Experimental data suggest an involvement of immune cellular components in the development of Alzheimer's disease (AD). Against this background, the spontaneous natural killer (NK) cell activity and the NK-induced cytotox...Experimental data suggest an involvement of immune cellular components in the development of Alzheimer's disease (AD). Against this background, the spontaneous natural killer (NK) cell activity and the NK-induced cytotoxicity after interleukin-2 (IL-2) were studied in healthy elderly subjects and in patients with dementia of Alzheimer type (SDAT) and multi-infarct type (MID). Higher NK cytotoxicity (expressed as total lysis and percent increase) at different IL-2 concentrations (50 and 100 IU/ml/cells) was demonstrated in patients with SDAT than in healthy elderly subjects (p < 0.001) and MID patients (p < 0.001). NK cell activity of MID patients was similar to that of healthy elderly and healthy young subjects. A negative correlation between the percent increase in NK cytotoxicity after IL-2 and the Mini Mental State Examination Score was also found in SDAT patients (p < 0.01). Alterations of IL-2-mediated NK cytotoxicity may therefore support the neuroimmune hypothesis of AD.
Neuropsychological screening tests such as the Mini Mental State Examination (MMSE) are commonly used for case finding in community studies on dementia or Alzheimer's disease (AD). However, the high proportion of false-p...Neuropsychological screening tests such as the Mini Mental State Examination (MMSE) are commonly used for case finding in community studies on dementia or Alzheimer's disease (AD). However, the high proportion of false-positives is an important limitation to the feasibility of such studies. The aim of this study was to evaluate whether adding apoliporotein E (apoE) genotyping to the MMSE is followed by a significant reduction of the false-positive rate. Subjects were 70 AD patients (MMSE 13-28) and 70 normal controls (MMSE 25-30). Multivariable discriminant analysis was used to classify subjects on the basis of age, gender, MMSE score and the presence of the epsilon 4 allele of apoE. When sensitivity was set at 99%, the model including age, gender and MMSE had a false-positive rate of 13.5%, while adding epsilon 4 to the previous variables decreased this figure to 6.7%. In a hypothetical community study screening for AD in a population of 1,000,000, this would turn in a decrease of false-positives from about 19,000 to about 9,500. We conclude that the use of apoE genotyping in community case-finding studies is promising and should deserve further consideration.
This paper addresses the synergy and antagonism between symptoms and signs among 2,914 elderly Canadians diagnosed in 15 categories, including no cognitive impairment, cognitive impairment but no dementia, mild, moderate...This paper addresses the synergy and antagonism between symptoms and signs among 2,914 elderly Canadians diagnosed in 15 categories, including no cognitive impairment, cognitive impairment but no dementia, mild, moderate and severe forms of Alzheimer's disease and vascular dementia, 4 subtypes of possible Alzheimer's disease, Parkinson's dementia, unspecified other dementias and unclassified dementias Attention is paid to the relationships between symptoms and signs rather than conventional analyses which assume independent signs. We demonstrate that dementia progression and specific aetiologies have characteristic patterns of decline and destruction from the strong synergy that exists between symptoms and signs among the population with no cognitive impairment. These findings have potential implications for the incorporation of new diagnostic criteria into existing databases.
The careful definition of cases is fundamental to diagnosis and to any study of cognitive, behavioural and functional problems in dementia. This paper presents an algorithmic approach which mimics a crucial component of...The careful definition of cases is fundamental to diagnosis and to any study of cognitive, behavioural and functional problems in dementia. This paper presents an algorithmic approach which mimics a crucial component of diagnostic decision-making; symptoms and signs do not occur independently, but are conditioned on each other. First, we examine whether the conditioned items can be assembled to yield a differential diagnosis of dementia which corresponds to clinical diagnoses, and second, we explore whether subjects whose algorithmic profiles do not fit the clinical diagnoses form new discernable patterns. Such a technique offers two advantages: it allows for the development of validation protocols which are crucial to epidemiological studies, and it allows for the analysis of new patterns of signs and symptoms for emerging criteria of dementia subtypes. This approach has the potential to refine and enhance criteria for the differential diagnosis of dementia and to have an impact on case identification and assessment, particularly in large epidemiologic studies.
In this study the best combination of quantitative electroencephalographic variables (qEEG) for the discrimination of groups with mild to moderate Alzheimer's disease (AD), mild cognitive impairment and healthy subjects...In this study the best combination of quantitative electroencephalographic variables (qEEG) for the discrimination of groups with mild to moderate Alzheimer's disease (AD), mild cognitive impairment and healthy subjects was defined and related to neuropsychological performance. The study population included 18 patients with mild to moderate probable AD, 19 subjects with objective memory disturbance, 17 subjects with subjective memory complaints who did not have clinical evidence of memory disturbance, and 16 healthy controls. AD patients had significantly increased theta and decreased alpha relative power, mean frequency, and temporoparietal coherence. There was no significant difference in the mean frequency in the left temporal region between AD patients and subjects with objective memory disturbances. Temporoparietal coherence appeared as a discriminant variable together with alpha and theta relative power only between AD patients and controls giving 77.8% sensitivity and 100% specificity. Significant correlations between regional changes in qEEG variables and cognitive functions were found.
This study measured brain atrophy in patients with idiopathic Parkinson's disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopammergic neurons and absence of Alzheimer's disease. Charact...This study measured brain atrophy in patients with idiopathic Parkinson's disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopammergic neurons and absence of Alzheimer's disease. Characteristic patterns of volume loss were found throughout the brain, depending on the age of onset and clinical signs. An equivalent loss of medial temporal lobe structures occurred in all parkinsonian patients. This atrophy was similar in magnitude to that seen in Alzheimer's disease and is likely to be the anatomical substrate for the memory deficits found in each of these patients groups. Frontal lobe atrophy was a feature of both late-onset Parkinson's disease (mild atrophy) and diffuse Lewy body disease (significant atrophy) groups, with all cases analyzed having dementia. Atrophy of frontal lobes correlated with the duration of motor symptoms in these patients and may suggest an association between dopammergic deafferentation, frontal atrophy and dementia.
This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholin...This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors.
Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This...Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This may be the consequence of age-related cholinergic impairment, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impairment, we verified the GH response to GHRH (1 microgram/kg i.v. at 0 min) alone or combined with pyridostigmine (PD), a cholinesterase inhibitor (60 and 120 mg, respectively, in children and adults, orally at -60 min) in 15 DS children (13.5 +/- 0.6 years) and in 11 DS young adults (24.0 +/- 1.2 years). Fifteen normal children (11.9 +/- 0.5 years), 15 normal adults (27.3 +/- 0.9 years) and 16 normal elderly (76.3 +/- 1.5 years) were studied as controls. IGF-I levels showed an age-related reduction both in DS (children vs. adults, mean +/- SEM:354.8 +/- 44.9 vs. 204.4 +/- 29.4 micrograms/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly:281.4 +/- 36.3 vs. 175.4 +/- 11.2 vs. 72.5 +/- 6.6 micrograms/l, p < 0.001). The GH response to GHRH in DS children was higher than in DS adults (areas under curve: 1,197.6 +/- 241.5 vs. 434.4 +/- 83.3 micrograms/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 +/- 128.4 vs. 800.8 +/- 124.5 micrograms/l/h) and both were higher than that in elderly subjects (296.0 +/- 61.0 micrograms/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children (1,068.1 +/- 145.7 vs. 1,897.4 +/- 198.8 micrograms/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 +/- 144.7 vs. 2,172.1 +/- 156.1 and 2,347.6 +/- 322.4 micrograms/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) than that in normal adults and similar to that in normal elderly subjects. In conclusion, the present data demonstrate that the stimulated GH secretion in DS undergoes an accelerated age-related reduction. They also suggest the existence of a precocious impairment of central cholinergic activity in DS, which, in turn, could cause somatostatinergic hyperactivity and reduced GH secretion.
Reported findings regarding sleep and sleep disorders in the elderly often conflict. Differences in results across studies may arise from selection of subjects, definitions and recording conditions. Our purpose was to te...Reported findings regarding sleep and sleep disorders in the elderly often conflict. Differences in results across studies may arise from selection of subjects, definitions and recording conditions. Our purpose was to test a method to study elderly, both healthy and demented, under the most natural conditions, without disturbing a fragile sleep. Using clinical parameters and a non-disturbing recording method, we evaluated sleep quality in patients with carefully diagnosed dementia and compared the results to a group of healthy subjects between 50 and 70 years of age. Healthy subjects awoke less and had more quiet sleep than patients, while in patients a tendency for delayed sleep latency and more active sleep was observed. Consistent with previous investigations, sleep-related respiratory disorders (SRRD) were more common in patients than in the matched control group, and periodic breathing appeared only among patients. SRRD, of both obstructive and central types, were only mild, with periodic breathing dominating only among patients. Most of the desaturations were less than 10%. We did not observe respiration of the Cheyne-Stokes type. Patients had more sleep-related movement disorders (SRMD), particularly with increase of twitches and long movements. Periodic movements were not significantly increased among the patients. The method, and the data obtained may be useful for practitioners dealing with sleep disorders in geriatric populations. In the elderly, interactivity between sleep, SRRD and SRMD may be bidirectional and as elderly and demented subjects might have a distorted homeostatic sleep response, SRRD and SRMD, even in a mild form, may cause sleep disruption and worsen dementia.
Apolipoprotein E (apoE) has been suggested to play a role in regenerative processes in the brain after trauma, and also in the pathogenesis of Alzheimer's disease (AD). We examined cerebrospinal fluid (CSF) apoE in a mat...Apolipoprotein E (apoE) has been suggested to play a role in regenerative processes in the brain after trauma, and also in the pathogenesis of Alzheimer's disease (AD). We examined cerebrospinal fluid (CSF) apoE in a material consisting of 23 patients with early-onset AD (EAD), 31 with late-onset AD (LAD), 16 with frontal-lobe dementia (FLD), 25 with vascular dementia (VAD) and 25 controls. CSF-apoE was decreased in all of EAD (1.8 +/- 1.1 mg/l; p < 0.0005), LAD (2.5 +/- 0.9 mg/l; p < 0.0005), VAD (2.3 +/- 1.4 mg/l; P < 0.0005) and FLD (3.0 +/- 1.3 mg/l; p < 0.05) compared to the control group (5.7 +/- 4.0 mg/l). Since apoE4 has been found to bind to beta/A4-amyloid, and AD patients homozygous for apoE4 to have higher number of senile plaques than apoE3 homozygotes, we also examined the relation between CSF-apoE and apoE alleles. However, CSF-apoE did not significantly differ between patients with different apoE isoforms. Our findings support that apoE is involved in the pathogenesis of dementia disorders, both degenerative and vascular, but the CSF-apoE level is not influenced by the apoE isoforms. CSF-apoE may be used as an unspecific marker for neurodegenerative disorders, but not in purpose of differential diagnostics between different dementia disorders.
Glial fibrillary acidic protein (GFAP) is the structural protein of the astroglial intermediate filament that forms the morphological basis of astrogliosis. In the present study, GFAP concentrations in cerebrospinal flui...Glial fibrillary acidic protein (GFAP) is the structural protein of the astroglial intermediate filament that forms the morphological basis of astrogliosis. In the present study, GFAP concentrations in cerebrospinal fluid were measured in patients with various dementia diseases. A significant correlation between GFAP and age was found both in the total dementia group and in the controls. Covariance analysis with GFAP as dependent variable and age and albumin ratio as covariates followed by multiple group comparisons showed that, with regard to GFAP levels, the controls (n = 39) differed significantly from the patients with vascular dementia (n = 20; p < 0.05), senile dementia of the Alzheimer type (n = 29; p < 0.05), and 'pure' Alzheimer's disease (n = 8; p < 0.05), but not from those with frontal lobe dementia (n = 5).
We studied the effects of 40 and 80 mg/day of tacrine on patients with probable Alzheimer's disease (AD) in an 8-week, randomized, double-blind, placebo-controlled crossover trial with an enriched-population design. In t...We studied the effects of 40 and 80 mg/day of tacrine on patients with probable Alzheimer's disease (AD) in an 8-week, randomized, double-blind, placebo-controlled crossover trial with an enriched-population design. In the initial dose titration phase, an intent-to-treat analysis showed significantly more improvement with 80 mg/day of tacrine than placebo. In the subsequent crossover trial that included only 'responders', no significant improvement was observed with tacrine, whether or not it was given with lecithin. We found that individualized dose titration and enrichment strategies were not helpful and had the effect of reducing the power of the study. In the dose titration phase of this study we found that more impaired subjects were as likely to improve as those who were less impaired, suggesting that tacrine should be further investigated in more severely demented AD patients.
Serum amyloid P component (AP) is a normal plasma constituent that is observed in senile plaques and neurofibrillary tangles in brains of Alzheimer's disease (AD) patients. In this study we have evaluated the AP levels i...Serum amyloid P component (AP) is a normal plasma constituent that is observed in senile plaques and neurofibrillary tangles in brains of Alzheimer's disease (AD) patients. In this study we have evaluated the AP levels in sera of 16 patients with AD and in 16 control subjects by enzyme-linked immunosorbent assay. The AP level was 22.4 +/- (SD) 7.0 micrograms/ml in the AD group and 34.4 +/- (SD) 6.6 micrograms/ml in the control group. The AP level in the AD group was significantly lower than that of the control group (p < 0.01). In the control group, there was no correlation between AP levels and age. Our results suggest that the production of AP by the liver (hepatocytes), thought to be the only source, may be suppressed in AD patients and that the deposition of AP in senile plaques and neurofibrillary tangles is not due to its overproduction.
Apolipoprotein E (apoE) epsilon 4 allele frequency among Alzheimer's disease (AD) patients is increased compared to control subjects and is influenced by the presence of other genetic factors and age at symptom onset. We...Apolipoprotein E (apoE) epsilon 4 allele frequency among Alzheimer's disease (AD) patients is increased compared to control subjects and is influenced by the presence of other genetic factors and age at symptom onset. We examined the relationship between age at AD symptom onset and apoE by comparing the apoE epsilon 4 allele frequency of normal, elderly control subjects (n = 107) to that in AD patients (n = 123), divided into four age-at-onset periods. Additionally, the distribution of symptom onset ages of AD patients with and without apoE epsilon 4 alleles was determined. We observed increased apoE epsilon 4 allele frequencies between the AD onset ages of 55 and 75 years, but not at the extremes of onset ages (i.e. onset between 45 and 54 years of age and after age 75). Our data suggests that having an apoE epsilon 4 allele increases the likelihood that AD patients will develop symptoms in the middle range of onset ages. At the extremes of AD onset ages, non-apoE factors, including other genetic factors and age, are more important determinants of risk of developing AD.
This study investigated differential patterns of performance by 40 Alzheimer's disease (AD) patients on standardised letter and category fluency tests. The performance of 24 age and education matched controls was used to...This study investigated differential patterns of performance by 40 Alzheimer's disease (AD) patients on standardised letter and category fluency tests. The performance of 24 age and education matched controls was used to classify patients as relatively more letter fluency impaired (L < C, n = 15) or more category fluency impaired (C < L, n = 25), and clinical features distinguishing these patient subgroups were investigated. Category performance was equally impaired in both patient subgroups, whereas the L < C subgroups were particularly impaired on letter fluency. The subgroups differed significantly in duration of illness (24 months for L < C group, 47 months for C < L group; t = 2.69, p = 0.01) but did not differ in global dementia severity, age, education, general language ability, or functional status. Data on annual rate of change (ARC) on the Mini-Mental State Examination were available for 26 patients. While not statistically significant, subgroup ARC differences were suggestive of more rapid decline in the L < C patients, consistent with the finding of shorter duration of illness in this group. Word fluency tests may have potential as early predictors of rate of progression in AD.
Regional cerebral glucose metabolism was surveyed in 37 Alzheimer's disease (AD) patients and 21 normal controls using positron emission tomography. Where possible, brain regions were specified according to their neurobe...Regional cerebral glucose metabolism was surveyed in 37 Alzheimer's disease (AD) patients and 21 normal controls using positron emission tomography. Where possible, brain regions were specified according to their neurobehavioral function rather than as anatomically demarcated structures. Absolute metabolic values revealed significant differences (p < 0.05) between AD patients and controls for whole brain and the more superior supratentorial brain slices. Normalized values (region/brain stem) showed the most striking declines (p < 0.001) in the association cortex (heteromodal region -21%; unimodal region -19%) and the primary sensory-motor cortex (-13%), with motor, auditory, and visual areas more affected than somatosensory areas. Limbic and paralimbic systems were equally affected (-14%; -11%; p < 0.001). Thalamus, striatum, cerebellum and brain stem were minimally or not affected. Neurobehaviorally defined hypometabolic regions largely parallel affected areas noted in anatomic and previous metabolic studies, with the possible exception of metabolic deficits in the primary sensory-motor complex. Conceivably, brain areas unaffected morphologically by the pathophysiological processes of AD may become dysfunctional due to a disruption of connectivity between regions.
It is known that proteases participate in cellular protein turnover and eliminate abnormal and potentially toxic proteins. Disturbed proteolysis may be responsible for generating the pathological features of some neurode...It is known that proteases participate in cellular protein turnover and eliminate abnormal and potentially toxic proteins. Disturbed proteolysis may be responsible for generating the pathological features of some neurodegenerative disorders. Alzheimer disease, for instance, is the most common neurodegenerative disorder and a condition in which proteins of the cell membrane and cytoskeleton are abnormally processed and accumulated in the brain. It is of interest to investigate the effect of protease inhibitors on neurons and neurotransmitter systems in the brain. We examined neurochemical and morphological neuronal changes in the rat brain following long-term intracerebroventricular infusion of leupeptin, a potent calcium-activated protease (calpain) inhibitor. Leupeptin (5 mg) was infused into the lateral ventricle using an osmotic minipump for 14 days. We found a significant reduction of regional choline acetyltransferase activities in the hippocampus, and of somatostatin concentrations in the hypothalamus and entorhinal cortex. Moreover, leupeptin caused a wide-spread, highly significant decrease in neuropeptide-Y concentrations. Leupeptin infusion produced severe degeneration of neuronal processes in both axons and dendrites, and accumulation of electron-dense bodies in the hippocampus. The results indicate that long-term intracerebroventricular infusion of leupeptin in the rat produces neurochemical and morphological changes resembling those of some neurodegenerative disease and aging. Abnormal proteolysis caused by either reduced protease or enhanced protease inhibitor activities might play an important role in these conditions.
We quantified the synaptic density in the outer molecular layer of the hippocampal dentate gyrus. Autopsy material from 9 individuals with Alzheimer disease (AD) were compared to 10 age-matched, postmortem-matched contro...We quantified the synaptic density in the outer molecular layer of the hippocampal dentate gyrus. Autopsy material from 9 individuals with Alzheimer disease (AD) were compared to 10 age-matched, postmortem-matched controls without dementia, using standard electron microscopy. Statistical analyses showed a significant change in the density of synapses between controls and AD subjects. There was a significant decline in the width of the entire molecular layer in the AD material. Synaptic density showed a significant correlation with synaptic apposition length in both AD and control groups. As the number of synapses declined, the synaptic apposition length increased. The decline in density of synapses in the AD group might reflect the degree of neuronal loss in the entorhinal cortex. Such a loss in synaptic connectivity could play a key role in memory-related problems associated with AD.
The prevalence of clinical dementia was assessed in three age groups of patients with Down syndrome in the county of Aarhus, Denmark: Group I: 14-16 years (n = 13), group 2: 23-29 years (n = 34), group 3: 50-60 years (n...The prevalence of clinical dementia was assessed in three age groups of patients with Down syndrome in the county of Aarhus, Denmark: Group I: 14-16 years (n = 13), group 2: 23-29 years (n = 34), group 3: 50-60 years (n = 25). Seventy-two (85%) of 85 patients participated. Caregivers were interviewed and a neurological examination was performed. An EEG was recorded in 50 patients. Definite clinical dementia was defined as an acquired and progressive decline in 4 or more out of 17 items that are considered to indicate dementia in Down syndrome. Possible dementia was considered when 1-3 items were affected. Six (24%) in group 3 had definite clinical dementia. A further 6 patients in group 3 and 2 (6%) in group 2 had possible dementia. This is the first population-based study with a clinical assessment of the prevalence of dementia in Down syndrome.
Two contrasting multivariate statistical methods, viz., principal components analysis (PCA) and cluster analysis were applied to the study of neuropathological variations between cases of Alzheimer's disease (AD). To com...Two contrasting multivariate statistical methods, viz., principal components analysis (PCA) and cluster analysis were applied to the study of neuropathological variations between cases of Alzheimer's disease (AD). To compare the two methods, 78 cases of AD were analyzed, each characterised by measurements of 47 neuropathological variables. Both methods of analysis revealed significant variations between AD cases. These variations were related primarily to differences in the distribution and abundance of senile plaques (SP) and neurofibrillary tangles (NFT) in the brain. Cluster analysis classified the majority of AD cases into five groups which could represent subtypes of AD. However, PCA suggested that variation between cases was more continuous with no distinct subtypes. Hence, PCA may be a more appropriate method than cluster analysis in the study of neuropathological variations between AD cases.