It is unknown whether aging and Alzheimer's disease (AD) are on the same continuum, or whether they are qualitatively distinct. Tau protein has been identified as a major constituent of paired helical filaments (PHFs) an...It is unknown whether aging and Alzheimer's disease (AD) are on the same continuum, or whether they are qualitatively distinct. Tau protein has been identified as a major constituent of paired helical filaments (PHFs) and AD is characterised by a major redistribution of the normal tau protein pool into PHFs. Little is known about the changes in tau protein distribution that occur in the course of normal aging. We have examined PHF-bound and normal tau fractions in frontal, temporal, parietal and occipital neocortex, cerebellum, hippocampus and entorhinal cortex in 15 cognitively unimpaired individuals aged 19-88 years at death. Insoluble tau protein in the PHF fraction did not increase with aging in any brain region, despite the appearance of neurofibrillary pathology at low density in the more elderly cases. By contrast, normal tau protein decreased with aging (r = 0.32, p < 0.001), with an average loss of 14% of soluble tau per decade after the age of 20 years. This was unrelated either to neurofibrillary or beta-amyloid pathology. Frontal grey matter and hippocampus were most vulnerable to age-related tau loss, decreasing by as much as 90% in the older subgroup. These findings contrast with those we have previously reported in AD, where the redistribution of tau protein into the PHF-bound fraction was highly correlated with the extent of neurofibrillary pathology, and suggest that the mechanisms of tau loss in aging and AD are distinct. Age-related tau loss may underlie the neuropsychological impairments seen in the non-demented elderly.
It is now known that immunologic mechanisms have a role in the initiation of atherosclerotic processes. No antibodies against vascular endothelial cell (VEC) specific antigenic systems have been demonstrated in the patho...It is now known that immunologic mechanisms have a role in the initiation of atherosclerotic processes. No antibodies against vascular endothelial cell (VEC) specific antigenic systems have been demonstrated in the pathogenesis of small vessel (lacunar) infarcts, though autoantibodies have been detected in 80% of patients with multi-infarct dementia. We studied VEC-specific antibodies in 17 patients with a diagnosis of vascular dementia; in 17 nondemented patients with small vessel infarcts and in 16 healthy, nondemented control group patients by using the Terasaki microtoxicity method. All three groups were correlated according to known risk factors. VEC-specific antibodies were positive in 94% demented patients, whereas no antibodies were detected in patients with small vessel infarcts or in the control group. This result may suggest the existence of an immunologic mechanism in the etiopathogenesis of vascular dementia differing form small vessel infarcts.
The spatial pattern of discrete beta-amyloid (A beta) deposits was studied in the superficial laminae of cortical fields of different types and in the hippocampus in 6 cases of Alzheimer's disease (AD). In 41/42 tissues...The spatial pattern of discrete beta-amyloid (A beta) deposits was studied in the superficial laminae of cortical fields of different types and in the hippocampus in 6 cases of Alzheimer's disease (AD). In 41/42 tissues examined, discrete A beta deposits were aggregated into clusters and in 34/41 tissues (25/34 of the cortical tissues), there was evidence for a regular periodicity of the A beta deposit clusters parallel to the tissue boundary. The dimensions of the clusters varied from 400 to > 12,800 microns in different tissues. Although the A beta deposit clusters were larger than predicted, the regular periodicity suggests that they develop in relation to groups of cells associated with specific projections. This would be consistent with the hypothesis that the distribution of discrete A beta deposits in AD could reflect progressive synaptic disconnection along interconnected neuronal pathways. This implies that amyloid deposition could be a response to, rather than a cause of, synaptic disconnection in AD.
We examined amyloid precursor protein (APP) mRNAs expression in skin fibroblasts from Down's syndrome (DS) patients of different ages to determine the time of occurrence of abnormal splicing. The ratio of APP770 + 751 mR...We examined amyloid precursor protein (APP) mRNAs expression in skin fibroblasts from Down's syndrome (DS) patients of different ages to determine the time of occurrence of abnormal splicing. The ratio of APP770 + 751 mRNA to APP695 mRNA (APP770 + 751/695) was significantly increased in the young DS group and adult DS group compared with the age-matched control groups (p < 0.01, p < 0.05), but no significant increase was observed in the aged DS group compared with the age-matched control group. These findings suggest that metabolic abnormalities of the APP gene occur at a very early stage of DS, at a mean age of about 5 years. Therefore, metabolic abnormalities of the APP gene are considered to appear at a very young age also Alzheimer's disease (AD). In this study, we confirmed that examination of the APP gene in skin fibroblasts might be useful for early diagnosis of AD.
Neurofibrillary tangles (NFT), neuritic plaques and amyloid load were quantified in sections of the hippocampus at the level of the lateral geniculate body in 41 consecutive cases fulfilling pathological criteria for dia...Neurofibrillary tangles (NFT), neuritic plaques and amyloid load were quantified in sections of the hippocampus at the level of the lateral geniculate body in 41 consecutive cases fulfilling pathological criteria for diagnosis of Alzheimer's disease (AD) and coming to autopsy after longitudinal study during life. A strong correlation was found between NFT density in the hippocampus and cognitive impairment scores obtained shortly before death, particularly with scores of memory impairment. Weaker and less consistent correlations were found for hippocampal neuritic plaques and amyloid load with cognitive/memory deficits. No significant correlations were found between hippocampal pathology and either age of onset or disease duration. All three measures of hippocampal pathology were inversely correlated with the minimum medial temporal lobe (MTL) width, a measure of the MTL atrophy made from temporal-lobe-oriented X-ray computed tomography scans performed during life; the strongest correlation being between atrophy of the MTL and NFT density in the hippocampus.
Down syndrome (DS) subjects develop Alzheimer disease (AD) histopathology before they develop dementia. We compared the resting and flash stimulated electroencephalogram (EEG) of nondemented adult DS and age-matched cont...Down syndrome (DS) subjects develop Alzheimer disease (AD) histopathology before they develop dementia. We compared the resting and flash stimulated electroencephalogram (EEG) of nondemented adult DS and age-matched control subjects, in search of EEG abnormalities that might correlate with AD histopathology. DS subjects had increased absolute power in all the EEG bands, independent of cognition functions measured by the Mini Mental State Examination and Picture Absurdities Test scores. In the power spectrum of the resting EEG, we found a cognition-related increase in power at 4.5 and 8.8 Hz, indicative of alpha-slowing, as in AD patients. In the stimulated EEG, we found several cognition-related abnormalities, such as decreased responses to 12-Hz stimulation and decreased integral of beta- and gamma-band responses, indicative of decreased responsiveness to photic stimulation, as in AD patients. Therefore, nondemented DS and AD patients share several cognition related EEG abnormalities which are probably due to AD histopathology.
We evaluated pattern visual evoked potentials (PVEPs) in patients with Alzheimer's disease (AD) and correlated the neurophysiological results with visuospatial performances in order to understand better the underlying ca...We evaluated pattern visual evoked potentials (PVEPs) in patients with Alzheimer's disease (AD) and correlated the neurophysiological results with visuospatial performances in order to understand better the underlying causes of visual disturbances. Latencies and topographical distribution of PVEP components were evaluated in 20 AD patients who underwent an extensive battery of neuropsychological tests. Mean latencies of N70 and P100 were normal in AD patients, while mean latencies of N140 and P200 were significantly increased in comparison with age-matched healthy controls. The topographical distribution of PVEP components did not show any significant difference between the two groups. Visuospatial impairment was detected in 8 patients (40%). Statistically significant positive correlations were observed between P200 amplitude (posterior right hemisphere mean z score) and performance in visuospatial tests. Our data are consistent with a sparing of foveal retinocortical pathways and with the selective dysfunction of either corticocortical connections between the striate cortex and the visual associative structures or of right temporo-parieto-occipital visual analyzers.
Prosody is defined as the melodic line of language. In this study we included 25 patients with probable Alzheimer's disease and 14 with multi-infarct dementia for a comparative cross-sectional study of prosody. Neuropsyc...Prosody is defined as the melodic line of language. In this study we included 25 patients with probable Alzheimer's disease and 14 with multi-infarct dementia for a comparative cross-sectional study of prosody. Neuropsychological analysis was based on Mini-Mental test, Blessed Scale and Clinical Dementia Rating. We used the criteria of Monrad-Krohn to evaluate prosodic categories. We found intrinsic aprosody in 8 patients with Alzheimer's disease and in none of the patients with multi-infarct dementia (prevalence ratio: 1.82, 95% CI: 1.32-2.51), and emotional aprosody in 17 patients with Alzheimer's disease in comparison to 4 with multi-infarct dementia (prevalence ratio: 1.8, 95% CI: 1.04-3.18). The differences in intellectual and inarticulate aprosody were not significant. We conclude that aprosody is more frequent and severe in Alzheimer's disease than in multi-infarct dementia.
To compare subcortical involvement of Parkinson's disease (PD) with that of Binswanger's disease (BD), we examined visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs) in 29 patients with PD and 7 p...To compare subcortical involvement of Parkinson's disease (PD) with that of Binswanger's disease (BD), we examined visual evoked potentials (VEPs) and somatosensory evoked potentials (SEPs) in 29 patients with PD and 7 patients with BD and 11 control subjects. The patients with PD were divided into two groups: PD without dementia (nD-PD: n = 18) and PD with dementia (D-PD: n = 11). The D-PD patients showed significantly longer P100 latencies in VEPs compared with the nD-PD patients or controls. The P100 latencies were negatively correlated with Mini-Mental State Examination (MMSE) score in the PD patients. The BD patients showed significantly longer central conduction time (CCT) in SEPs (interpeak latency between N13 and N20 responses) compared with the nD-PD patients or controls. There was no correlation between CCT and MMSE score in the BD patients. These results suggest that PD has a predilection for sensory system involvement distinct from that of BD. In D-PD, the visual system seems more vulnerable than the somatosensory system, but almost the reverse is true of BD.
Eighteen patients with probable Alzheimer's disease (NINCDS/ADRDA criteria) participated in a placebo-controlled, double-blind study, with a crossover design. The patients had mild or moderate dementia (MMSE = 20.3 +/- 4...Eighteen patients with probable Alzheimer's disease (NINCDS/ADRDA criteria) participated in a placebo-controlled, double-blind study, with a crossover design. The patients had mild or moderate dementia (MMSE = 20.3 +/- 4.6, range 12-28). The trial consisted of two 4-week periods with a 2-week washout period in between. Nicotine was given in the form of dermal plasters. Most of the patients tolerated the highest doses of 21 mg nicotine/24 h, but some received 14 mg/24 h. The effect was monitored with tests of short-term memory, verbal fluency, attention and psychomotor speed. Nicotine was also determined in the blood. Short-term memory improved significantly after 4 weeks of treatment, both on nicotine and placebo (p < 0.05/p < 0.01). The results of our study thus do not indicate that nicotine applied in the form of dermal plasters is of any significance in the treatment of memory deficits in patient with Alzheimer's disease.
Dementia of the Alzheimer type, senile onset (SDAT), and multi-infarct dementia (MID) exhibit differences in cerebrovascular blood flow velocity profiles, which were investigated by means of transcranial Doppler sonograp...Dementia of the Alzheimer type, senile onset (SDAT), and multi-infarct dementia (MID) exhibit differences in cerebrovascular blood flow velocity profiles, which were investigated by means of transcranial Doppler sonography. The pulsatility indices (PI), as angle-independent parameters of peripheral vascular resistance measured in the basal cerebral arteries, were significantly increased in MID patients with respect to SDAT cases. In an analysis of the correlations between several variables and the magnitude of PI, we found strong inverse correlations of the CAMCOG score, and strong direct correlations of the blood pressure and the duration of illness, with the PI of all basal cerebral arteries only in MID patients. In SDAT patients, we found a direct correlation between the Hachinski ischemia score and the PI of all basal cerebral arteries. All 3 ischemia scores (Hachinski, Rosen, Loeb and Gandolfo) were significantly correlated with the PI of the middle cerebral and basilar arteries. By analyzing the correlations of the single items of the 3 different ischemia scores with the PI values obtained, we only found a clearcut correlation with the item focal neurological signs. Thus, our findings stress the relative importance of a concomitant cerebrovascular factor in the development of dementia in old age, even in patients with probable SDAT. A raise of the PI in the basal cerebral arteries allows early suspicion of a cerebrovascular factor even in only slight dementia so that possible risk factors for further aggravation of this type of vascular dementia might be detected and treated early in the course of disease.
This longitudinal study measured the rate of spontaneous speech decline in patients with Alzheimer's disease (AD) at a 1-year follow-up and determined the effect of clinical and demographic factors on that rate. In addit...This longitudinal study measured the rate of spontaneous speech decline in patients with Alzheimer's disease (AD) at a 1-year follow-up and determined the effect of clinical and demographic factors on that rate. In addition the pattern of spontaneous speech impairment was examined. The expected pattern of spontaneous speech impairment with prominent disturbances of communication and semantics, moderate disturbances of automatic speech, but with retained phonematic structures, was found at baseline and at follow-up in the majority of our rather large sample (n = 63). This result is discussed in terms of intrafunctional homogeneity and of selective involvement of neuronal systems in AD. There was a trend for a more rapid language decline in patients with a family history of dementia. No relationship was detected between the rate of spontaneous speech decline and other clinical and demographic factors, with the exception of initial spontaneous speech impairment.
Ten patients with a clinical diagnosis of frontal lobe degeneration (FLD) were compared with a group of patients with probable Alzheimer's disease (AD) and with nondemented controls matched for gender and age. In compari...Ten patients with a clinical diagnosis of frontal lobe degeneration (FLD) were compared with a group of patients with probable Alzheimer's disease (AD) and with nondemented controls matched for gender and age. In comparison with AD, the duration of illness was slightly shorter and cognitive performance was better in patients with FLD. The greatest enlargement of cerebrospinal fluid volumes was found in FLD and this effect was most pronounced in the anterior fissure and lateral ventricles. Estimates of EEG band-power and EEG coherence in FLD were not remarkably different from nondemented controls, whereas delta- and theta-power were significantly increased in AD. These observations may indicate different disease processes with a dissociation of volumetric computed tomography and quantitative EEG changes, which may be of differential diagnostic value.
The association of aphasia, apraxia and agnosia with cortical but not subcortical dementias, is a widely held belief. The purpose of the present study was to determine the frequency of aphasia, apraxia, and agnosia in gr...The association of aphasia, apraxia and agnosia with cortical but not subcortical dementias, is a widely held belief. The purpose of the present study was to determine the frequency of aphasia, apraxia, and agnosia in groups of cortical and subcortical dementia patients, and to assess the diagnostic utility of these symptoms. Subjects were 64 patients with subcortical dementias (Parkinson's disease and normal pressure hydrocephalus) and 192 patients with cortical dementia (probable Alzheimer's disease) matched for sex, age, and Mini-Mental State Examination score. Each patient was evaluated for the presence of aphasia, apraxia, and agnosia. Results indicated that only aphasia was reported significantly more often in cortical dementia patients than in subcortical dementia patients. The presence of either of these three symptoms has very low diagnostic sensitivity, specificity, and total predictive value. The severity of the patient's dementia was predicted whether the patient had aphasia or apraxia; type of dementia had no predictive value. These data led to the conclusion that cortical and subcortical dementias cannot be reliably dissociated on the basis of aphasia, apraxia, or agnosia.
Diagnosis of Alzheimer's disease is made on clinical grounds, and the availability of a simple and sensitive quantitative index of the disease might aid in the routine diagnosis. The aim of this study was to assess wheth...Diagnosis of Alzheimer's disease is made on clinical grounds, and the availability of a simple and sensitive quantitative index of the disease might aid in the routine diagnosis. The aim of this study was to assess whether linear measures of brain atrophy as detected by magnetic resonance imaging can be helpful in the differentiation of mild to moderate Alzheimer's disease from nondemented elderly. Measures of global (bifrontal index and interuncal distance) and hippocampal (minimum thickness of the medial temporal lobe, hippocampal height, width of the choroid fissure, and width of the temporal horn) atrophy were taken from 26 cases and 21 controls. Measures of hippocampal atrophy were the most sensitive in the differentiation of cases from controls, and among them width of the temporal horn yielded the highest sensitivity, predicting the disease in 73% of cases with 95% specificity. A compound measure comprising width of the temporal horn, width of the choroid fissure, and hippocampal height increased sensitivity to 85%. These results suggest that selected simple indices of hippocampal atrophy might be useful in the diagnosis of Alzheimer's disease.
The aim of the study was to assess the specificity of temporal amygdala (TA) atrophy with magnetic resonance imaging (MRI) by comparing a group of early impaired patients with Alzheimer's disease (AD) with 'other types o...The aim of the study was to assess the specificity of temporal amygdala (TA) atrophy with magnetic resonance imaging (MRI) by comparing a group of early impaired patients with Alzheimer's disease (AD) with 'other types of dementia' and controls. In this prospective case-control study, 41 patients were selected: 12 with probable AD according to NINCDS-ADRDA and CERAD inclusion and exclusion criteria, 14 with other types of dementia and 15 age-matched control subjects. Two radiologists blindly measured the TA volumes on coronal oblique contiguous slices with a 1.5-tesla MRI scanner. TA volume measurements obtained by the 2 observers and right-left TA values were not significantly different. A significant TA atrophy was found in the AD group as compared to the other groups, with 39.7% (p < 0.001) difference in TA volumes between AD and other types of dementia groups and 41.4% (p < 0.0005) difference between AD and control groups. There was no significant difference between other types of dementia and control groups. There was an overlap between the three groups for 4 patients. TA atrophy assessed with MRI could be of diagnostic value in AD, especially in the early stage of the disease.
Chronic exposure to aluminium (Al) remains a controversial possible cause of sporadic forms of Alzheimer's disease (AD). This article reviews the evidence that once Al enters the brain and individual brain cells, it may...Chronic exposure to aluminium (Al) remains a controversial possible cause of sporadic forms of Alzheimer's disease (AD). This article reviews the evidence that once Al enters the brain and individual brain cells, it may be involved in three pathological processes: (1) the production of abnormal forms of tau leading to the formation of cellular neurofibrillary tangles and neuropil threads; (2) the processing of the amyloid precursor protein, resulting in the formation of beta-amyloid deposits and senile plaques, and (3) that via the mutual histocompatibility system, Al could be involved in the initiation of the immune response observed in AD patients. Despite recent evidence that Al could be involved in these processes, a conclusive case that exposure to Al initiates the primary pathological process in sporadic AD remains to be established.
The cumulative risk of Alzheimer-like dementia (AD) was investigated in first-degree relatives (n = 176) of 35 probands with autopsy-confirmed clinical diagnoses of Alzheimer's disease. Seventeen of the 176 first-degree...The cumulative risk of Alzheimer-like dementia (AD) was investigated in first-degree relatives (n = 176) of 35 probands with autopsy-confirmed clinical diagnoses of Alzheimer's disease. Seventeen of the 176 first-degree relatives showed evidence of AD. Cumulative morbid risk for the first-degree relatives was estimated to be 28.8%. This result is broadly consistent with previously reported studies, and affirms the presence of substantial disease risk in close relatives of those with Alzheimer's disease.
Serum and cerebrospinal fluid (CSF) from 44 patients with clinical probable Alzheimer's disease (AD) (subdivided in two groups with 18 early onset, EO, and 26 late onset, LO, cases), 10 patients with vascular dementia (V...Serum and cerebrospinal fluid (CSF) from 44 patients with clinical probable Alzheimer's disease (AD) (subdivided in two groups with 18 early onset, EO, and 26 late onset, LO, cases), 10 patients with vascular dementia (VD) and 24 patients with major depression (MD) were assayed for concentrations of albumin and IgG. The severity of dementia was assessed with the Mini Mental State Examination. The CSF/serum ratio for albumin and IgG as well as the IgG index were used to evaluate blood-CSF barrier function. Various patients showed signs of blood-CSF-barrier (BCB) dysfunction and only few displayed evidence of local IgG synthesis in the central nervous system (CNS) in the AD, VD and in the MD group (IgG index > 0.7). The permeability of the blood-CSF barrier was not correlated to measures of dementia severity. Our data support the hypothesis of a BCB leakage in a subgroup of all investigated patients. Furthermore, we found a small number of patients with increased intrathecal IgG synthesis. Elevated CSF immunoglobulins combined with BCB impairment might be associated or caused by a general immune activation. Our data are in agreement with the assumption that an inflammatory process may play a role in a subgroup of patients with AD but also with MD and less likely in VD. In conclusion BCB impairment and elevated IgG immunoglobulin levels are unspecific either for AD, VD or MD.
We evaluated the relationship between periventricular white matter lesions (PWMLs) and EEG abnormalities in probable Alzheimer's disease (AD). We visually analyzed the EEG of 27 probable AD patients with mild to moderate...We evaluated the relationship between periventricular white matter lesions (PWMLs) and EEG abnormalities in probable Alzheimer's disease (AD). We visually analyzed the EEG of 27 probable AD patients with mild to moderate degree of cognitive impairment participating in a longitudinal study of dementia. Patients had both CT and MRI scans performed at baseline examination, which also included an EEG. PWMLs were rated in CT and MRI films using a semiquantitative method. The EEGs were classified according to the Mayo Clinic Classification System. Abnormal EEGs correlated with PWMLs rating scores were detected on CT, but not on MRI. These data suggest that the presence of PWMLs contribute to the abnormal EEGs observed in AD patients, and that white matter abnormalities in CT correlate better with both the clinical findings and EEG than does the more sensitive but less specific MRI.