Alzheimer's and Dementia: Translational Research and Clinical Interventions
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From brain collections to modern brain banks: A historical perspective Abstract Our current knowledge of the structure, function, and diseases of the brain comes from direct examination of its substance. In the last centuries, only a few elite had managed to retrieve, gather, and preserve the elusive brain for their own research. The resulting brain collections, stored in formalin‐filled jars or dried up in cabinets, served anatomical, neuropathological, anthropometric, ideological, and diagnostic purposes. In the 1960s, the first modern brain banks actively collecting and strategically preserving both diseased and healthy brains to be consequently distributed to the scientific community were instituted. In an era where state‐of‐the‐art biochemical “Omic” studies and advanced metabolic and molecular neuroimaging exist, it is now, more than ever, that postmortem brain investigations must be performed. Only through the comparison and integration of postmortem neuropathological and biochemical findings and antemortem data from clinical, neuropsychological neuroimaging, and other biomarker examinations can we truly understand neurological disease mechanisms. Brain banks supplying brain specimens, antemortem information, and postmortem diagnosis are a major benefactor of brain research.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 52-60 - 2019
Preclinical Alzheimer's disease and longitudinal driving decline Abstract Introduction Links between preclinical Alzheimer's disease (AD) and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. Methods One hundred four OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries, and self‐reported their driving habits. Results Higher values of cerebrospinal fluid (CSF) tau/Aβ42 and phosphorylated tau (ptau181 )/Aβ42 ratios, but not uptake on Pittsburgh compound B amyloid imaging (P = .12), predicted time to a rating of marginal or fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70–19.53), P = .005 for CSF tau/Aβ42 ; 6.19 (1.75–21.88), and P = .005 for CSF ptau181 /Aβ42 . Discussion Preclinical AD predicted time to receiving a marginal or fail rating on an on‐road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 3 - Trang 74-82 - 2017
Sedentary behavior as a risk factor for cognitive decline? A focus on the influence of glycemic control in brain health Abstract Cognitive decline leading to dementia represents a global health burden. In the absence of targeted pharmacotherapy, lifestyle approaches remain the best option for slowing the onset of dementia. However, older adults spend very little time doing moderate to vigorous exercise and spend a majority of time in sedentary behavior. Sedentary behavior has been linked to poor glycemic control and increased risk of all‐cause mortality. Here, we explore a potential link between sedentary behavior and brain health. We highlight the role of glycemic control in maintaining brain function and suggest that reducing and replacing sedentary behavior with intermittent light‐intensity physical activity may protect against cognitive decline by reducing glycemic variability. Given that older adults find it difficult to achieve current exercise recommendations, this may be an additional practical strategy. However, more research is needed to understand the impact of poor glycemic control on brain function and whether practical interventions aimed at reducing and replacing sedentary behavior with intermittent light intensity physical activity can help slow cognitive decline.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 3 Số 3 - Trang 291-300 - 2017
Alzheimer's Prevention Initiative Generation Program: Development of an <i>APOE</i> genetic counseling and disclosure process in the context of clinical trials Abstract Introduction As the number of Alzheimer's disease (AD) prevention studies grows, many individuals will need to learn their genetic and/or biomarker risk for the disease to determine trial eligibility. An alternative to traditional models of genetic counseling and disclosure is needed to provide comprehensive standardized counseling and disclosure of apolipoprotein E (APOE ) results efficiently, safely, and effectively in the context of AD prevention trials. Methods A multidisciplinary Genetic Testing, Counseling, and Disclosure Committee was established and charged with operationalizing the Alzheimer's Prevention Initiative (API) Genetic Counseling and Disclosure Process for use in the API Generation Program trials. The objective was to provide consistent information to research participants before and during the APOE counseling and disclosure session using standardized educational and session materials. Results The Genetic Testing, Counseling, and Disclosure Committee created a process consisting of eight components: requirements of APOE testing and reports, psychological readiness assessment, determination of AD risk estimates, guidance for identifying providers of disclosure, predisclosure education, APOE counseling and disclosure session materials, APOE counseling and disclosure session flow, and assessing APOE disclosure impact. Discussion The API Genetic Counseling and Disclosure Process provides a framework for large‐scale disclosure of APOE genotype results to study participants and serves as a model for disclosure of biomarker results. The process provides education to participants about the meaning and implication(s) of their APOE results while also incorporating a comprehensive assessment of disclosure impact. Data assessing participant safety and psychological well‐being before and after APOE disclosure are still being collected and will be presented in a future publication.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 705-716 - 2019
A randomized, double‐blind, placebo‐controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer's disease: A pilot study Abstract Introduction Human studies on low‐dose resveratrol are scarce. This study aims to evaluate the safety, tolerability, and efficacy of an oral preparation of resveratrol, glucose, and malate (RGM) in slowing the progression of Alzheimer's disease (AD). Methods Thirty‐nine subjects with mild to moderate AD who were free of life‐threatening disease and who did not have contraindications to the use of the study product were screened. Progression of AD was measured by change in the cognitive portion of the Alzheimer's Disease Assessment Scale–cognitive subscale. Secondary outcomes included Clinician's Global Impression of Change, Mini–Mental State Examination, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, and Neuropsychiatric Inventory. 15 mL of the following preparation per dose, i.e., 5 g dextrose, 5 g malate, and 5 mg resveratrol, or matching placebo was ingested with an 8 oz glass of commercial unsweetened grape juice twice a day for 1 year. Group differences in the rate of change in the outcome measures were examined using generalized estimating equations. Results The treatment and control groups were similar on all of the screening variables. At 12 months, change scores on Alzheimer's Disease Assessment Scale–cognitive subscale, Mini–Mental State Examination, Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale, or Neuropsychiatric Inventory all showed less deterioration in the treatment than the control group; however, none of the change scores reached statistical significance. The most common AE were falls, all in the control group. None of the falls were deemed to be study related. Conclusion Low‐dose oral resveratrol is safe and well tolerated. Interpretation of the effects on clinical outcomes trajectories remains uncertain. A larger study is required to determine whether low‐dose resveratrol may be beneficial. Trial Registration ClinicalTrials.gov (NCT00678431 ), Registered 05/15/2008.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 4 - Trang 609-616 - 2018
Inflammation as a central mechanism in Alzheimer's disease Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia‐related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 4 Số 1 - Trang 575-590 - 2018
A blood‐based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial Abstract Introduction Multinutrient approaches may produce more robust effects on brain health through interactive qualities. We hypothesized that a blood‐based nutritional risk index (NRI) including three biomarkers of diet quality can explain cognitive trajectories in the multidomain Alzheimer prevention trial (MAPT) over 3‐years. Methods The NRI included erythrocyte n‐3 polyunsaturated fatty acids (n‐3 PUFA 22:6n‐3 and 20:5n‐3), serum 25‐hydroxyvitamin D, and plasma homocysteine. The NRI scores reflect the number of nutritional risk factors (0–3). The primary outcome in MAPT was a cognitive composite Z score within each participant that was fit with linear mixed‐effects models. Results Eighty percent had at lease one nutritional risk factor for cognitive decline (NRI ≥1: 573 of 712). Participants presenting without nutritional risk factors (NRI=0) exhibited cognitive enhancement (β = 0.03 standard units [SU]/y), whereas each NRI point increase corresponded to an incremental acceleration in rates of cognitive decline (NRI‐1: β = −0.04 SU/y, P = .03; NRI‐2: β = −0.08 SU/y, P < .0001; and NRI‐3: β = −0.11 SU/y, P = .0008). Discussion Identifying and addressing these well‐established nutritional risk factors may reduce age‐related cognitive decline in older adults; an observation that warrants further study.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 953-963 - 2019
A single systemic inflammatory insult causes acute motor deficits and accelerates disease progression in a mouse model of human tauopathy Abstract Introduction Neuroinflammation, which contributes to neurodegeneration, is a consistent hallmark of dementia. Emerging evidence suggests that systemic inflammation also contributes to disease progression. Methods The ability of systemically administered lipopolysaccharide (LPS ‐ 500 μg/kg) to effect acute and chronic behavioural changes in C57BL/6 and P301S tauopathy mice was assessed. Markers of pathology were assessed in the brain and spinal cord. Results P301S mice display regional microgliosis. Systemic LPS treatment induced exaggerated acute sickness behaviour and motor dysfunction in P301S mice compared with wild‐type controls and advanced the onset and accelerated chronic decline. LPS treatment was associated with increased tau pathology 24 hours after LPS injection and spinal cord microgliosis at the end stage. Discussion This is the first demonstration that a single systemic inflammatory episode causes exaggerated acute functional impairments and accelerates the long‐term trajectory of functional decline associated with neurodegeneration in a mouse model of human tauopathy. The findings have relevance to management of human dementias.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 579-591 - 2019
Computer Interactive Reminiscence and Conversation Aid groups—Delivering cognitive stimulation with technology Abstract Introduction Group‐based cognitive stimulation is the only nonpharmacologic intervention recommended by the UK National Institute for Clinical and Health Excellence for people with dementia. The potential of technology to extend the availability of group‐based cognitive stimulation has not been tested. Methods One hundred sixty‐one people with dementia participated in an eight‐session group activity using Computer Interactive Reminiscence and Conversation Aid (CIRCA). Cognition, quality of life, and general health were assessed before intervention, postintervention, and 3 months later. Results There was a significant improvement in cognition and quality of life at the end of the CIRCA group intervention, which was further improved at 3‐month follow‐up. Discussion CIRCA group sessions improved cognition and quality of life similar to group‐based cognitive stimulation approved by the National Institute for Clinical and Health Excellence. These benefits were maintained at 3‐month follow‐up. The data confirm the potential of CIRCA, which can be populated with different cultural and language contents for different user groups.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 4 - Trang 481-487 - 2018
Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse Abstract Introduction Translational inhibition of amyloid precursor protein (APP) by Posiphen has been shown to reduce APP and its fragments in cell culture, animal models, and mildly cognitively impaired patients, making it a promising drug candidate for the treatment of Alzheimer's disease. Methods We used a mouse model of Alzheimer's disease (APP/presenilin‐1) to examine Posiphen's efficacy, pharmacodynamics, and pharmacokinetics. Results Posiphen treatment normalized impairments in spatial working memory, contextual fear learning, and synaptic function in APP/presenilin‐1 mice, without affecting their visual acuity, motor skills, or motivation and without affecting wild‐type mice. Posiphen had a prolonged effect in reducing APP and all related peptides for at least 9 hours after the last dose. Its concentration was higher in the brain than in plasma, and the most abundant metabolite was N8 ‐norPosiphen. Discussion This is the first study demonstrating the therapeutic efficacy of inhibiting the translation of APP and its fragments in an Alzheimer's disease model.
Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 4 - Trang 37-45 - 2018
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