Excessive stimulation of glutamate receptors and elevation of intracellular calcium levels initiate the neurodegenerative process resulting from cerebral ischemia. However, the subsequent cascade of molecular changes whi...Excessive stimulation of glutamate receptors and elevation of intracellular calcium levels initiate the neurodegenerative process resulting from cerebral ischemia. However, the subsequent cascade of molecular changes which are of pathogenic significance is less well understood. Breakdown of the cytoskeleton may be involved in the progression from compromise of neuronal viability to irreversible damage. Alteration of the microtubule-associated protein tau, as reflected by increased Alz-50 immunoreactivity, was induced by permanent focal cerebral ischemia in vivo but only in a proportion of neurones. Alz-50 immunoreactive neurones did not exhibit the characteristics of irreversible ischemic cell damage. Increased immunoreactivity to the stress response protein ubiquitin was also induced by ischemia in a proportion of neurones. Both proteins are components of neurofibrillary tangles in Alzheimer's disease. Alterations of the microtubule-associated protein tau may be a feature of the early stages of the ischemia-induced degeneration and the ubiquitin response may be an attempt by compromised neurones to deal with the presence of abnormal proteins.
Vascular dementia (VAD) is cognitive impairment caused by changes in the blood circulation of the brain. It is not synonymous with multi-infarct dementia. The latter is a subgroup of VAD. Neurochemical investigations of...Vascular dementia (VAD) is cognitive impairment caused by changes in the blood circulation of the brain. It is not synonymous with multi-infarct dementia. The latter is a subgroup of VAD. Neurochemical investigations of noninfarcted brain tissue from patients with VAD show general changes in VAD brains. The serotonin metabolism is severely reduced and so is the activity of choline acetyltransferase. Monamine oxidase B is significantly increased in the white matter. A severe decrease in myelin components indicates white matter disturbances of such a degree that they must be considered to be of pathogenetic importance. The levels of some neuropeptides in the hypothalamus are increased. This is a finding which is in agreement with clinical findings of a high activity in the hypothalamic-pituitary-adrenal axis in patients with VAD. This high activity is possibly due to a loss of serotonergic inhibitory tone on the hypothalamus in VAD brains.
The condition of the brain parenchyma in cases of vascular dementia and other cerebrovascular conditions may be influenced by structural and functional changes of the terminal intracerebral blood vessels. Arterioles can...The condition of the brain parenchyma in cases of vascular dementia and other cerebrovascular conditions may be influenced by structural and functional changes of the terminal intracerebral blood vessels. Arterioles can develop obliterative lesions, capillaries and postcapillary venules can be altered, causing edema. The first part of this review is focused on expression of different types of collagens and other components of the extracellular matrix in intracerebral arterioles. The changes present in hereditary multi-infarct disease of the brain are compared with those occurring in the Binswanger type of encephalopathy and cases presenting hyalinosis of intracerebral vessels. Deposition of collagens in degenerated parts of the media and adventitia of the arterioles may contribute to impaired blood flow regulation in the brain parenchyma. Fibrillary collagens and basal laminae are probably the most important components of the hyaline material in vessels showing 'hyalinosis'. The second part of our review concerns the possibility that the vasoactive peptide, endothelin-1, released from reactive astrocytes, can influence the function of intracerebral arterioles. Normal astrocytes do not show endothelin-1-like immunoreactivity, but in cases of infarcts, lacunes, hereditary multi-infarct disease, Binswanger's encephalopathy and Alzheimer's disease numerous reactive astrocytes express such immunoreactivity. If endothelin-1 is produced and released from reactive astrocytes it may reach intracerebral arterioles and induce long-lasting vasoconstriction. Endothelin-1 is the most powerful vasoconstrictor peptide known to date and has mitogenic capacity. It may promote cellular mechanisms leading to astrocytic gliosis and neovascularization.
Although white matter lesions (WMLs) are among the most common structural neuroimaging changes found on computed tomography and magnetic resonance imaging of older persons with dementia, their presence should not be misc...Although white matter lesions (WMLs) are among the most common structural neuroimaging changes found on computed tomography and magnetic resonance imaging of older persons with dementia, their presence should not be misconstrued as proof that vascular disease is causing or contributing to the dementia. We report the results of several studies examining the neurobehavioral manifestations of persons meeting explicit operational criteria for Binswanger's disease (BD) and the clinical correlates of white matter changes in persons with autopsy-proven Alzheimer's disease (AD). The findings suggest that relative to persons with AD of comparable dementia severity, persons with BD have less profound impairments in episodic memory, more depressive symptomatology and a more variable rate of cognitive decline; among persons with AD, some WMLs are associated with incontinence and gait disturbance, but they do not appear to contribute to dementia severity.
The brains of 175 consecutive autopsy cases of dementia, clinically studied prospectively, were analyzed pathoanatomically with regard to type, size and site of lesions. Pure groups of vascular dementia caused by large o...The brains of 175 consecutive autopsy cases of dementia, clinically studied prospectively, were analyzed pathoanatomically with regard to type, size and site of lesions. Pure groups of vascular dementia caused by large or small vessel disease and by hypoperfusion could be defined. The infarcts were either complete with a more or less pronounced incomplete perifocal component or of an incomplete type only. Incomplete infarction appears to be an important and yet little appreciated cause of brain dysfunction. These groups could be used as a basis for a pathoanatomical classification of vascular dementias. Vascular dementia is much more common than generally assumed.
In recent years, interest in vascular causes of dementia has increased and it has been proposed that vascular dementia (VAD) may be more common than previously supposed. This may have important implications, because VAD...In recent years, interest in vascular causes of dementia has increased and it has been proposed that vascular dementia (VAD) may be more common than previously supposed. This may have important implications, because VAD at present may be more amenable to prevention and treatment than Alzheimer's disease (AD). Several vascular factors have been related to cognitive decline and dementia in the elderly, including stroke and white matter disease. However, while numerous case-control studies have been concerned with the risk factors for AD, studies on risk factors for VADs are rare. The problems inherent in the diagnostic criteria make it difficult to interpret the results from the few studies that have been performed. Generally, risk factors for multi-infarct dementia are supposed to be the same as those for stroke, and include hypertension, diabetes mellitus, advanced age, male sex, smoking and cardiac diseases. White matter dementia has mainly been related to hypertension. Recent research suggests that vascular factors may also be important in AD, especially in the late-onset type. In stroke patients, dementia has been associated with higher age, less formal education, cerebral atrophy, left-sided or bilateral infarcts, volume of macroscopic infarcts, bilateral symptoms, previous stroke and white matter lesions. The pathogenetic mechanism through which these factors cause dementia is still not clear. Furthermore, it is not known if risk factors for VAD differ from those found in stroke patients. There is now an urgent need for further research on risk factors for VAD and on factors related to dementia in subjects with cerebrovascular disorders.
There are several factors that might be important in the development of dementia due to cerebrovascular disease. These include the volume of infarcted brain, the bilaterality and symmetry of lesions, the strategic locati...There are several factors that might be important in the development of dementia due to cerebrovascular disease. These include the volume of infarcted brain, the bilaterality and symmetry of lesions, the strategic location of small lesions, the number of lesions, the extent and density of white matter lesions and the coexistence of other pathologies, particularly Alzheimer's disease. No one factor is solely related to dementia and in most patients several of these factors combine to exceed the critical threshold for normal cognition. It is the extent of the disease which determines the development of dementia, rather than its etiology. Conversely, the possibility of treatment depends more on the etiology of the vascular disease than on the extent.
'Vascular dementia' may be the leading cause of cognitive impairment in the world, yet there is little agreement as to what this concept encompasses or how it is defined. A critical review reaches the conclusion that the...'Vascular dementia' may be the leading cause of cognitive impairment in the world, yet there is little agreement as to what this concept encompasses or how it is defined. A critical review reaches the conclusion that the concept of 'vascular dementia' has become obsolete. 'Vascular' is too generic, and fails to identify specific etiologies which may be subject to current and future preventive measures. 'Dementia' identifies patients too late to do much about their problem. An alternate approach is suggested. Identify patients across the whole spectrum of vascular cognitive impairment, from high risk with no deficit ('brain-at-risk stage') to full-blown dementia. Describe the cognitive impairment in terms of standardized neuropsychological measures, and relate the dementia to the specific vascular cause, so that the appropriate preventive measures can be implemented.
Over 3 years we followed 8 pairs of male twins one or both of whom had suspected Alzheimer's disease (AD) including 'mild/ambiguous' changes suggestive of incident AD. These pairs were screened in 1988 and 1989 from 339...Over 3 years we followed 8 pairs of male twins one or both of whom had suspected Alzheimer's disease (AD) including 'mild/ambiguous' changes suggestive of incident AD. These pairs were screened in 1988 and 1989 from 339 pairs in the (US) National Academy of Sciences-National Research Council Registry (NASR) of aging veteran twins, then 61-72 years of age. Most of the suspected cases (10 of 12) had mild/ambiguous changes. Including these subjects, we had estimated the prevalence of AD in the NASR as about 2%. We now describe briefly the longitudinal evaluation of these 8 pairs. Only 1 of the 10 individuals with mild/ambiguous changes has progressed to show well-defined clinical symptoms of AD. Two others remain in their original research category, while 7 clearly do not have AD. Thus, we now estimate the 1988-1989 prevalence of AD in the NASR as 0.5%. These results contrast with other follow-up studies of mild cases from a university-based Alzheimer's clinic. We suggest that the contrasting findings reflect the nature of the samples studied, and we show that the present results are predicted by Bayesian reasoning.
70 patients with probable Alzheimer's disease were randomly allocated to four groups: 17 patients received only social support, 18 cognitive training twice a week, in 17 cognitive training was combined with pyritinol 2 x...70 patients with probable Alzheimer's disease were randomly allocated to four groups: 17 patients received only social support, 18 cognitive training twice a week, in 17 cognitive training was combined with pyritinol 2 x 600 mg/day and in 18 cognitive training was combined with phosphatidylserine 2 x 200 mg/day. Treatment duration was 6 months. Before and after treatment, the patients underwent neuropsychological testing as well as measurement of the regional cerebral metabolic rate for glucose using positron emission tomography and 18F-2-fluoro-2-deoxy-D-glucose. Before treatment the groups were comparable in respect to resting and activated glucose pattern achieved by a visual recognition task. Electrophysiological changes were assessed as EEG power, globally and in 4 frequency bands. This 6-month study in four groups of patients with Alzheimer's disease indicated that phosphatidylserine treatment has an effect on different measures of brain function. Since neuropsychological improvements were best documented after 8 and 16 weeks and faded towards the end of the treatment period, it must be concluded that this symptomatic therapy is mainly of short-term benefit and was overcome by the progressive pathological changes at the end of the treatment period.
It has been shown recently that in Alzheimer's disease the degree of dementia is strongly correlated with a reduction of the synaptophysin reactivity of the cortical neuropil as a measure of synapse density, while counts...It has been shown recently that in Alzheimer's disease the degree of dementia is strongly correlated with a reduction of the synaptophysin reactivity of the cortical neuropil as a measure of synapse density, while counts of neuritic plaques showed a weak correlation. This suggests that mechanisms acting at the synaptic level, finally resulting in a numerical decline of synapses, may represent an important factor in the pathogenesis of dementia. Under these aspects, we wanted to examine whether changes of synaptophysin immunoreactivity may also occur in dementia of vascular origin such as Binswanger's disease, where the white matter atrophy is usually conceived to be the main morphologic correlate of dementia. However, infrequently patients with morphologically typical Binswanger's subcortical encephalopathy including white matter atrophy are not demented. We found in 9 cases of vascular dementia of Binswanger type a significant reduction in synaptophysin immunoreactivity of the cortical neuropil (9.1%), the magnitude of which was not much less than in Alzheimer type dementia (10.9%). These results suggest that a reduction in cortical synaptic population density may also play a significant role in the pathogenesis of dementia in Binswanger's disease. In view of the fact that similar conditions have been shown to occur in neurodegenerative disorders with dementia other than Alzheimer type dementia, there seems to be evidence for a possible common pathogenetic link between these forms of dementia at the synaptic level, where different etiologic factors may result in similar changes.
Correlational analysis of cerebral metabolic (rCMRglc) data obtained with positron emission tomography (PET) assesses group differences and has demonstrated reduced frontal-parietal rCMRglc interdependencies in Alzheimer...Correlational analysis of cerebral metabolic (rCMRglc) data obtained with positron emission tomography (PET) assesses group differences and has demonstrated reduced frontal-parietal rCMRglc interdependencies in Alzheimer's disease (AD). A multivariate analysis of rCMRglc data assesses individual differences. We recently identified discriminant functions, reflecting frontal-parietal rCMRglc interdependencies, that separated AD from control subjects. To test if the functions would identify an AD rCMRglc pattern in older Down syndrome (DS) adults with (DS DAT+) or without (DS DAT-) dementia, we applied the functions to longitudinal rCMRglc data in: young DS (n = 15), DS DAT- (n = 10), DS DAT+ (n = 4), and young controls (n = 15). All DS DAT+ and some of the later DS DAT- scans were classified as AD. The results provide additional validation of the functions and suggest their utility for the early detection of AD.
Cerebral cortex from humans and rats was extracted sequentially with detergent-containing and low-ionic-strength buffers. The resulting pellet was extracted with detergent/high-ionic-strength buffer to yield a soluble en...Cerebral cortex from humans and rats was extracted sequentially with detergent-containing and low-ionic-strength buffers. The resulting pellet was extracted with detergent/high-ionic-strength buffer to yield a soluble enzyme preparation. This was incubated with substrate prepared from rat cerebral cortical membranes containing amyloid precursor protein-like immunoreactivity (APPLIR) of 116 kD approximate apparent molecular mass. The effectiveness of various enzyme preparations to degrade APPLIR was: routine-post-mortem (pm)-delay human samples > rat pup > short-pm-delay human samples >> adult rat. In incubations with human samples only a 100-kD product accumulated. The activity in human brain was inhibited by phenylmethylsulphonylfluoride, insensitive to Ca2+, correlated with pyramidal neurone numbers but not those of astrocytes and was not significantly higher in Alzheimer's disease compared with controls. These data are discussed in terms of other approaches for studying proteolytic activity to explain the deposition of beta-amyloid protein in this disease.
Multichannel (19) EEG were analyzed in 23 female patients with rather advanced late-onset Alzheimer's disease (AD) and compared with 56 age- and sex-matched healthy control subjects. The quantified EEG was correlated wit...Multichannel (19) EEG were analyzed in 23 female patients with rather advanced late-onset Alzheimer's disease (AD) and compared with 56 age- and sex-matched healthy control subjects. The quantified EEG was correlated with psychometric and clinical variables. The control subjects showed increasing theta activity with age but the EEG changes did not correlate significantly with psychometric features. The AD patients showed highly significant increases in delta and theta activity and decreases in beta activity compared with controls. The EEG changes were most marked over posterior regions of the brain. The individual EEG variables showed a high degree of intercorrelation and an almost complete discrimination between patients and controls was accomplished by taking only the posterior delta activity into account. In a subgroup of 10 patients, in which a Mini Mental test score could be obtained, the score correlated with the relative theta power.
This morphometric, quantitative and correlative multivariate study of the hippocampal formation in human brains from two distinct normal aging populations provides an additional support to the notion that neuritic plaque...This morphometric, quantitative and correlative multivariate study of the hippocampal formation in human brains from two distinct normal aging populations provides an additional support to the notion that neuritic plaques (NP) are an earlier stage of the pathological process underlying neurofibrillary tangle (NFT) formation. It is shown that the rate of transformation of NP-affected neurons into NFT-bearing neurons may vary remarkably between distinct populations. In addition, it is put forward that different rates of neuronal degeneration may be one of the explanations for the existence of conflicting hypotheses regarding pathogenesis of NP and NFT and the relationships of these important histological markers to psychical deterioration.
To study dementia in the extremely aged, I evaluated 40 centenarians with a mean age of 101.6 years (range: 100-107). The group completed 5.8 years of education, on average. Bradyphrenia and bradykinesia were common and...To study dementia in the extremely aged, I evaluated 40 centenarians with a mean age of 101.6 years (range: 100-107). The group completed 5.8 years of education, on average. Bradyphrenia and bradykinesia were common and most had impaired awareness and concern. The Folstein Mini-Mental State Exam and Washington University's Clinical Dementia Rating Scale indicated moderately advanced dementia in more than half; 4 had a clinical pattern that suggested senile dementia of the Alzheimer's type. A common pattern of dementia emerged consisting of preserved awareness of the environment, normal participation in conversations, mild bradyphrenia and bradykinesia with normal latency to respond to questions and memory impairment with diminished ability to learn new information. They had a constricted universe with limited awareness of events outside their personal sphere; they repeated themes and topics endlessly. This study suggests senile dementia is common in centenarians.
Morphometrical changes with aging in nerve growth factor receptor (NGFR) immunoreactive neurons in the basal forebrain were studied in juvenile and aged rat brains by means of NGFR immunohistochemistry. The nucleus basal...Morphometrical changes with aging in nerve growth factor receptor (NGFR) immunoreactive neurons in the basal forebrain were studied in juvenile and aged rat brains by means of NGFR immunohistochemistry. The nucleus basalis of Meynert (NBM) had cell loss and atrophy of NGFR immunoreactive neurons, and the horizontal nucleus of diagonal band of Broca (HNDB) showed only atrophy of these neurons. The medial septal nucleus and vertical nucleus of diagonal band of Broca had no significant change. Neuropil NGFR immunostaining was reduced in its intensity in the aged rats. As nerve growth factor is synthesized in the target areas and retrogradely transported to the nerve cell body within the basal forebrain and NGFR immunoreactive neurons are largely cholinergic ones, degeneration of NGFR-positive neurons in the basal forebrain may be related to a decreased cholinergic activity. The degeneration of the dendrites of NGFR-immunoreactive neurons were reported to be extensively found in the basal forebrain nuclei, in contrast, degeneration of the cell body of NGFR-immunoreactive neurons was confined to those in the NBM and HNDB in the present study. These findings suggest that atrophic changes in the dendrites precede those in the cell bodies of NGFR-immunoreactive neurons.
We have previously shown that phosphatidylinositol (PI) kinase activity is 40-50% lower in cytosolic fractions of neocortical regions from brains of patients with Alzheimer's disease (AD) in contrast to phosphatidylinosi...We have previously shown that phosphatidylinositol (PI) kinase activity is 40-50% lower in cytosolic fractions of neocortical regions from brains of patients with Alzheimer's disease (AD) in contrast to phosphatidylinositol phosphate (PIP) kinase activity, which was not affected. After preparing different enzyme fractions by solubilization, the PI kinase activity in the salt-solubilized protein preparation of the temporal cortex of AD brains was predominantly affected (70% decrease). PIP kinase activity in AD brains was not different from that of control brains in any of the fractions tested. PI kinase in the salt-solubilized fractions was inhibited (-75%) by 1% Triton X-100, whereas the PI kinase in the detergent solubilized protein preparation was stimulated (+80%) by 1% Triton X-100. PI kinase activity in the salt-solubilized protein preparation was almost unaffected by adenosine in contrast to PI kinase activity in the detergent solubilized protein preparation, which was strongly inhibited by adenosine. These results indicate that the PI kinase that is specifically affected in AD is the PI 3-kinase, or type 1 PI kinase, because the fraction which was affected most severely has (1) a cytosolic localization; (2) a high sensitivity to inhibition by the non-ionic detergent Triton X-100, and (3) an insensitivity to adenosine inhibition, which are characteristic features of type 1 PI kinase. The relevance of our findings is that type 1 PI kinase is thought to be involved in the regulation of cytoskeletal turnover processes.(ABSTRACT TRUNCATED AT 250 WORDS)