Toshifumi Matsui

Consensus Report of the Working Group on : Molecular and Biochemical Markers of Alzheimer's Disease

The ideal biomarker for Alzheimers disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases; it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias; it should be reliable, reproducible, non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD, it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Abeta42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD, these measures are not useful, but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD, cerebrospinal fluid assays showing low levels of Abeta42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.The ideal biomarker for Alzheimers disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases: it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias: it should be reliable, reproducible non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD. it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Aβ 42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD. these measures are not useful. but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD. cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.

Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression.

There is evidence that certain components of the renin-angiotensin system (RAS) may have a crucial role in learning and memory processes.1,2⇓ Angiotensin-converting enzyme (ACE) is overexpressed in the hippocampus, frontal cortex, and caudate nucleus of patients with Alzheimer disease (AD).1 In an animal model with AD, brain-distributing ACE inhibitors are reported to rescue neuronal damage and improve behavior.2 Furthermore, we have shown that brain-penetrating ACE inhibitors can reduce the incidence of AD in elderly hypertensive patients.3 In the present study, we tested the hypothesis that treatment with brain-penetrating ACE inhibitors3 would slow the rate of cognitive decline in mild-to-moderate AD patients with hypertension.nnWe performed a randomized, prospective, parallel group trial with 1-year exposure to study medications. Participants were recruited from three long-term care facilities in Sendai, Japan. Patients eligible for this study had a diagnosis of mild to moderate AD,4,5⇓ were aged 65 years and older, had Mini-Mental State Examination (MMSE) scores within the range of 13 to 23, showed no evidence of stroke; insulin-dependent diabetes mellitus, or other endocrine disorders, or asthma or obstructive pulmonary disease, and had a blood pressure of higher than 140 mm Hg systolic or 90 mm Hg diastolic. The diagnosis of probable AD was made according to National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria with no clinical or laboratory evidence of a cause other than AD for dementia.5 Brain MRI was obtained in all participants within 3 months prior to the study enrollment to exclude patients with possible or probable vascular dementia and other neurodegenerative dementias. Patients …

Elevated Plasma Homocysteine Levels and Risk of Silent Brain Infarction in Elderly People

Background and Purpose Silent brain infarction (SBI) on MRI is common in elderly people, and recent studies have demonstrated that SBI increases the risk of progression to clinically apparent stroke and cognitive decline. Therefore, an early and accurate detection of SBI and a search for potential treatable risk factors may have a significant impact on public health. Methods Community-dwelling elderly people aged ≥66 years who participated in the present study (n=153) underwent brain MRI and standardized physical and neuropsychological examinations as well as blood biochemistry determinations, including total plasma homocysteine (pHcy), renal function, vitamin status, and polymorphisms of the methylenetetrahydrofolate reductase gene. Results SBI was found in 24.8% of the participants. In the univariate analysis, the pHcy levels in subjects with SBI (13.6±4.1 &mgr;mol/L) were significantly higher (P =0.0004) than those in subjects without SBI (11.0±3.3 &mgr;mol/L). When pHcy levels were stratified into high (≥15.1 mmol/L), moderate (11.6 to 15.0 mmol/L), and low (≤11.5 mmol/L) groups, age (P <0.0001), male sex (P <0.0001), the habits of cigarette smoking (P <0.0001) and of alcohol consumption (P =0.0002), and folate levels (P =0.01) were significantly associated with an elevation of pHcy levels. The elevated pHcy levels were significantly associated with SBI after individual adjustment for age, sex, hypertension, renal function, and the habits of smoking and alcohol consumption. Conclusions pHcy level is associated with age and nutritional and other lifestyle factors, and it contributes to a risk for SBI.

Relation between incidence of pneumonia and protective reflexes in post‐stroke patients with oral or tube feeding

Abstract. Nakajoh K, Nakagawa T, Sekizawa K, Matsui T, Arai H, Sasaki H (Tohoku University School of Medicine, Sendai, Japan). Relation between incidence of pneumonia and protective reflexes in post‐stroke patients with oral or tube feeding. J Intern Med 2000; 247: 39–42.

Sleep Patterns and Mortality among Elderly Patients in a Geriatric Hospital

Background: Sleep disturbance is one of the major and unsolved problems in older people. Most of the previous sleep studies rely on self-reported documents, and memory disturbance in older people might bias sleep complaints and health status. Objective: Sleep disturbances were studied as a mortality risk. Methods: In 272 patients who were aged, infirmed and chronically institutionalized in a skilled-care geriatric hospital, the presence or absence of sleep disturbances were examined by hourly observations of patients over 2 weeks at baseline, and they were prospectively followed up for 2 years to assess mortality. Results: Mortality after 2 years was significantly higher in the nighttime insomnia, daytime sleepiness, and sleep-onset delay groups. Further, adjusted for age, gender and activities of daily living status, the presence of nighttime insomnia and sleep-onset delay remained associated with a higher risk of mortality. Conclusion: Sleep disturbance may be one of the symptoms indicating poor health or functional deficits, and be an independent risk factor for survival.

CSF phosphorylated tau protein and mild cognitive impairment: a prospective study.

Cerebrospinal fluid (CSF) tau protein phosphorylated at both Thr231 and Ser235 sites (CSF/phospho-tau(231-235)) and total tau (CSF/total-tau) were quantified by sandwich ELISA in 20 patients with mild cognitive impairment (MCI) who eventually developed AD on follow-up as well as seven memory complainers with no objective memory loss. 13/20 (65%) of the MCI patients had high CSF/total-tau and detectable levels of CSF/phospho-tau(231-235), whereas these markers were low and under a detectable level in all of the memory complainers. Although either a total-tau, phospho-tau measurement or a combination of these can help in predicting if MCI will develop AD, our results suggest that the pathogenic steps of AD may be at the stage that finally leads to an accumulation of abnormally phosphorylated tau and neuron death, at least in some brain areas, when MCI patients present with the earliest detectable clinical symptoms of dementia.

18F-fluorodopa PET study of striatal dopamine uptake in the diagnosis of dementia with Lewy bodies

Article abstract Using 18F-fluorodopa PET and a constant 0.0062 influx rate in the putamen, dementia with Lewy bodies (n = 7) was distinguished from AD (n = 10) with a sensitivity of 86% and a specificity of 100%. A constant 0.0071 influx rate in the caudate yielded a sensitivity of 71% and a specificity of 100% for distinction of the two disorders. Despite a limited sample size, these findings suggest that assessing nigrostriatal dopaminergic function with 18F-fluorodopa PET may be a useful diagnostic aid in cases of dementia with Lewy bodies while patients are alive.–1576

Cerebrospinal Fluid Amyloid β1–42 Levels in the Mild Cognitive Impairment Stage of Alzheimer's Disease

Cerebrospinal fluid (CSF) levels of amyloid beta-protein ending at amino acid position 42 (CSF-A beta(1-42)) and CSF-tau levels were quantified by sandwich ELISAs in 19 patients with mild cognitive impairment (MCI) who eventually developed Alzheimers disease (AD) on follow-up as well as in 15 age-matched normal controls and 54 AD patients at diverse stages of the disease. In the present study, the annual conversion rate was approximately 15%. The CSF-A beta(1-42) levels did not differ significantly between the normal control group and the MCI group, however, these values declined significantly once AD became clinically overt. In contrast to CSF-Abeta(1-42), CSF-tau levels were significantly increased in the MCI stage, and these values continued to be elevated thereafter, indicating that increased levels of CSF-tau may help in detecting MCI subjects who are predicted to develop AD. We propose that CSF-tau and CSF-A beta(1-42) must be used as two distinct biomarkers that should be applied appropriately in clinical settings.

Brain-derived neurotrophic factor gene polymorphisms and Alzheimer’s disease

Summary.Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer’s disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP) – i.e., C270T and G196A – in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, pu2009=u20090.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, pu2009=u20090.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, pu2009=u20090.035) or positive for AD family history (2.8 vs. 7.1%, pu2009=u20090.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.

Plasma orexin-A is lower in patients with narcolepsy.

Recently identified hypothalamic peptides called orexins (or hypocretins) have been implicated in the sleep-wake cycle and in sleep disorder narcolepsy. Neuropathological studies have shown that in patients with narcolepsy, global reduction in the expression of orexins occurs due to the loss of orexin neurons in the hypothalamus. Cerebrospinal fluid analysis has confirmed a reduced or undetectable level of orexin-A in most narcolepsy patients. In this study, measurement of plasma orexin showed significantly lower concentrations in patients with narcolepsy than in age- and gender-matched normal controls. These data suggest that low levels of orexin-A in plasma could serve as a biological marker for narcolepsy.