The cholinergic deficiency syndrome and its therapeutic implications

Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer's disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electroencephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer's disease, Lewy body dementia and Parkinson's disease and to respond well to cholinesterase inhibitor therapy.     

Different MRI findings for normal elderly and very mild Alzheimer's disease in a community: implications for clinical practice the Tajiri Project

To investigate magnetic resonance imaging (MRI) findings of very mild dementia, 485 participants were randomly selected in a community. Three hundred and forty participants were of Clinical Dementia Rating (CDR) 0 (healthy), 113 were of CDR 0.5 (questionable dementia), and 32 were of CDR 1 and 2 (including 20 Alzheimer's disease, AD). Cortical atrophy, white matter lesion, etc., were visually assessed. We found that each part of the brain showed atrophy in older adults for CDR 0. For CDR 0.5, the relationships between MRI findings and age were weaker, and for AD, there were no such relationship. Atrophy related with dementia severity was found to be limited to the lateral and medial temporal lobes. For CDR 0.5, amygdala atrophy was the only finding indicating CDR effect but no age effect. The amygdala or anterior entorhinal atrophy is important for discriminating very mild dementia from normal elderly.     

Gallyas-Braak银染法在神经系统变性疾病中的应用

目的 评估Gallyas-Braak银染色方法在几种神经系统变性疾病病理诊断中的作用和价值。方法 采用修订Gallyas-Braak染色法,对经临床和常规病理方法诊断的22例神经系统变性病的脑和脊髓标本进行了回顾性研究。结果 Gallyas-Braak银染色可良好显示Alzheimer病（AD）,其他变性病痴呆,正常老年人的海马及额、颞叶皮层神经原纤维缠结,且较Bodian染色清楚。在4例有痴呆症状和明显锥体外体征患者的中脑,基底节观察到大量神经元球形团样缠结,同时在运动皮层,基底节,中脑观察到星形细胞丛状缠结,其中2例符合进行性核上性麻痹的病理诊断标准,另2例观察到运动皮层和基底节区星形细胞斑,加之皮层神经元气球样变,符合皮质基底节变性的病理特征。3例多系统萎缩的脑和脊髓白质显示广泛分布少突胶质细胞包涵体。1例AD病的颞叶和海马皮质2－3层神经毡内显示嗜银颗粒,而Bodian染色未观察到这些病理改变。结论 Gallyas-Braak染色除显示神经原纤维缠结外,还能较好显示胶质细胞变性和神经毡异常结构,因此对进行性核上性麻痹,皮质基底节变性,多系统萎缩,嗜银颗粒病的病理诊断有重要价值。     

A clinicopathological study of CT scans in Alzheimer's disease.

OBJECTIVE: To investigate the accuracy of cranial computerized tomography (CT) scans in distinguishing patients with Alzheimer's disease from those with other dementing conditions. DESIGN: Retrospective clinicopathological correlation with pre-mortem CT scans. SETTING: Urban and rural hospitals and nursing homes in the Upper Midwest. PATIENTS: All 507 patients had clinical dementia diagnosed as Alzheimer's disease during life and the subsequent referral of their brains to a dementia brain bank. Of these, 375 patients had had CT scans as part of the diagnostic work-up for dementia. MAIN OUTCOME MEASURES: The presence of neuropathological evidence of Alzheimer's disease and the specific findings on CT scans. RESULTS: Of the 375 patients evaluated with a CT, 28% were misdiagnosed (lacked neuropathological evidence of Alzheimer's disease); of the 132 patients evaluated without a CT scan, only 18% were misdiagnosed (P less than 0.05). The degree of atrophy and other CT findings were similar in the correctly diagnosed and misdiagnosed groups except for increased ventricular size in the correctly diagnosed patients (P less than 0.05). CONCLUSION: Although CT scans do not usually contribute to the recognition of Alzheimer's disease, the presence of ventricular enlargement may help distinguish Alzheimer's disease from other dementias.     

Mild cognitive impairment and preclinical Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by a gradual decline of numerous cognitive processes, culminating in dementia. Mild cognitive impairment (MCI) is a relatively broad clinical condition involving a slight memory deficit, which in many cases represents a transitional state between normal cognition and AD. Much research is currently being conducted on MCI, since any therapy that is effective at treating this early manifestation of dementia may provide an opportunity for managing the disease while patient function is relatively preserved. Current research seeks to develop disease-modifying treatments that intervene in the pathobiologic processes involved in MCI and AD. Another goal of current research is to develop antecedent biomarkers that can be used to detect AD prior to the appearance of symptoms and before substantial and irreversible brain damage occurs.     

Presenile dementia combined with amyotrophy: a review of 34 Japanese cases

Thirty-four Japanese cases exhibiting presenile dementia combined with amyotrophy were reviewed with four case reports. The clinical feature of dementia was generally unspecific and could not be clearly diagnosed as Pick's disease or Alzheimer's disease. But most of these patients did not exhibit manifest visual agnosia or apraxia suggesting 'posterior dementia'. Brain CTs showed mild diffuse atrophy with non-circumscribed fronto-temporal accentuation. PSD (periodic synchronous discharge on EEG) as seen in Creutzfeldt-Jakob disease (CJD) was not noted in any of these cases. Although individual neurological findings were not contradictory to amyotrophy lateral sclerosis (ALS), the clinicopathologic findings, on the whole, could be regarded as indicative of an atypical spinal progressive muscular atrophy. The brain pathology lacked specific changes. A mild to moderate degree of glial proliferation, subcortical gliosis and a moderate spongy state of the upper cortical layers were seen mainly in the fronto-temporal area. Nigral degeneration was observed in half of the cases. No Pick's cells, Pick's balls, Alzheimer's neurofibrillary changes or senile plaques were observed except in two cases, in whom it could be regarded as physiological. Brain weight was lighter than that of normal Japanese but heavier than that of Pick's disease, Alzheimer's disease or CJD. The brain pathology was similar to that of progressive subcortical gliosis. We have concluded that the disease under discussion might be a new disease entity.     

Prevalence of senile dementia in a rural community in Japan: the Tajiri project

Knowledge of the prevalence of dementia in different age groups is needed for the planning of a health policy. This study shows the prevalence of dementia and magnetic resonance imaging (MRI) findings in elderly people aged 65 years and over, living in the town of Tajiri in the northern part of Japan. They were shown by two cognitive screening tests, the Mini-Mental State examination (MMS) and the Dementia Screening Test (DST) and medical diagnosis. Two subject groups were assessed, those who completed both tests (Subjects I, n=2066) and those from among the 200 'MRI-administered subjects' who were interviewed and diagnosed (Subjects II, n=170). For Subjects I, there were 6.3 and 10.2% 'dementia range' according to the severe and mild criteria, respectively. As for Subjects II, 9.4% were clinically diagnosed as having dementia. They met the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria of probable Alzheimer's disease (AD) or possible AD with cerebrovascular disease. The estimated prevalence rate of dementia was 8.0%. Visual ratings of brain atrophy using MRI disclosed two distribution patterns. The 'continuous' pattern of the frontal and temporal lobes atrophy suggest that both are affected by the aging process, while a 'discontinuous' pattern of the hippocampal atrophy could indicate a pathologic background such as early changes of AD.     

Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study

The extent to which cerebral atrophy in Alzheimer's disease changes with time is unknown. We used multiple MRI scans to measure progression of cerebral atrophy in 12 patients with Alzheimer's disease who were followed up from a presymptomatic stage through to moderately severe dementia. Analysis with hierarchical regression models with quadratic terms in time provided evidence of increasing yearly percentage losses in brain volume. At the time when patients were judged to have mild dementia (mini-mental state examination score MMSE=23), mean yearly loss of brain volume was 2.8% (95% CI 2.3-3.3), which rose by 0.32% per year (0.15-0.50). Our findings reinforce the need for early diagnosis and therapeutic intervention in Alzheimer's disease.     

Prevention of common neurodegenerative disorders in the elderly

Since population aging has become a worldwide phenomenon, the burden of the age-related neurodegenerative diseases is expected to increase dramatically in both developed and developing nations. Alzheimer's disease is the most common neurodegenerative disorder among old people. Prevention may represent an ideal solution to the challenge posed by this condition. Recent epidemiological studies have revealed a number of risk and protective factors that could influence occurrence of dementia including Alzheimer type dementia. We propose that an active and stimulating lifestyle in late life as well as an optimal control of vascular and other chronic diseases both at middle age and late life can be two possible intervention strategies to prevent or postpone the onset of dementia, and perhaps other neurodegenerative disorders such as Parkinson's disease.     

Mild cognitive impairment in older people

CONTEXT: As public awareness of Alzheimer's disease increases, more people are asking for help and advice about memory problems. Memory complaints may be secondary to psychiatric, psychological, and physical conditions and is an almost universal early symptom of dementia. The concept of amnestic mild cognitive impairment attempts to describe those people in whom memory loss is not of such severity to merit a diagnosis of dementia. The importance of this group of people is not just the need to develop interventions which ameliorate individual suffering but that they represent a population at high risk of developing dementia, especially Alzheimer's disease, and are an appropriate target for dementia prevention strategies. STARTING POINT: K Kantarci and colleagues (Dement Geriatr Cogn Disord 2002; 14: 198-207) looked at the diagnostic accuracy of magnetic-resonance hippocampal volumetry and spectroscopy in patients with mild cognitive impairment, in normal older people, and in patients with Alzheimer's disease. Hippocampal volumes and N-acetyl aspartate/creatine spectroscopy were the most sensitive assessments discriminating people with mild cognitive impairment from Alzheimer's disease. Combination assessments were better at discriminating these two groups from normal controls. The histological underpinning of cognitive symptoms in older people has been demonstrated by the Cognitive Function and Ageing study (Lancet 2001; 357: 169-75), which showed that a third of people with no clinical evidence of dementia had histopathological hallmarks of Alzheimer's disease. WHERE NEXT? 25 million people across the world have dementia. Mild cognitive impairment, if a validated concept, represents an opportunity for preventing dementia. As more information becomes available about the cause of Alzheimer's disease and prospects emerge for prevention, identification of predementia states offers considerable scope to reduce the individual and societal cost of the illness. Continued validation of the criteria for mild cognitive impairment and studies of intervention should be a priority. As more evidence becomes available highlighting the relatively arbitrary nature of dementia diagnosis (based largely on interference with activities) and interventions become available for the prevention of dementia, mild cognitive impairment and related conditions will become more important.     

A neuroradiological study on the influence of cerebral atrophy and white matter lesion on cognitive function in the elderly

We investigated the influence of brain atrophy and white matter lesions on cognitive function in elderly people. We selected 33 subjects (mean age, 79.2 +/- 5.1yrs) with a MMSE score from 14 to 30 who had no previous history of stroke from the outpatients in the Memory Clinic of our hospital. These subjects were divided into four groups on the basis of their MMSE score as follows: 14-20; moderate dementia (Moderate-D, n = 9), 21-23; mild dementia (Mild-D, n = 9), 24-27; mild cognitive impairment (MCI, n = 10), 28-30; normal (Normal, n = 5). Among these four groups, we compared the frequency of the associated risk factors for cerebral infarction (hypertension, diabetes mellitus, hyperlipidemia, heart disease), and the severity of brain atrophy and cerebral white matter lesion which were visually evaluated by MRI technique. Brain atrophy and white matter lesions were assessed by reviewing the cerebral cortex and hippocampus, and deep white matter lesion (DWML) and periventricular hyperintensity (PVH), respectively. Brain atrophy was divided into three grades (mild, moderate, severe) and white matter lesions were classified into four grades (0-3) using Fazekas's criteria. We performed statistical analysis to detect t parameters which correlate with and influence MMSE scores from among the MRI findings. The cases with dementia were all diagnosed as Alzheimer's disease. There were no significant differences among the four groups in mean age, the incidence of individual associated risk factors, the severity of cortical atrophy, or the grade of DWML (< or = 2) and PVH (< or = 2). However, the frequency of hippocampal atrophic change greater than a moderate grade increased in parallel with the exacerbation of reduced cognitive function (Normal; 20%, MCI: 40%, Mild-D; 56%, Moderate-D 89%), and approximately 76% with such a change were AD cases. Statistical analysis showed a significant negative correlation between the grade of hippocampal atrophy and MMSE score (r = -0.518, p < 0.005) and a great influence of hippocampal atrophy on that score (step-wise regression analysis: r = 0.518, p < 0.005). From the above results, it was suggested that more than moderate atrophic change in the hippocampus might possibly be related with cognitive impairment and that both DWML and PVH less than the second grade had little influence on the decline of brain function.     

Superficial siderosis of the central nervous system: a rare cause of dementia with therapeutic consequences

A 75-year-old patient was evaluated for dementia. His past medical history included an ischaemic cardiomyopathy treated with aspirin daily. His neurological examination showed mild ataxia syndrome and central deafness. The neuropsychological examination did not suggest Alzheimer's disease. No specific aetiology was found from biological investigations, but MRI scans revealed a superficial siderosis, which was further confirmed with CSF exams. This case highlights the interest of MRI with echo-gradient-T2 weighted sequences in patients investigated for memory disorders. Once the diagnosis is known, specific preventive measures have to be taken: searching for a treatable source of bleeding and the interruption of antiplatelet aggregation or anticoagulant treatments.     

Executive function deficits in normal aging, Alzheimer's disease, and frontotemporal dementia

An increasing number of studies suggest that executive functions are among the first cognitive functions to bear negative effects of normal aging. Executive functions also appear to be early affected in Alzheimer's disease and frontotemporal dementia. This article reviews studies in neuropsychology and experimental cognitive psychology with a focus on normal aging, Alzheimer's disease as well as frontotemporal dementia. Study results suggest that so called executive tasks are not equally impaired by normal ageing or dementia in agreement with the recent theoretical models, which state that a set of distinct elementary mechanisms subserve the executive control of cognitive behavior. These models are therefore particularly relevant to address issues stemming from aging.     

C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer's disease

Caenorhabditis elegans has been used to model aspects of a number of age-associated neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases. These models have typically involved the transgenic expression of disease-associated human proteins. Here I describe my laboratory's specific experience engineering C. elegans models of Alzheimer's disease, and give a general consideration of the advantages and disadvantages of these C. elegans models. The type of insights that might be gained from using these (relatively) simple models are highlighted. In particular, I consider the potential these models have for uncovering common and unique fundamental toxic mechanisms underlying human neurodegenerative diseases.     

What are the possibilities of preventing dementia?

Population ageing makes issue of dementia prevention very important. Measures used in prevention of other diseases are also effective in prevention of dementia. Incidence of vascular dementia is decreased by effective treatment of hypertension, diabetes and anticoagulatory treatment in patients with atrial fibrillation. Nonsteroidal antiinflammatory drugs and statins reduce incidence of Alzheimer's disease.     

Is there any role for computed tomography measurements of medial temporal lobe atrophy in dementia? A review of the literature and case series from a memory clinic

Neuroimaging in dementia has focused on documenting any burden of vascular disease or excluding any reversible intracranial pathology. We review the use of computed tomography to examine for medial temporal lobe atrophy in dementia and compare this with a case series of such measurements from our memory clinic. Measures of medial temporal lobe atrophy were used to separate patients with Alzheimer's disease from those with normal cognition, mood disorders or other forms of early dementia.     

Proton magnetic resonance spectroscopy reveals similar white matter biochemical changes in patients with chronic hypertension and early Alzheimer's disease

OBJECTIVES: Hypertension is a risk factor for dementia and is associated with some of the brain changes that are found in Alzheimer's disease and other neurodegenerative diseases, such as atrophy and neurofibrillary tangles. We evaluated the cerebral white matter biochemical pattern in healthy older subjects, older patients with chronic hypertension, and patients with Alzheimer's disease (AD) using proton magnetic resonance spectroscopy (1H-MRS). DESIGN: Cross-sectional study. SETTING: University-affiliated outpatient clinic. PARTICIPANTS: Ten healthy older subjects, 10 cognitively intact older patients with chronic hypertension, and 10 older patients with early AD. MEASUREMENTS: All subjects underwent clinical examination, neuropsychological assessment, and 1H-MRS to measure N-acetylaspartate (NAA), myoinositol, choline, and creatine resonance signals in an 8-cm3 voxel located in the paratrigonal white matter region bilaterally. NAA/creatine, myoinositol/creatine, and choline/creatine ratios were measured, and the mean values were compared using one-way analysis of variance with Tukey test for post hoc analysis. RESULTS: A significantly higher mean myoinositol/creatine (ratio +/- standard deviation) was found in hypertensive patients (0.67 +/- 0.05) and in AD patients (0.68 +/- 0.08) than in controls (0.56 +/- 0.04) (P <.001). Conversely neither NAA/creatine ratio nor choline/creatine ratio differed among the three groups. CONCLUSIONS: In this study, cognitively intact chronic hypertensive older patients had a higher white matter myoinositol/creatine ratio compared with healthy older subjects, suggesting that myoinositol may be a sensitive marker of the effects of chronic hypertension on the brain. Moreover, the similar increase of myoinositol/creatine ratio in patients with hypertension and in those with early AD provides further evidence of common brain changes with these conditions.     

Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of many common age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common neurodegenerative disorder characterized by dementia, memory loss, neuronal apoptosis and eventually death of the affected individuals. AD is characterized by two pathologic hallmark lesions that consist of extracellular plaques of amyloid-beta peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated microtubular protein tau. Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein and tau alterations in this type of dementia remains controversial.     

Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

As populations across the world both age and become more obese, the numbers of individuals with Alzheimer′s disease and diabetes are increasing; posing enormous challenges for society and consequently becoming priorities for governments and global organizations. These issues, an ageing population at risk of neurodegenerative diseases such as Alzheimer′s disease and an increasingly obese population at risk of metabolic alterations such as type 2 diabetes, are usually considered as independent conditions, but increasing evidence from both epidemiological and molecular studies link these disorders. The aim of this review was to highlight these multifactorial links. We will discuss the impact of direct links between insulin and IGF‐1 signalling and the Alzheimer′s disease‐associated pathological events as well as the impact of other processes such as inflammation, oxidative stress and mitochondrial dysfunction either common to both conditions or perhaps responsible for a mechanistic link between metabolic and neurodegenerative disease. An understanding of such associations might be of importance not only in the understanding of disease mechanisms but also in the search for novel therapeutic options.     

Diagnostic criteria for vascular dementia.

The term vascular dementia implies the presence of a clinical syndrome (dementia) caused by, or at least assumed to be caused by, a specific disorder (cerebrovascular disease). In this review, the various sets of criteria used to define vascular dementia are outlined. The various sets of criteria are judged whether they contain criteria for both dementia and vascular disease as well as for the relationship between the two. We conclude that only the criteria of the State of California Alzheimer's Disease Diagnostic and Treatment Centers and of NINDS-AIREN provide sufficient operational criteria for dementia suitable for use in patients with vascular disease as well as for the diagnosis of cerebrovascular disease and for the establishment of a relationship between dementia and vascular disease. The latter criteria include also specific recommendations to the use of CT and MRI. However, the interpretation of the neuroimaging findings in the context of mixed vascular and degenerative dementia demands further study. Given the heterogeneous pathophysiology and pathology of vascular dementia and the modest reliability of the criteria, it seems plausible that the diagnosis of vascular dementia will become more reliable when specific diagnostic tests for the various degenerative diseases, from which vascular dementia has to be differentiated, become available.