cerebral blood flow (CBF), and to what extent it varies by dementia subtypes.

Objective: To explore the associations between VB hemodynamics and CBF by dementia subtypes.

Methods: This research recruited a total of 120 dementia patients [43 subcortical ischemic vascular dementia (SIVD); 59 Alzheimer's disease (AD); 18 mixed dementia] and 40 older adults with normal cognition and compared their transcranial doppler (TCD) flow parameters and arterial spin labeling-measured CBF. Using the partial correlation analysis, the associations between TCD parameters and CBF values were explored among the defined subgroups.

Results: A higher VB pulsatility index (PI) was related to lower parietal CBF and lower VB end-diastolic velocity (EDV). Moreover, the significance of flow parameters in the basilar artery (BA) to parietal CBF was identified: peak-systolic velocity (PSV) unanimously showed positive correlations among all subgroups except SIVD, and both PSV and EDV showed positive correlations in AD. Of note, there were more noticeable "BA flow-frontoparietal CBF" associations among the high than low VB PI group, and AD than SIVD group.

Conclusions: The findings indicate that VB-resistance-related parietal vulnerability and topological CBF associations vary by dementia subtypes. Given VB hemodynamics-CBF relationships, the current research extends our understanding of the vasocognopathic effects among dementia patients.

Background: The α-Klotho is known to be involved in longevity and various age-related diseases, including cognitive impairment. BACE1, an important enzyme associated with the pathological process of Alzheimer's disease (AD), serves as a biomarker for predicting changes in cognitive function. Although both proteins are closely linked to age-related cognitive function, the mechanism of their interaction remains unclear.

Objective: To identify the enzymatic digestion relation between α-Klotho and BACE1 and the specific cleavage site.

Methods: Thirty elderly and forty-five young individuals were recruited. The cleavage product was identified by Coomassie blue staining, western blot, and MALDI-TOF mass spectrometry. The concentrations of plasma proteins were measured by ELISA.

Results: A new protein product was identified after the digestion reaction. BACE1 cleaved the α-Klotho peptide 951-981 at the F-T residues. When the F-T residues were replaced with K-K, BACE1 was unable to cleave the mutant peptide. The plasma levels of α-Klotho were significantly lower in elderly participants than in young participants (p < 0.0001). However, there was no significant difference in plasma BACE1 levels between elderly and young participants (p = 0.164). In elderly adults, there was a significant positive correlation between plasma BACE1 and α-Klotho protein levels (p = 0.009, r = 0.469), while this correlation was not observed in young adults (p = 0.170, r = -0.208).

Conclusions: The anti-aging protein α-Klotho is a substrate of BACE1 with a specific cleavage site at F-T. The BACE1/α-Klotho pathway may serve as a common axis for age-related cognitive decline.