The Journal of Prevention of Alzheimer's Disease最新文献

Alzheimer’s disease is a neurodegenerative disorder marked by cognitive decline and brain pathology involving amyloid plaques and neurofibrillary tangles. Current drug development focuses on disease-modifying therapies, primarily antibodies targeting amyloid or tau. However, the blood-brain barrier (BBB) poses a challenge for drug delivery to the brain. Pre-and early clinical data suggests that Focused Ultrasound (FUS) technology safely enhances BBB permeability without damaging brain tissue, enabling drug delivery. This systematic review discusses the application of FUS to open the BBB for the treatment of Alzheimer’s disease (AD). We review the safety, efficacy, and potential biological effects of FUS-mediated BBB opening in AD patients.

Background

The focus of medicine is shifting from treatment to preventive care. The expression of biomarkers of dementia and Alzheimer’s disease (AD) appear decades before the onset of observable symptoms, and evidence has emerged supporting pharmacological and non-pharmacological interventions to treat modifiable risk factors of dementia. However, there is limited research on the epidemiology, clinical phenotypes, and underlying pathobiology of cognitive diseases in Asian populations.

Objectives

The objectives of the Biomarkers and Cognition Study, Singapore(BIOCIS) are to characterize the underlying pathobiology of Cognitive Impairment through a longitudinal study incorporating fluid biomarker profiles, neuroimaging, neuropsychological and clinical outcomes in a multi-ethnic Southeast Asian population.

Design, Setting, Participants

BIOCIS is a 5-year longitudinal study where participants are assessed annually. 2500 participants aged 30 to 95 will be recruited from the community in Singapore. To investigate how pathology presents with or without minimal clinical symptoms and vice versa, CI and unimpaired individuals will be recruited. Participants will undergo assessments to characterise biomarkers of dementia through neuroimaging, fluid biomarkers, cognitive assessments, behavioural and lifestyle profiles, retinal scans and microbiome indicators.

Results

Since commencement of recruitment in February 2022, 1148 participants have been enrolled, comprising 1012 Chinese, 62 Indian, and 35 Malay individuals. Mean age and education is 61.32 years and 14.34 years respectively with 39.8% males. 47.9 % of the cohort are employed and 32.06% have a family history of dementia. The prevalence of cerebral small vessel disease is 90.2% with a mean modified Fazekas white matter hyperintensity score of 4.1.

Conclusion

The BIOCIS cohort will help identify novel biomarkers, pathological trajectories, epidemiology of dementia, and reversible risk factors in a Southeast Asian population. Completion of BIOCIS longitudinal data could provide insights into risk-stratification of Asians populations, and potentially inform public healthcare and precision medicine for better patient outcomes in the prevention of Alzheimer’s disease and dementia.

Recent positive trials for novel disease modifying therapies of anti-amyloid monoclonal antibodies represent a paradigm shift in the prevention and management of Alzheimer’s disease, a relentlessly progressive and debilitating disease of old age. The reported efficacy of these new agents when given early in the disease trajectory is dependent on an early and accurate disease diagnosis, which is currently based on cerebrospinal fluid tests or/and neuro-imaging studies such as positron emission tomography. These confirmatory tests provide in vivo evidence of the pathological signature of Alzheimer’s disease, of increased cerebral amyloid and tau burden and neurodegeneration. The emergence of blood-based biomarkers represents another breakthrough, offering a less invasive and scalable diagnostic tool that could be applied in both primary and specialist care settings, potentially revolutionizing Alzheimer’s disease clinical pathways. However, healthcare systems face challenges in the adoption of these new technologies and therapies due to diagnostic and treatment capacity constraints, as well as financial and infrastructure requirements.

Background

Hypertension may harm cognitive performance, but the potential correlates of longitudinal patterns of blood pressure (BP), especially diastolic BP (DBP), to cognition have been unclear.

Objectives

To examine long-term BP trajectories in relation to subsequent cognitive decline, incident dementia and all-cause mortality in the general population.

Design

Population-based cohort study.

Setting

Communities in England.

Participants

The study included 7566 participants from the English Longitudinal Study of Ageing (ELSA).

Measurements

BP were measured in 1998, 2004, 2008. Group-based trajectory modeling was used to identify longterm patterns of systolic BP (SBP) and DBP. Outcomes including cognitive function, incident dementia, and all-cause mortality were followed up to 10 years.

Results

Five distinct trajectories were identified for SBP and DBP, respectively. The normal-stable trajectory was used as the reference. For cognitive decline, both SBP and DBP trajectories were independently associated with subsequent cognitive decline, with the fastest decline appeared in the high-stable SBP group of 180 mmHg and the low-stable DBP group of 60 mmHg (both P<0.005). For incident dementia, the multivariable adjusted hazard ratio (HR) was also greatest in high-stable group (4.79, 95% confidence interval: 2.84 to 8.07) across all SBP trajectories. Conversely, low (HR: 1.58) and moderate-low stable (HR: 1.56) DBP trajectories increased dementia risk (both P<0.005). Similar patterns were found in BP trajectories in relation to all-cause mortality.

Conclusion

Our study evaluates the potential health impact from different BP trajectories and suggests that controlling long-term SBP and maintaining adequate DBP may be relevant for the current practice to promote cognitive health and extend lifespan.

Background

There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer’s disease (AD).

Methods

The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness.

Results

Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI.

Conclusion

These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions.

Background

The number of cases of all types of dementia is increasing, and a significant increase in prevalence has been noted among veterans. Evidence of an association between dementia and exposure to chemicals such as Agent Orange from the Vietnam War is still limited, and there is a reported lack of awareness.

Objective

This study aimed to investigate the risk of dementia among Vietnam War veterans in Korea.

Design

This retrospective longitudinal study compared the incidence of dementia between Vietnam War veterans and the general population.

Setting

This study used data from the nationally representative Korean Vietnam War Veterans’ Health Study Cohort, a combined dataset sourced from the Ministry of Patriots and Veterans Affairs in Korea and the National Health Insurance Sharing Service database.

Participants

There were 191,272 Vietnam War veterans and 1,000,320 people of different ages, sexes, and residences. matched control in 2002. The total number of person-years were 18,543,181.

Measurements

The dementia group included participants who had visited a medical facility with any of the following ICD-10 codes in the follow-up periods: “F00 Dementia in Alzheimer’s disease,” “F01 Vascular dementia,” “F02 Dementia in other diseases classified elsewhere,” or “F03 Unspecified dementia.”

Results

The incidence rate ratio for all types of dementia was 1.16, with higher ratios observed for vascular and unspecified dementia, particularly in the younger age groups. There was a significant increase in the risk of dementia, Alzheimer’s disease, vascular dementia, and unspecified dementia.

Conclusion

Vietnam War veterans showed an increased risk for all types of dementia. These findings are hypothesized to be due to the effects of the chemicals used during the Vietnam War, which can cause a variety of neurodegenerative diseases. Further studies are warranted to investigate the potential health determinants related to the Vietnam War, focusing on the neurodegenerative effects.

Introduction

Metrics of a participant’s socioeconomic status (SES) are not routinely collected or standardized in clinical trials. This omission limits the ability to evaluate the generalizability of trial results and restricts clinicians from confidently interpreting the efficacy of new treatments across important sub-populations.

Methods

We adapted an SES measure of social disparity; the Hollingshead Two Factor Index of Social Position, which combines education and occupation into a single metric. We modernized the 1965 occupations to reflect the 2017 careers tabulated by the US Bureau of Labor Statistics. We currently use this adapted measure in Alzheimer’s Clinical Trials Consortium studies.

Results

We present the revised table of occupations. We found that the collection of SES data using the modified Hollingshead was feasible in a multi-site clinical trial and scores were distributed across all SES strata.

Discussion

The modified Hollingshead provides a standardized method for collecting SES information, enabling data aggregation, monitoring, and reporting.

Background

Multiple disease modifying treatment for Alzheimer’s disease are currently in clinical development or have been recently approved for use. They have vastly different treatment properties but so far, little work has been done to quantify the impact of treatment properties on the treatment’s value in terms of medical and social care costs and caregiver burden.

Objectives

This study aims to analyze how the mode of treatment administration, treatment frequency and duration, and monitoring requirements affect the value of disease modifying treatments. In order to isolate these effects, we compare five hypothetical disease modifying treatments with equal efficacy and safety: (1) chronic bi-weekly intravenous infusion, (2) chronic four-weekly intravenous infusion, (3) 52 weeks fixed duration four-weekly intravenous infusion, (4) chronic subcutaneous injections, and (5) chronic oral prescription on their direct medical costs, caregiver burden, and preservation of treatment value.

Design

Survey of Alzheimer’s disease treatment clinics and retrospective data analysis.

Setting

United States.

Measurements

Direct medical cost and caregiver burden of treatment administration and monitoring compared to gross treatment benefit.

Results

Chronic bi-weekly infusion treatment had the highest direct medical cost ($45,208) and caregiver burden ($6,095), reducing the treatment value by 44%, while oral treatment with the lowest direct medical cost ($1,983) and caregiver burden ($457) reduced the treatment value by only 2%. Substantial caregiver burden was reported from the survey, with a reported average of 2.3 hours for an office visit and infusion, 44 minutes of round-trip travel time, and 78% of patients being accompanied by a caregiver for treatment.

Conclusion

Burden of chronic intravenous treatments exceed the gross medical and social care cost savings and value of caregiver benefit. The results suggest the need for less complex treatments that require fewer clinic visits to preserve the economic value of disease modifying treatments.

Background

Abnormal tau proteins are independent contributors to cognitive impairment. Nevertheless, not all individuals exposed to high-level tau pathology will develop cognitive dysfunction. We aimed to construct a model to predict cognitive trajectory for this high-risk population.

Method

Longitudinal data of 181 non-demented adults (mean age= 73.1; female= 45%), who were determined to have high cerebral burden of abnormal tau by cerebrospinal fluid (CSF) measurements of phosphorylated tau (ptau181) or total tau, were derived from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Cognitive decline was defined as Mini-Mental State Examination scores decline ≥ 3 over three years. A predictive nomogram was constructed using stepwise backward regression method. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated. The model was validated in another 189 non-demented adults via a cross-sectional set (n=149, mean age = 73.9, female = 51%) and a longitudinal set (n= 40, mean age = 75, female = 48%). Finally, the relationships of the calculated risk scores with cognitive decline and risk of Alzheimer’s disease were examined during an extended 8-year follow-up.

Result

Lower volume of hippocampus (odds ratio [OR] = 0.37, p< 0.001), lower levels of CSF sTREM2 (OR = 0.76, p = 0.003), higher scores of Alzheimer’s Disease Assessment Scale-Cognitive (OR = 1.15, p = 0.001) and Functional Activities Questionnaire (OR = 1.16, p = 0.016), and number of APOE ε4 (OR = 1.88, p = 0.039) were associated with higher risk of cognitive decline independent of the amyloid status and were included in the final model. The nomogram had an area of under curve (AUC) value of 0.91 for training set, 0.93 for cross-sectional validation set, and 0.91 for longitudinal validation set. Over the 8-year follow-up, the high-risk group exhibited faster cognitive decline (p< 0.001) and a higher risk of developing Alzheimer’s dementia (HR= 6.21, 95% CI= 3.61–10.66, p< 0.001).

Conclusion

APOE ε4 status, brain reserve capability, neuroinflammatory marker, and neuropsychological scores can help predict cognitive decline in non-demented adults with high burden of tau pathology, independent of the presence of amyloid pathology.