Biomarkers,mild cognitive impairment and early diagnosis of Alzheimer's disease

Elderly people are concerned about changes in their cognitive functioning. Since cholinergic therapies for Alzheimer's disease have been developed and become widely accepted, elderly people have come to visit clinics to seek medical advice about whether such a subtle change in cognitive ability may represent an early manifestation of Alzheimer's disease (AD). If they are likely to develop dementia or AD, they want to receive immediate medical treatment as soon as possible to prevent further loss of cognitive functioning so that they can live independently as long as possible. The first priority in the clinical application of a biomarker is that biomarker should contribute to early diagnosis of dementia. Among such biomarkers, we believe that cerebrospinal fluid markers and functional brain imaging are clinically the most applicable procedures. Since 1993, we have collected 623 cerebrospinal fluid (CSF) samples at The Tohoku University Hospital for evaluation of dementia (age: 42-93). We found that CSF/phospho-tau measures produced the most adequate sensitivity (85.2%) and specificity (85.0%) in the diagnosis of AD as a sole bio-marker. The CSF levels of A beta 1-42 showed a strong positive correlation with the Mini-mental state examination score and brain glucose metabolism by positron emission tomography. The baseline levels of both total-tau and phospho-tau in CSF increased in approximately 70% of patients with mild cognitive impairment who later developed AD, suggesting that pathological change in the brain might start years before dementia becomes clinically manifested. A combined use of CSF-tau and IMP-SPECT improved the predictability of the transition from mild cognitive impairment into AD.     

Alzheimer's disease. Accurate and early diagnosis in the primary care setting

Alzheimer's disease is the most common dementia type and is characterized by a gradual, progressive decline in multiple areas of cognition and function. Early diagnosis is key because it can initiate the process of patients and family adapting to and managing disease symptoms. Moreover, certain pharmacologic interventions can impede symptom progression and significantly improve quality of life. A spectrum of basic tests and instruments make clinical diagnosis of AD attainable in the primary care setting. Treatment with cholinesterase inhibitors is targeted toward cognitive enhancement. Neuroprotection involves delaying dementia progression and remains experimental. Problematic cases should be referred.     

MRI and CSF studies in the early diagnosis of Alzheimer's disease

The main goal of our studies has been to use MRI, FDG-PET, and CSF biomarkers to identify in cognitively normal elderly (NL) subjects and in patients with mild cognitive impairment (MCI), the earliest clinically detectable evidence for brain changes due to Alzheimer's disease (AD). A second goal has been to describe the cross-sectional and longitudinal interrelationships amongst anatomical, CSF and cognition measures in these patient groups. It is now well known that MRI-determined hippocampal atrophy predicts the conversion from MCI to AD. In our summarized studies, we show that the conversion of NL subjects to MCI can also be predicted by reduced entorhinal cortex (EC) glucose metabolism, and by the rate of medial temporal lobe atrophy as determined by a semi-automated regional boundary shift analysis (BSA-R). However, whilst atrophy rates are predictive under research conditions, they are not specific for AD and cannot be used as primary evidence for AD. Consequently, we will also review our effort to improve the diagnostic specificity by evaluating the use of CSF biomarkers and to evaluate their performance in combination with neuroimaging. Neuropathology studies of normal ageing and MCI identify the hippocampal formation as an early locus of neuronal damage, tau protein pathology, elevated isoprostane levels, and deposition of amyloid beta 1-42 (Abeta42). Many CSF studies of MCI and AD report elevated T-tau levels (a marker of neuronal damage) and reduced Abeta42 levels (possibly due to increased plaque sequestration). However, CSF T-tau and Abeta42 level elevations may not be specific to AD. Elevated isoprostane levels are also reported in AD and MCI but these too are not specific for AD. Importantly, it has been recently observed that CSF levels of P-tau, tau hyperphosphorylated at threonine 231 (P-tau231) are uniquely elevated in AD and elevations found in MCI are useful in predicting the conversion to AD. In our current MCI studies, we are examining the hypothesis that elevations in P-tau231 are accurate and specific indicators of AD-related changes in brain and cognition. In cross-section and longitudinally, our results show that evaluations of the P-tau231 level are highly correlated with reductions in the MRI hippocampal volume and by using CSF and MRI measures together one improves the separation of NL and MCI. The data suggests that by combining MRI and CSF measures, an early (sensitive) and more specific diagnosis of AD is at hand. Numerous studies show that neither T-tau nor P-tauX (X refers to all hyper-phosphorylation site assays) levels are sensitive to the longitudinal progression of AD. The explanation for the failure to observe longitudinal changes is not known. One possibility is that brain-derived proteins are diluted in the CSF compartment. We recently used MRI to estimate ventricular CSF volume and demonstrated that an MRI-based adjustment for CSF volume dilution enables detection of a diagnostically useful longitudinal P-tau231 elevation. Curiously, our most recent data show that the CSF isoprostane level does show significant longitudinal elevations in MCI in the absence of dilution correction. In summary, we conclude that the combined use of MRI and CSF incrementally contributes to the early diagnosis of AD and to monitor the course of AD. The interim results also suggest that a panel of CSF biomarkers can provide measures both sensitive to longitudinal change as well as measures that lend specificity to the AD diagnosis.     

Nursing home admission for African Americans with Alzheimer's disease.

BACKGROUND: For African Americans with Alzheimer's disease (AD), little is known about the time to, and risk factors for, nursing home admission (NHA). Using Consortium To Establish a Registry for Alzheimer's Disease (CERAD) data, this study provides information on NHA for African Americans. METHODS: This longitudinal study followed subjects (N=122) for as long as 7 years and used survival analysis methodology and variable values at baseline and at follow-up to identify NHA risk factors. Studied were sociodemographic variables, physical symptom and disease status variables, the Blessed Dementia Rating Scale (including subscores), the Clinical Dementia Rating (CDR), and the Mini-Mental State Examination. RESULTS: Only 25% of African Americans with AD were estimated to have had a NHA by 3.4 years (confidence interval 2.1, 5.4). Being unmarried resulted in a five times earlier NHA (p< .01), and each unit increase in the CDR resulted in a 74% earlier NHA (p<.01). In the absence of the CDR, limitation in activities of daily living was associated with earlier NHA (p<.05). CONCLUSIONS: Findings suggest that African Americans with AD spend a substantial time in the community prior to NHA, a longer time than observed in similar studies among whites. This raises public health and clinical concern that African Americans with AD may be residing in the community with substantial unmet needs, and that their caregivers have potentially high levels of burden. The independent associations with time to NHA observed here, although few in number, are consistent with other related research.     

老年性痴呆影像学诊断

临床上老年性痴呆 (ＡＤ)诊断是一个复杂的过程。以ＣＴ、ＭＲＩ、正电子发射计算机断层扫描 (ＰＥＴ)和单光子发射电子计算机断层扫描 (ＳＰＥＣＴ)等为主的现代影像学检测手段已经成为ＡＤ临床诊断的重要组成部分。下面着重叙述ＭＲＩ和ＳＰＥＣＴ在ＡＤ诊断中的应用。1　ＣＴ对ＡＤ ,早期的ＣＴ主要的改变是皮质萎缩、脑沟增宽 ;中晚期 ,还表现有脑室扩大。通常观察海马周围裂的变化 ,并测量海马内侧的脑脊液池 (ＨＣＳＦ) ,即测定环池内侧边到颞叶内侧边之间的距离 ,ＨＣＳＦ是ＣＴ诊断ＡＤ较特异的指标之一。有研究通过测定三脑室的宽…     

言语流畅性测验用于帕金森病痴呆与阿尔茨海默病早期诊断的价值研究

约40%的帕金森病患者在疾病过程中会发展成痴呆,称帕金森病痴呆(PDD),相对于其他认知领域的损害,PDD的执行功能破坏尤其严重。阿尔茨海默病(AD)是老年期常见的痴呆。本研究应用3项言语流畅性测验,评估帕金森病痴呆与阿尔茨海默病患者的言语流畅性损害状况、归纳出对AD、PDD早期诊断和鉴别诊断有价值的流畅性指标,并对流畅性测验内部加工机制进行探讨分析。     

Cognitive screening and neuropsychological assessment in early Alzheimer's disease

Cognitive screening and detailed neuropsychological assessment provide a reliable means of detecting dementia in its earliest stages, tracking the progression of cognitive decline over time, and aiding in the differential diagnosis of various dementing disorders. In addition, recent studies have shown that mild cognitive changes, and particularly declines in memory function, are evident in the "preclinical" phase of Alzheimer's disease and may help to identify elderly individuals who are likely to develop dementia in the near future. Until effective and easily obtainable biological markers for detecting the onset and progression of Alzheimer's disease are developed, neuropsychological assessment will continue to have an important role in the dementia evaluation.     

Women and Alzheimer's disease.

AD is a major public health problem, and demographic trends have led to its being called the epidemic of the century. Because of increased longevity and the special challenges of ERT, women are well placed to both be at risk for and the beneficiaries of advances in AD therapy. Overall increases in health consciousness may impact future AD risk, and it is encouraging that women frequently outnumber men in clinical trials of new therapeutic agents in AD. The risk of AD from environmental exposures in the overall life experiences of women is unclear. To the extent that education and work promote the development of brain areas such as the association cortex that are preferentially affected in AD, creating a neuronal reserve, advances in women's overall place in society may further help protect them from the ravages of AD.     

Preserved blood pressure and heart rate circadian rhythm in early stage Alzheimer's disease.

BACKGROUND: This study investigated the blood pressure (BP) values over the day-night period in 11 noninstitutionalized patients affected by probable Alzheimer's disease (AD) in its early stage. The scientific aim was to detect whether the BP circadian rhythm (CR) was preserved, given the fact that CR disruption was observed in advanced or institutionalized AD patients. METHODS: The BP within-day values were gathered via noninvasive ambulatory monitoring. The BP time series were analyzed according to the chronobiological procedure, called Cosinor method with three harmonic components. RESULTS: The biometric analysis was able to document that BP changes over the 24-h scale in AD patients as a function of a significant CR. Such a preserved circadian regulation is, however, compromised in the second and third harmonic component, suggesting that the BP within-day variability is desynchronized by the environmental clues that act as synchronizers during the diurnal part of the day. CONCLUSIONS: The preservation of the BP CR in the early stage of AD suggests using such a finding as a clinical tool for confirming the recent onset of the disease. As a matter of fact, it is presumed that the disease is not evolved enough to reach the suprachiasmatic nuclei, wherein is located the BP circadian pacemaker. The abolition of the ultradian components is another precocious sign that, in turn, indicates early-stage AD patients to be particularly compromised in their synchronization to diurnal cues, such as social routines, meal timing schedule, psycho-physical activity, and occupational schemes.     

Donepezil provides greater benefits in mild compared to moderate Alzheimer's disease: Implications for early diagnosis and treatment

We assessed the cognitive and functional outcomes of donepezil treatment in mild versus moderate Alzheimer's disease (AD) patients. We performed a 6-month prospective, observational, multicenter study of the progression of cognitive and functionality abilities in a large sample patients with AD who initiated treatment with donepezil in monotherapy. According to baseline mini mental state examination (MMSE), patients were divided in two groups: mild AD (MMSE ≥ 21) and moderate AD (MMSE < 21). Patients were evaluated with the memory alteration test (M@T) and the Alzheimer's disease functional assessment and change scale (ADFACS) at baseline and at 6 months. A total of 403 patients finished the study (mild AD = 152; moderate AD = 251). The MMSE total score and M@T score remained stable at 6 months in the whole sample, with MMSE memory domain and M@T free and cued recall domains improving significantly from baseline. Total ADFACS, instrumental (IADL) and basic activities of daily living (BADL) got significantly worse, with the worsening being significantly greater in the moderate AD group. Significant differences between the groups favoring mild AD were observed for MMSE memory, orientation and language domains, M@T temporal orientation and semantic memory domains, and for IADL. We concluded that in AD patients on donepezil, cognition remains stable at 6 months. The beneficial effect of donepezil treatment, in terms of cognition and functionality, is greater for mild than for moderate AD.