Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein ...(Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH), ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.
Epidemiological studies have suggested that diets rich in polyphenols/phenolic compounds are associated with reduced risk of cognitive impairment and Alzheimer’s disease (AD). Experimental studies ...have indicated that these compounds have specific effects on AD pathogenesis as well as anti-oxidant and anti-inflammatory effects. For clinical use, several compounds have been investigated by clinical trials to establish their efficacy for prevention and treatment of AD or cognitive impairment.
Aging of population is rapidly growing in Japan and all over the world. To overcome problem associated with an increase of older people with dementia, we have conducted a population‐based cohort ...study for dementia in Nakajima, Ishikawa, Japan (the Nakajima study) since 2006, and an educational program for development of dementia experts (the NINPRO) since 2014. The Nakajima study aimed to develop methods for early detection, prevention, and treatment of dementia; we developed a computerized assessment battery for cognition (C‐ABC) that can detect mild cognitive impairment (MCI) as well as dementia around 5 min and reported usefulness of magnetoencephalography as a tool of detection of early Alzheimer's disease (AD); we explored potentials of dietary polyphenols as preventive and therapeutic agents for AD/dementia leading to clinical trials. The NINPRO has provided activities for learning the basics, clinical practice, and care of dementia using e‐learning lectures and web‐based conferences, and has involved about 2,300 people of medical doctors, nurses, caregivers, and other professionals related to dementia. The Nakajima study and the NINPRO would contribute to improvement of prevention, early detection, medical practice, care, social welfare, and all other aspects of dementia in a super‐aged society in the middle of the 21st century.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
5.
Vitamin A and Alzheimer's disease Ono, Kenjiro; Yamada, Masahito
Geriatrics & gerontology international,
April 2012, Volume:
12, Issue:
2
Journal Article
Peer reviewed
The deposition of amyloid β‐protein (Aβ) in the brain is an invariant feature of Alzheimer's disease (AD). Vitamin A, which has been traditionally considered an anti‐oxidant compound, plays a role in ...maintaining higher function in the central nervous system. Plasma or cerebrospinal fluid concentrations of vitamin A and β‐carotene have been reported to be lower in AD patients, and these vitamins have been clinically shown to slow the progression of dementia. Vitamin A (retinol, retinal and retinoic acid) and β‐carotene have been shown in in vitro studies to inhibit the formation, extension and destabilizing effects of β‐amyloid fibrils. Recently, the inhibition of the oligomerization of Aβ has been suggested as a possible therapeutic target for the treatment of AD. We have recently shown the inhibitory effects of vitamin A and β‐carotene on the oligomerization of Aβ40 and Aβ42 in vitro. In previous in vivo studies, intraperitoneal injections of vitamin A decreased brain Aβ deposition and tau phosphorylation in transgenic mouse models of AD, attenuated neuronal degeneration, and improved spatial learning and memory. Thus, vitamin A and β‐carotene could be key molecules for the prevention and therapy of AD. Geriatr Gerontol Int 2012; 12: 180–188.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and ...fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1–42), a key pathogenetic agent of Alzheimer’s disease. Our data demonstrate two different growth modes of Aβ1–42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
J. Neurochem. (2011) 117, 19-28. ABSTRACT: The pathogenesis of Alzheimer's disease involves the progressive accumulation of amyloid β-protein (Aβ). Recent studies using synthetic Aβ peptides, a cell ...culture model, Aβ precursor protein transgenic mice models suggest that pre-fibrillar forms of Aβ are more deleterious than extracellular fibril forms. Recent findings obtained using synthetic Aβ peptides and human samples indicated that low-n oligomers (from dimers to octamers) may be proximate toxins for neuron and synapse. Here, we review the recent studies on the soluble oligomers, especially low-n oligomers in Alzheimer's disease.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis (M. officinalis) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to ...Alzheimer's disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients (n = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference (P = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms.Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is ...sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cerebral amyloid angiopathy (CAA) of amyloid β-protein (Aβ) type is common in Alzheimer's disease (AD). Aβ immunotherapies have been reported to induce CAA-related intracerebral hemorrhages (ICH) or ...vasogenic edema. For the purpose of developing a method to predict CAA-related ICH and other cerebrovascular disorders in AD, the biomarkers, and risk factors are reviewed. The biomarkers include (1) greater occipital uptake on amyloid positron emission tomography imaging and a decrease of cerebrospinal fluid Aβ40 levels as markers suggestive of CAA, and (2) symptomatic lobar ICH, lobar microhemorrhages, focal subarachnoidal hemorrhages/superficial siderosis, cortical microinfarcts, and subacute encephalopathy (caused by CAA-related inflammation or angiitis) as imaging findings of CAA-related ICH and other disorders. The risk factors include (1) old age and AD, (2) CAA-related gene mutations and apolipoprotein E genotype as genetic factors, (3) thrombolytic, anti-coagulation, and anti-platelet therapies, hypertension, and minor head trauma as hemorrhage-inducing factors, and (4) anti-amyloid therapies. Positive findings for one or more biomarkers plus one or more risk factors would be associated with a significant risk of CAA-related ICH and other cerebrovascular disorders. To establish a method to predict future occurrence of CAA-related ICH and other cerebrovascular disorders in AD, prospective studies with a large number of AD patients are necessary, which will allow us to statistically evaluate to what extent each biomarker or risk factor would increase the risk. In addition, further studies with progress of technologies are necessary to more precisely detect CAA and CAA-related cerebrovascular disorders.
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