Comparability in respect of severity of dementia and determination of the nature and degree of disabilities in daily living due to dementia are important in population-based surveys. In physical diseases impairment of a...Comparability in respect of severity of dementia and determination of the nature and degree of disabilities in daily living due to dementia are important in population-based surveys. In physical diseases impairment of a system or organ may be established independently of disability using the ICIDH framework but there are problems in measuring cognitive abilities apart from the characteristic behavioural limitations and aberrations that constitute the dementia syndrome. Both DSM-III-R and ICD-10 require as a criterion of dementia that social activities are interfered with, and the degree of dependency is the measure of severity. This suggests that assessment of disability should be the first objective, and the mental or physical causes uncovered next. A suitable informant may be the best judge of the nature of the disability. This procedure would show what services demented persons actually require, clarify the implications of dementia for estimates of active life-expectancy, and increase comparability between studies. Problems associated with this approach and the role of cognitive testing are briefly discussed.
Paired helical filaments (PHF) are fibrillar structures that accumulate in degenerating neurons of AD brain. We have purified their components, PHF-tau and PHF-smear, and analyzed them protein chemically. PHF-tau is abno...Paired helical filaments (PHF) are fibrillar structures that accumulate in degenerating neurons of AD brain. We have purified their components, PHF-tau and PHF-smear, and analyzed them protein chemically. PHF-tau is abnormally phosphorylated. Although the characteristic of this phosphorylation is similar to that of fetal tau, its extent is higher in PHF-tau. The additional phosphorylation in PHF-tau may cause its loss of microtubule assembly capacity. Our results on the phosphorylation sites suggested that fetal tau and presumably PHF-tau are in vivo substrates of proline-directed protein kinases. PHF-smear consisted largely of the carboxyl-terminal portion of tau and ubiquitin. The ubiquitin-targeted protein was identified as tau in PHF and the conjugation sites were localized to the microtubule-binding region. It is most likely that abnormally phosphorylated full-length tau (PHF-tau) accumulates as PHF, which is then gradually processed from its amino-terminus and followed by ubiquitination.
The CANTAB battery was administered to a large group (n = 787) of elderly volunteers in the age range from 55 to 80 years. This battery, which is based on tests used to identify the neural substrates of learning and memo...The CANTAB battery was administered to a large group (n = 787) of elderly volunteers in the age range from 55 to 80 years. This battery, which is based on tests used to identify the neural substrates of learning and memory in non-human primates, has now been extensively used in the assessment of various forms of dementia and also validated on patients with neurosurgical lesions of the frontal and temporal lobes. The tests employed were pattern and spatial recognition, simultaneous and delayed matching to sample, learning of visuospatial paired associates, a matching to sample, reaction time task and a test of spatial working memory. The sample was banded into different IQ bands based on performance on 5 standard tests of intelligence. The MMSE was also administered to exclude cases of possible dementia (n = 16) in the normal sample. In general, performance declined with age and IQ, but these factors did not interact. A factor analysis (with varimax rotation) identified 4 factors with eigenvalues greater than 1, which accounted for over 60% of the variance. Factor 1 was equated with general learning and memory ability and loaded significantly with the Intelligence scores; factor 2 was related to speed of responding and loaded most heavily with Age. Comparisons were also made of performance on CANTAB of those subjects with dementing scores on the MMSE and the lowest 5th percentile of the population sample. The results are discussed in terms of the utility of the CANTAB battery for the assessment of dementia and of the implications for theories of changes in cognitive function during normal aging.
The present study compares the sensitivity and specificity of the short and full forms of the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) interview in diagnosing dementia. We tested 73 subjects mee...The present study compares the sensitivity and specificity of the short and full forms of the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX) interview in diagnosing dementia. We tested 73 subjects meeting DSM-IIIR criteria for dementia and 61 matched controls. The short version was applied 3 months after the full one to guarantee a relative stability of the tested functions. Referred to an independent clinical rating made at the beginning of the study, the levels of sensitivity and specificity were not significantly different in the two forms and fully comparable with those of the original full English version. Moreover, the scores on analogous sections of the two versions were highly correlated in the demented and control groups. These findings support the hypothesis that the short form of the CAMDEX maintains the psychometric properties of the full one, and consequently can be used in diagnostic routines for a variety of clinical and research purposes.
In 40 patients with Alzheimer's disease (AD, < 65 years), 56 patients with senile dementia of the Alzheimer type (SDAT, > or = 65 years) and 45 patients with vascular dementia (VAD), basal cortisol levels were estimated...In 40 patients with Alzheimer's disease (AD, < 65 years), 56 patients with senile dementia of the Alzheimer type (SDAT, > or = 65 years) and 45 patients with vascular dementia (VAD), basal cortisol levels were estimated and the dexamethasone test (DST) was performed. The degree of dementia was assessed according to DSM-III-R and the GBS scale was used for quantitative measures of functional impairment. There were no significant differences in basal cortisol levels. Especially in the VAD group, scores on functional impairment correlated significantly with post-DST cortisol levels. The results indicate hypothalamic overactivity in demented patients which can be correlated to the degree of dementia. In VAD, and to a certain extent also in SDAT, there appears to be a disconnection between cortical areas, including the hippocampus and the hypothalamus.
The density of senile plaques (SP) and neurofibrillary tangles (NFT) was estimated at post-mortem in areas B17 and B18 of the visual cortex in 18 Alzheimer's disease (AD) cases which varied in disease onset and duration....The density of senile plaques (SP) and neurofibrillary tangles (NFT) was estimated at post-mortem in areas B17 and B18 of the visual cortex in 18 Alzheimer's disease (AD) cases which varied in disease onset and duration. The density of SP in B17 and NFT in B17 and B18 declined significantly with age at death of the patient. The density of SP and NFT was greater in B18 than B17 but only in cases of earlier onset and shorter duration. The pathological differences between B17 and B18 could explain the visual evoked responses (VER) that have been reported in AD. However, the differences were small, and changes in the afferent pathways remain the most likely explanation for the VER in AD.
To assess the feasibility of one approach to combined cholinergic/noradrenergic treatment in Alzheimer's disease, ten patients were enrolled in a 2-week placebo-controlled study of oral physostigmine plus clonidine. The...To assess the feasibility of one approach to combined cholinergic/noradrenergic treatment in Alzheimer's disease, ten patients were enrolled in a 2-week placebo-controlled study of oral physostigmine plus clonidine. The Alzheimer's Disease Assessment Scale (ADAS) was used as the primary outcome measure. Neither physostigmine alone, nor the combination of physostigmine plus clonidine, was associated with a statistically significant improvement for the group. Three patients did show an improvement of at least 4 points on the total ADAS score with the drug combination. The implications of these results for treatment strategies are discussed.
The frequency of the epsilon 4 allele of the apolipoprotein E (apoE) is increased in familial and sporadic late-onset Alzheimer's disease, but its prevalence in non-Alzheimer dementias in Caucasian populations is unknown...The frequency of the epsilon 4 allele of the apolipoprotein E (apoE) is increased in familial and sporadic late-onset Alzheimer's disease, but its prevalence in non-Alzheimer dementias in Caucasian populations is unknown. We found that the frequency of the apoE epsilon 4 allele was 0.45 in 93 Alzheimer's disease patients, 0.46 in 23 vascular dementia patients, 0.31 in 13 dementia of the frontal type patients, and 0.18 in 51 elderly controls. The association of apoE epsilon 4 allele is not unique to Alzheimer's disease, and its importance as a risk factor for the disease should be reconsidered.
Lipofuscin, the age pigment, is of interest in Alzheimer's disease because of its property to accumulate in neurons and because of the hypothesis that Alzheimer's dementia is a kind of premature ageing. The amount of int...Lipofuscin, the age pigment, is of interest in Alzheimer's disease because of its property to accumulate in neurons and because of the hypothesis that Alzheimer's dementia is a kind of premature ageing. The amount of intraneuronal lipofuscin in the inferior olivary nucleus of 20 brains from patients with histologically confirmed Alzheimer's disease according to the CERAD protocol and of 20 controls has been measured microfluorometrically. Patients and controls were matched for age. The amount of lipofuscin in the neurons of the inferior olivary nucleus did not differ significantly between the cases of Alzheimer's disease and the controls. The result is discussed taking the findings of previous authors into account. We conclude that there is no evidence that lipofuscin plays an important role in the pathogenesis of Alzheimer's disease.
Using computer-enhanced image analysis, the amount of lipofuscin was measured in 500 hippocampal pyramidal neurons (regions CA2 and CA3) with and without neurofibrillary tangles (NFT), in brains of 10 patients with Alzhe...Using computer-enhanced image analysis, the amount of lipofuscin was measured in 500 hippocampal pyramidal neurons (regions CA2 and CA3) with and without neurofibrillary tangles (NFT), in brains of 10 patients with Alzheimer's disease (AD), as well as in 6 age-matched controls. The average content of lipofuscin in those cells from AD brains carrying NFT is only 10% of the total perikaryal area, whereas in the AD neurons free of NFT, and in age matched controls, lipofuscin amounted to 31 and 33% of cellular area, respectively. Measurements of lipofuscin's intrinsic autofluorescence confirmed this material to be three times more abundant in AD neurons without NFT and in controls. We propose that a breakdown in the capacity for making lipofuscin may result in the neuronal inability to store toxic waste. Such a defect could be responsible for the generation of NFT and ultimately may contribute to neuronal demise.
We have used biochemical assays to examine cingulate and occipital cortices from age-matched cases of Alzheimer's disease (AD; n = 12), senile dementia of the Lewy body type (SDLT; n = 13), Parkinson's disease (PD; 5 non...We have used biochemical assays to examine cingulate and occipital cortices from age-matched cases of Alzheimer's disease (AD; n = 12), senile dementia of the Lewy body type (SDLT; n = 13), Parkinson's disease (PD; 5 non-demented cases and 7 cognitively impaired cases) and controls (n = 11) for paired helical filaments (PHFs), phosphorylated and normal tau protein and beta/A4-protein. Whereas cingulate cortex is characterised by relatively high densities of cortical Lewy bodies in the SDLT cases and lower numbers in PD, these inclusion bodies were absent in the cingulate cortex from AD and control cases. Protease-resistant PHFs and hyperphosphorylated tau protein were found in AD and, at low levels, in a minority of SDLT cases. Qualitatively, both of these preparations were indistinguishable in SDLT from those found in AD but levels of both parameters in SDLT were less than 5% of those in AD. SDLT, PD and control groups did not differ from each other in terms of the quantity of protease-resistant PHFs or the level of hyperphosphorylated tau. Furthermore, PHF accumulation did not distinguish between PD cases with or without dementia. The levels of normal tau protein did not differ between the four groups. beta/A4 protein levels did not distinguish between PD and control groups, between AD and SDLT groups, or between SDLT and control groups for either cingulate or occipital cortices. Thus extensive accumulation of PHFs in either neurofibrillary tangles or dystrophic neurites is not a feature of either SDLT or PD. Our findings provide molecular support for the neuropathological and clinical separation of SDLT as a form of dementia that is distinct from AD.
Amyloid depositions mainly consist of proteins with a fibrillary structure. A large number of different proteins have amyloidogenic properties. Amyloids are now categorized on the basis of their chemical structure, but t...Amyloid depositions mainly consist of proteins with a fibrillary structure. A large number of different proteins have amyloidogenic properties. Amyloids are now categorized on the basis of their chemical structure, but the clinical classification of localized and systemic amyloid is still useful. The proteins that can be found in cerebral amyloid angiopathy are cystatin C, beta/A4 and transthyretin. Cerebral amyloid angiopathy can remain symptom-free, but can also give a broad spectrum of clinical and radiological manifestations, including (vascular) dementia, cerebellar and cerebral hemorrhage, subarachnoid hemorrhage, and leukoencephalopathy. It is debated whether amyloid angiopathy plays a causative role in Alzheimer's disease, but it is strongly correlated with the presence of cerebral plaques. In this review, the clinical spectrum of cerebral amyloid angiopathy will be described, based on retrospective studies from the literature. Hereditary cerebral hemorrhage with amyloidosis (Dutch) will be presented as a 'prospective' model to study the clinical effects of amyloid angiopathy.
The hypothesis that vascular dementia (VAD) may be associated with a specific pattern of neuropsychological dysfunction as compared to Alzheimer's disease (AD) is reviewed. The empirical findings were evaluated with rega...The hypothesis that vascular dementia (VAD) may be associated with a specific pattern of neuropsychological dysfunction as compared to Alzheimer's disease (AD) is reviewed. The empirical findings were evaluated with regard to methodology, most importantly the comparability between groups regarding demographic variables and severity of dementia. They were also classified according to the cognitive and sensory-motor functions affected. No consistent differences were found between VAD and AD patients in neuropsychological performance testing general cognitive functioning, syntax, verbal comprehension, visuospatial tasks, and primary as well as semantic memory, indicating a functional similarity between VAD and AD. However, inferior performance was found for VAD in executive functioning, verbal fluency, attention, and motor performance. Superior performance for VAD was found in naming and with regard to intrusion errors. The findings on episodic memory were inconclusive. These results should be considered in light of possible selection bias due to the fact that all studies used a hospital-based sample of subjects and not subjects from the community. Bias may also arise from the variations in lesion site, size, number, and timing between different VAD groups. Third, the risk of confounding errors due to a lack of comparability between etiological groups in terms of demographic variables as well as cognitive decline cannot be excluded. Future studies should take into account variation in the severity of cognitive decline, variation regarding lesion characteristics, etiological factors, and subtypes of VAD in order to increase our knowledge about the functional features of VAD.
The objective of this study was to correlate clinical and brain imaging findings with walking inabilities in patients with possible vascular dementia. For 24 patients with suspected initial vascular dementia according to...The objective of this study was to correlate clinical and brain imaging findings with walking inabilities in patients with possible vascular dementia. For 24 patients with suspected initial vascular dementia according to DSM-III-R, structured neurological, neuropsychological and neuroimaging (magnetic resonance tomography) examinations were evaluated alongside computerized gait analysis. All patients revealed an increased variability of gait lines of various degrees: mild (11%), moderate (32%) and severe (57%). Lateralization of gait patterns was present in 68% and bipedal instabilities of posture in 54%. These findings were significantly correlated with frontal periventricular white matter lesions (WMLs), which probably affect the thalamo-cortico-mediocapsular pathways. The association of gait abnormalities with WMLs of the frontocentral subcortical and periventricular territories in patients with possible vascular dementing illnesses may be used as an early indicator of the disease for follow-up and treatment trials. However, since the degree of gait impairment varies considerably relative to the common mild intellectual limitations, these structural lesions are unlikely to be directly related to the dementing process.
Computed X-ray tomography and magnetic resonance imaging are two imaging modalities widely used in the evaluation of patients with dementia disorders. The role of the methods in relation to vascular dementia is discussed...Computed X-ray tomography and magnetic resonance imaging are two imaging modalities widely used in the evaluation of patients with dementia disorders. The role of the methods in relation to vascular dementia is discussed as well as their physical and clinical differences. Moreover, the concept of leukoaraiosis or white matter hyperintensities in relation to normal aging and dementia is also discussed. Finally, the relationship between white matter hyperintensities and the cognitive decline in patients with vascular dementia is discussed.
Vascular dementia (VAD) is the second most common cause of dementia. In addition, cerebrovascular disease (CVD) coexists with other causes, including Alzheimer's disease. Cognitive impairment related to CVD may be preven...Vascular dementia (VAD) is the second most common cause of dementia. In addition, cerebrovascular disease (CVD) coexists with other causes, including Alzheimer's disease. Cognitive impairment related to CVD may be preventable, and these patients could benefit from therapy. This emphasizes the need for early detection, diagnostic consistency and accuracy of the clinical diagnosis of VAD. A number of current limitations in our knowledge about VAD have restricted the construction of clinical criteria, especially the concept of a behavioral syndrome due to vascular factors affecting the brain, and the main pathophysiological factors related to VAD. The latter include the type, extent, location and tempo of vascular brain lesions, as well as the causality between brain lesions and cognitive impairment. However, relevant information on VAD is beginning to emerge. The NINDS-AIREN Workshop on VAD made an attempt to facilitate international discussion and cooperation by defining consequences of CVD and the criteria for the VAD syndrome, for epidemiological and clinical studies. Here the concepts, pathophysiological factors, current conceptual barriers, and the criteria for the clinical diagnosis are reviewed.
The World Health Organization recently introduced the new ICD-10. Chapter V ('Mental and behavioural disorders including disorders of psychological development') contains operationalized diagnostic guidelines for the cla...The World Health Organization recently introduced the new ICD-10. Chapter V ('Mental and behavioural disorders including disorders of psychological development') contains operationalized diagnostic guidelines for the classification of psychiatric disorders, i.e. the term vascular dementia is clearly defined. Furthermore, the criteria of the ICD-10 allow a differentiation of vascular dementia into subtypes (vascular dementia of acute onset, multi-infarct dementia, subcortical vascular dementia, and mixed or unspecified types). The clinical feasibility of the ICD-10 criteria for subtypes of vascular dementia is proven in an investigation of 72 demented patients (75.0 +/- 8.3 years) showing vascular lesions of the computed tomography scan. Only 18 cases (25.0%) fulfill the ICD-10 criteria for vascular dementia. 61.1% of the cases could be sufficiently classified into subtypes. These results suggest that the ICD-10 criteria for vascular dementia are rather selective.
The question was addressed whether the three vascular dementia (VAD) subtypes, multi-infarct dementia (MID), strategic-infarct dementia (SID), and subcortical white matter dementia (SWMD) fulfil the basic criteria for a...The question was addressed whether the three vascular dementia (VAD) subtypes, multi-infarct dementia (MID), strategic-infarct dementia (SID), and subcortical white matter dementia (SWMD) fulfil the basic criteria for a disease: does a distinct pattern of clinical features match a distinct pathological picture for the various VAD subtypes? No obvious correspondence between structural pathological changes and symptoms or signs was found in the MID and SID subtypes. Therefore, the disease status of these VAD subtypes can be questioned. The VAD subtype SWMD, however, appeared to fulfil the basic criteria for a disease, as the subcortical white matter changes corresponded to the subcortical symptom pattern, with mental slowness, extrapyramidal and bilateral pyramidal deficits.
Vascular dementia (VAD) is common, and small vessel disease is one of the most frequent etiologies of the disorder. Lacunar state and Binswanger's disease are the two types of VAD associated with small vessel disease. La...Vascular dementia (VAD) is common, and small vessel disease is one of the most frequent etiologies of the disorder. Lacunar state and Binswanger's disease are the two types of VAD associated with small vessel disease. Lacunar state and Binswanger's disease produce a dementia syndrome with characteristics of subcortical dementia including slowing of information processing, impaired memory, and poor sustained attention. Executive dysfunction includes poor word list generation and verbal fluency (design generation), impaired motor programming with perseveration and impersistence, and difficulty with set shifting. Memory loss in subcortical VAD is characterized by poor retrieval and intact recognition. Apathy is ubiquitous in VAD and depression and psychosis are common. Parkinsonism with prominent gait disturbances in conjunction with pyramidal tract signs, dysarthria, pseudobulbar affect, and incontinence are frequent motor manifestations of VAD with small vessel disease. The lesions of subcortical VAD affect the structures--caudate nucleus, globus pallidus, thalamus-and connecting fibers of frontal--subcortical circuits and produce a clinical syndrome similar to that seen in other subcortical diseases.
In spite of the fact that hypertension is the main risk factor for cerebrovascular disease, retrospective studies have not given a clear answer concerning the role of hypertension in vascular dementia. Hypertension predi...In spite of the fact that hypertension is the main risk factor for cerebrovascular disease, retrospective studies have not given a clear answer concerning the role of hypertension in vascular dementia. Hypertension predisposes to intracerebral and extracerebral arterial alterations which may cause cerebrovascular events by a number of mechanisms. In addition to the established association between hypertension and stroke, the role of hypertension for silent white matter hyperintensities (WMHIs) observed on magnetic resonance imaging is debated. Data are presented indicating that WMHIs are rare below the age of 55 in normotensive individuals but are not infrequent when the blood pressure is moderately or markedly increased. It is proposed that the possible role of hypertension in vascular dementia should be evaluated in prospective studies of hypertensive populations.