The presence of amyloid precursor protein (APP) and beta-amyloid protein (beta A4) was investigated in the cerebra of 4 patients with Alzheimer's disease (AD), 1 patient with Down's syndrome, 4 patients with dementia of...The presence of amyloid precursor protein (APP) and beta-amyloid protein (beta A4) was investigated in the cerebra of 4 patients with Alzheimer's disease (AD), 1 patient with Down's syndrome, 4 patients with dementia of the Lewy body type (DLB) and 4 age-matched, clinically nondemented controls, of which one displayed many amyloid plaques. The different types of amyloid plaques stained strongly with antibodies against beta A4. Antibodies against the C-terminal region of APP reacted only weakly with small swollen neurites and with globular deposits in neuritic-type plaques from patients with AD. The antibody against the N-terminal region of APP stained strongly cellular elements in the neuritic type plaques of patients with AD but not dense cored plaques. In contrast, patients with DLB displayed with this antibody a homogeneous staining of dense cored amyloid plaques. Some Lewy bodies stained with the antibody against the N-terminal region of APP as well. These results indicate that the processing of APP in AD and DLB could be different, to yield different fragments deposited in AD and DLB amyloid plaques.
The study was aimed at estimating the effect size of practice, retention interval and dementia severity on free recall performance in Alzheimer patients. Patients met DSM-III-R criteria for dementia of Alzheimer type. Di...The study was aimed at estimating the effect size of practice, retention interval and dementia severity on free recall performance in Alzheimer patients. Patients met DSM-III-R criteria for dementia of Alzheimer type. Different picture sets were presented on 4 days. The forgetting curves on different days were compared using ANOVA for repeated measurements. Practice had a minor, but significant negative effect on recall performance explaining 1% of the variance in recall performance. The retention interval varied between zero and 24 h explaining 23% of the total variance. Dementia severity explained 52% of the variance. For the development of memory improvement strategies in Alzheimer patients, the repeated measurement design using intraindividual comparisons seems more powerful than group comparisons.
We reviewed and independently ranked the measurement properties of quality of life (QL) instruments currently used in anti-dementia drug trials for Alzheimer's disease. Of 36 read reports, 5 measured and 4 mentioned QL....We reviewed and independently ranked the measurement properties of quality of life (QL) instruments currently used in anti-dementia drug trials for Alzheimer's disease. Of 36 read reports, 5 measured and 4 mentioned QL. Eight instruments, labelled QL measures, included questionnaires measuring function, self-rating instruments measuring the caregivers' impression of the impact of sickness and deterioration of memory, and observational rating scales measuring function. The most thoroughly tested QL measure was the Progressive Deterioration Scale. The instruments with the most promising measurement properties were the Progressive Deterioration Scale and the Italian Quality of Life Scale. Most instruments now used to assess QL in antidementia drug trials have not been adequately validated in patients with Alzheimer's disease. Effort should be directed both to conceptual and practical development in the assessment of QL in dementia.
Several factors have been reported to predict death and institutionalization in demented patients, even if the results of the studies are often conflicting. We conducted a study on a group of 86 consecutive noninstitutio...Several factors have been reported to predict death and institutionalization in demented patients, even if the results of the studies are often conflicting. We conducted a study on a group of 86 consecutive noninstitutionalized probable Alzheimer disease (AD) patients, to evaluate clinical and social factors predicting mortality and institutionalization 1 year after discharge from the Alzheimer Dementia Unit at 'Sacro Cuore Fatebenefratelli' Hospital, Brescia, Italy. The 1-year mortality rate was 13.9% and the 1-year rate of admission to a nursing home was 34%. Our data indicate that the number of lost functions on the Activity of Daily Living scale is the most important predictor of short-term mortality, independently of the degree of cognitive impairment, the duration of the dementia, the age of the patients and the number of chronic diseases. Our data also demonstrate that, in a short period of observation, behavioral disturbances (and in particular insomnia) and availability of social services play a major role in the decision to institutionalize AD patients.
Change in calcium response was studied to clarify the pathological process of Alzheimer's disease (AD). Cultured fibroblasts from patients with familial Alzheimer's disease (FAD; n = 6), sporadic Alzheimer's disease (SAD...Change in calcium response was studied to clarify the pathological process of Alzheimer's disease (AD). Cultured fibroblasts from patients with familial Alzheimer's disease (FAD; n = 6), sporadic Alzheimer's disease (SAD; n = 4), and age-matched healthy control subjects (n = 4) were studied with an ACAS Interactive Laser Cytometer (ACAS-470). Fibroblasts from two independent families with FAD (OS-1, and OS-2 families) showed a suppressed calcium response after stimulation by 100 nM bradykinin (BK) 100 nM vasopressin (VP) or 10% FCS in Ca(2+)-free condition compared with control fibroblasts at 48 h after plating. However, on the 7th day after plating, the abnormal calcium response was no longer observed. The height of the calcium peak showed periodic variation, indicating a relationship of calcium response with the cell cycle. When fibroblasts from OS-1 and OS-2 families were arrested in S phase, they showed a significantly suppressed calcium peak after BK stimulation. However, when those fibroblasts were arrested in other phases, they showed the same calcium peak as the other cells. The suppression of calcium response in S phase was indistinguishable from the calcium suppression induced by A23187 administration. Since Hardy type mutation on amyloid precursor protein gene is found in the OS-1 family, the observed abnormalities in calcium response might be related with pathological processing of amyloid precursor protein in AD. The reported abnormal calcium response, which is observed most obviously in fibroblasts in S phase, may indicate participation of the cell-cycle-dependent process in the pathology of AD.
Education and occupation as sociodemographic risk factors for dementias of the Alzheimer (DAT) and ischemic vascular types (IVD) were evaluated by two case series studies. Cases were compared to well-evaluated individual...Education and occupation as sociodemographic risk factors for dementias of the Alzheimer (DAT) and ischemic vascular types (IVD) were evaluated by two case series studies. Cases were compared to well-evaluated individuals identified as healthy normals acting as controls. There were 150 patients with probable DAT, 102 patients with probable IVD, and 188 neurologically and cognitively normal subjects. Logistic regression indicated that for DAT, education with occupation was the best predictor (OR, 1.51; 95% CI, 1.23-1.87). For IVD, the two predictors were: education with occupation (OR, 1.84; 95% CI 1.38-4.50) and education with gender (OR, 3.40; 95% CI, 1.29-8.92). We conclude that risk of dementia is increased in those with limited educational background and occupational achievement.
This study examines selected demographic, psychometric, and biological measures as predictors of visuospatial performance in a sample of 98 persons with mild to moderate dementia. Visuospatial performance was measured us...This study examines selected demographic, psychometric, and biological measures as predictors of visuospatial performance in a sample of 98 persons with mild to moderate dementia. Visuospatial performance was measured using standardized neuropsychology instruments, namely: Poppelreuter's figures, the clock test, and block design. Although multiple measures were initially correlated with performance on the selected visuospatial tests, the Mini-Mental State Examination was the exclusive predictor of Poppelreuter's figures and the clock test scores. For block design, years of education also contributed to the prediction model, but only among mildly demented persons. These results suggest that disease severity plays a dominant role in the prediction of visuospatial performance in dementia, particularly in more advanced stages of the disease. The differential role of education in predicting block design performance in mild vs. moderate dementia was also highlighted.
The relationship between chronic obstructive pulmonary disease (COPD) and cognitive functioning was analyzed in a study with 50 aging patients. A complex pattern of interactions was identified between emotional and cogni...The relationship between chronic obstructive pulmonary disease (COPD) and cognitive functioning was analyzed in a study with 50 aging patients. A complex pattern of interactions was identified between emotional and cognitive functioning and chronic respiratory disease when the effects of age, sex, type and severity of disease were controlled. These patients did not show any global and diffuse cognitive impairment. Only a portion of COPD patients (about 30%) evidenced memory impairment which was confined to immediate memory. Memory impairment found in these patients did not appear to be associated with those changes present in the aging process but was mainly related to those specific clinical and instrumental parameters which are considered valid indicators of respiratory efficiency. Two types of cognitive and emotional problems were identified. A progressive stage-dependent set of characteristics was associated with the course of the disease and a fluctuating, probably reversible state-dependent set of characteristics was associated with the temporary condition of the patients during the period of examination. Patients who had received more recent medical treatment or who were under protection of vaccination for influenza showed a better cognitive and emotional efficiency.
In a previous transcranial Doppler (TCD) study, we demonstrated a decrease in blood flow velocity in the proximal tract of the middle cerebral artery (MCA) in patients with Alzheimer's disease (AD). In these patients the...In a previous transcranial Doppler (TCD) study, we demonstrated a decrease in blood flow velocity in the proximal tract of the middle cerebral artery (MCA) in patients with Alzheimer's disease (AD). In these patients there was also an asymmetry in blood flow velocity which positively correlated with the cognitive asymmetry often seen in the early phase of AD. In this study we found a correlation between the absolute values and asymmetry indexes of MCA blood flow velocity with adjusted metabolic values and asymmetry indexes of the relative cortical frontotemporoparietal (FTP) areas, evaluated by FDG-PET, and with neuropsychological asymmetry indexes. Patients with prevalent visuospatial deficits (right hemisphere dysfunction) showed significant decreases in right MCA blood flow velocity and right FTP cortical glucose hypometabolism, whereas in patients with prevalent language deficits (left hemisphere dysfunction), these signs were observed on the other side. In AD patients, the decrease of blood flow velocity in MCA might be due to reduced metabolic demands in the temporoparietal cortical areas primarily affected by AD.
We have performed a quantitative analysis of the amyloid load (plaques), neuritic plaques and neurofibrillary tangles (NFT) in the frontal, temporal and parietal association cortices of autopsied brains from 49 prospecti...We have performed a quantitative analysis of the amyloid load (plaques), neuritic plaques and neurofibrillary tangles (NFT) in the frontal, temporal and parietal association cortices of autopsied brains from 49 prospectively evaluated patients with Alzheimer's disease (AD) diagnosed according to three sets of published pathological criteria. These patients had been assessed clinically with psychological testing of cognitive abilities within 6 months of death. Correlations were sought between severity of pathological change and cognitive status before death, duration of disease and age at death. Using Khachaturian and CERAD criteria highly positive correlations were obtained between the extent of cognitive deficit and the density of NFT in frontal and parietal lobes. The percentage area of cortex occupied by amyloid in the parietal lobe was correlated to the cognitive deficit only in the CERAD-diagnosed cases. The density of all amyloid plaques (AP) showed no correlation with the extent of cognitive deficit, but the densities of neuritic plaques did correlate with cognitive deficit. Both amyloid load and tangle densities were positively correlated with disease duration. All these correlations were reduced or absent in a subgroup of cases fulfilling the Tierney et al. A3 diagnostic criteria for AD. We found no pathological measure that correlated with the age of patients at death. Amyloid loads and NFT densities showed highly significant but selective positive correlations, the most striking being between temporal lobe NFT density and frontal and parietal lobe amyloid load and between temporal lobe NFT density and frontal and parietal lobe NFT densities. Correlations involving AP density as a measure of amyloid load were almost always less significant than those involving the percentage area of cortex occupied by amyloid, suggesting that the latter measures amyloid load more accurately. However, the highest correlations of NFT densities were with neuritic plaque densities. Overall this study highlights the relevance of neuritic changes (revealed by NFT and neuritic plaques) and the irrelevance of amyloid plaques to the dementia of AD.
A portion of Alzheimer's disease (AD) patients have elevated serum levels of the acute phase reactant alpha 1-antichymotrypsin (A1ACT) compared to age-matched controls. We measured serum levels of A1ACT in AD patients, a...A portion of Alzheimer's disease (AD) patients have elevated serum levels of the acute phase reactant alpha 1-antichymotrypsin (A1ACT) compared to age-matched controls. We measured serum levels of A1ACT in AD patients, age-matched controls, Down's syndrome patients, and nondemented first-degree relatives of AD patients. Significantly elevated levels of A1ACT were found in both AD patients and first-degree-relatives. In AD patients, serum A1ACT concentrations decreased with increasing severity of cognitive impairment. These results may suggest that inflammatory phenomena may be an early component of AD pathophysiology.
Motor neuron disease (MND) can be associated with frontotemporal dementia (FTD) and circumscribed lobar atrophy of frontal and temporal lobes. Neuropathological correlations were sought in postmortem studies from a woman...Motor neuron disease (MND) can be associated with frontotemporal dementia (FTD) and circumscribed lobar atrophy of frontal and temporal lobes. Neuropathological correlations were sought in postmortem studies from a woman with these associated conditions. Cerebral blood flow imaging and autopsy showed cortical abnormalities in the frontal and temporal lobes, but typical argyrophilic Pick's bodies were absent and ubiquitin-positive neuronal cytoplasmic inclusions were rare. However, hematoxylin and eosin staining revealed eosinophilic, granular, central cytoplasmic 'clearing' in most neurons of the substantia nigra and in cervical anterior horn cells. Electron microscopy showed that these neurons contained a central cytoplasmic zone cleared of neuromelanin and normal cytoplasmic organelles containing small mitochondria with matrix inclusions and randomly oriented filamentous material. A mitochondrial dysfunction or defective transport of mitochondria into axonal processes needs to be studied as a potential cause for the coassociation of MND and FTD.
To examine the neuropathological characteristics of senile dementia of the Alzheimer type (SDAT) in very old people, we performed a quantitative analysis of the distribution of neurofibrillary tangles and senile plaques...To examine the neuropathological characteristics of senile dementia of the Alzheimer type (SDAT) in very old people, we performed a quantitative analysis of the distribution of neurofibrillary tangles and senile plaques in the brains of 12 demented patients aged from 96 of 104 years. The hippocampal formation and the inferior temporal cortex displayed numerous neurofibrillary tangles in most cases, whereas the superior frontal cortex was relatively spared. The only statistically significant difference between demented and control cases was in the density of neurofibrillary tangles in the CA1 field of the hippocampus. High senile plaque densities were observed in the cerebral cortex and were correlated with the duration of SDAT. These results confirm the crucial role of the hippocampus in the neuropathological diagnosis of SDAT in oldest-old patients. Furthermore, they suggest that senile plaque formation may be a pathological hallmark of severe SDAT in this particular age group.
The relative risk (RR) of acquiring a hospital diagnosis of dementia was estimated in 101,104 patients (1 in 25 fraction) randomly selected from total admissions to Scottish general hospitals between 1968 and 1977. The p...The relative risk (RR) of acquiring a hospital diagnosis of dementia was estimated in 101,104 patients (1 in 25 fraction) randomly selected from total admissions to Scottish general hospitals between 1968 and 1977. The patients were allocated to putative at-risk groups according to main diagnosis at time of index admission, and RR of dementia (ICD 9,290) was contrasted between ten risk groups and a reference group. Record linkage was used to reduce admission episodes to individual cases, to link general and psychiatric Scottish Morbidity Records (SMR 1 and SMR 4), to identify subsequent admission diagnoses of dementia, and to establish person-years-at-risk for each case by linking to the Registrar General's mortality file. For males, RR was significantly increased in the 'hypertensive' risk group (RR 3.88:95% CI 2.18-9.89: p < 0.05) and was significantly reduced in the 'arterial disease' risk group (RR 0.57:95% CI 0.34-0.95: p < 0.05). There was a trend towards increased risk in the cerebrovascular category. For females, RR was significantly reduced in the 'cancer' risk group (RR 0.46:95% CI 0.34-0.63: p < 0.05). There was no evidence of significant alteration in RR in a number of other possible risk groups (endocrine, head injury, CNS/NS disease, ischaemic heart disease, peptic ulcer). Morbidity registers provide access to large data sets of low reliability. No attempt was made to distinguish between Alzheimer's disease and multi-infarct dementia cases, which limited scope for comparison with studies focused on Alzheimer's disease. Previous reports positive associations between head injury, thyroid disorder, and subsequent Alzheimer's disease were not replicated.
There is growing evidence that AD consists of different subtypes, and that language is a pertinent factor to identify a subgroup with a fast rate of cognitive decline. We report the first results of a longitudinal study...There is growing evidence that AD consists of different subtypes, and that language is a pertinent factor to identify a subgroup with a fast rate of cognitive decline. We report the first results of a longitudinal study in which we compared two groups of patients with probable AD. The main result showed that a subgroup with stable MMSE scores during a 1-year follow-up period had an impairment in language domains which are usually preserved until an advanced stage of the disease. It is proposed that this group may correspond to a variety of AD who, in addition to symptoms of AD, present characteristics of primary progressive aphasia. In other respects, we underscore that the high loading in language-mediated tasks of the MMSE makes it a poor index to accurately measure the rate of cognitive decline.
The intention of this study was to examine the relation of clinical variables and cognitive dysfunction to cerebrovascular blood flow in a sample of patients with Alzheimer's disease without any sign or symptom of cardio...The intention of this study was to examine the relation of clinical variables and cognitive dysfunction to cerebrovascular blood flow in a sample of patients with Alzheimer's disease without any sign or symptom of cardiovascular or cerebrovascular disease. The patients met DSM-III-R criteria for dementia of Alzheimer type. Blood flow velocities in the anterior, middle (MCA) and posterior cerebral arteries were recorded using transcranial Doppler sonography. Several psychometric tests including the Mini-Mental State Examination (MMSE) were performed. The patients' age correlated significantly with the systolic flow velocity in the left MCA (r = -0.57) explaining 24% of the total variance; there was a reduction of the mean flow velocity of 0.7 +/- 0.2 mm/s for every additional year. The MMSE correlated significantly with the systolic flow velocity in the left MCA (r = 0.62) explaining 29% of the total variance. The correlations of flow velocities with age indicate that even in very old patients there is a progressive reduction of cerebral blood flow velocities. The independent negative correlations of flow velocities with cognitive dysfunction indicate that there are progressive cerebrovascular flow reductions in the course of Alzheimer's disease. Both facts should be taken into account when Alzheimer patients are compared with other samples.
A case-control study of Alzheimer's disease was conducted in Japan; it involved 60 cases matched for sex and age with two resident controls each. Life-style was particularly highlighted in this study. Among many factors,...A case-control study of Alzheimer's disease was conducted in Japan; it involved 60 cases matched for sex and age with two resident controls each. Life-style was particularly highlighted in this study. Among many factors, 5 were accepted as significant risk factors: psychosocial inactivity, physical inactivity, head injury, loss of teeth and low education. A multiple logistic model was applied in order to evaluate synergism of major factors. Compared with those who have none of the factors, those who have all were 934.5 times more liable to develop Alzheimer's disease. Risk factors are not only useful for etiological studies but they give clues to identify high-risk individuals, and by eliminating these factors, the studies may also be applicable in the primary and the secondary prevention of this tragic disease.
Chromosome investigations were carried out on lymphocyte cultures of 21 patients with probable Alzheimer's disease in comparison to an age-matched control group of 11 healthy subjects. Different cytogenetic parameters we...Chromosome investigations were carried out on lymphocyte cultures of 21 patients with probable Alzheimer's disease in comparison to an age-matched control group of 11 healthy subjects. Different cytogenetic parameters were analyzed: sister chromatid exchanges, polyploid mitoses, mitotic activity and secondary chromosomal aberrations such as gaps, breaks and exchanges. Only the average rate of sister chromatic exchanges was slightly decreased in patients (8.4 +/- 1.7; control group: 10.4 +/- 2.1). There were interindividual differences of values for each of the cytogenetic parameters analyzed, but these were not related to the onset, duration or severity of dementia.
Thirteen women with senile dementia of Alzheimer's type (SDAT) according to NINCDS-ADRDA and 21 age-matched control women, aged 75-96 years, were investigated with clinical examination, dementia rating scales and single...Thirteen women with senile dementia of Alzheimer's type (SDAT) according to NINCDS-ADRDA and 21 age-matched control women, aged 75-96 years, were investigated with clinical examination, dementia rating scales and single photon emission computed tomography (SPECT) using 99mTc-hexamethylpropyleneamine oxime (HM-PAO) as a tracer of regional cortical blood flow. The aim was to study whether typical SPECT findings of SDAT were seen also in the very old having the disease for a longer period. Neuropsychological assessment with vocabulary and spatial tests was performed in the control women, and the results were divided in three subgroups, normal, borderline and abnormal. Regional perfusion values, expressed as a ratio between cortical and cerebellar HM-PAO uptake, were lower in frontal, temporoparietal and occipital cortices in SDAT patients than in controls. The SDAT patients had the lowest uptake in the posterior temporoparietal region (0.67 +/- 0.06) and the corresponding value in the controls (0.79 +/- 0.05) differed significantly, p < 0.0001. The interhemispheric ratio between right and left posterior temporoparietal regions was 0.99 +/- 0.05. Nine of the control women (43%) had pathological SPECT with hemispheric asymmetries in 6 cases and bilateral temporooccipital reductions in 3 women. The neuropsychological assessment matched the findings in 7 of these women. One of the control women was judged as pathological and 10 women as borderline according to the spatial and vocabulary tests. Four of the 10 women with borderline results had normal SPECT. The sensitivity of the assessment to detect abnormalities compared to SPECT was 78% if borderline and abnormal results were expressed as true-positive cases. The specificity was 67%.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochemical and histochemical studies have demonstrated a widespread deficit in the activity of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (DAT). Multiple disturbances in several trans...Biochemical and histochemical studies have demonstrated a widespread deficit in the activity of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (DAT). Multiple disturbances in several transmitter systems have been found. The most consistent neurochemical changes in DAT are reductions in the cholinergic system. The major pharmacological approach today in DAT is based on the cholinergic theory assuming that acetylcholine has a major cortical impact on cognitive processes. Tetrahydroaminoacridine (THA, tacrine) is a centrally active reversible acetylcholinesterase inhibitor. A large number of trials have been performed in patients with DAT. This article was to evaluate whether THA treatment induced neuropeptide alteration in DAT before and after 1 year on oral THA treatment.