Alzheimer-type Dementia Patients Research Articles

HPA axis responsivity to dexamethasone and cognitive impairment in dementia

1. Animal and human studies suggest a possible relationship between dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and cognitive impairment. 2. In animals, prolonged exposure to high plasma cortisol levels causes irreversible hippocampal damage. 3. Abnormal cortisol plasma levels in response to dexametnasone challenge have been frequently observed in dementia of Alzheimer's type (DAT) patients. 4. The authors studied the relationship of responsivity of the HPA axis to cognitive impairment in 34 DAT patients drug free for at least 10 days. A decrease in HPA axis responsivity significantly correlated with greater cognitive impairment.

CSF choline and acetylcholinesterase in early-onset vs. late-onset Alzheimer's disease patients.

Cerebrospinal fluid acetylcholinesterase (AChE) activity levels and choline (Ch) levels were studied in 52 dementia of Alzheimer type (DAT) patients and 20 age-matched controls. The AChE activity was significantly lower and Ch levels were significantly higher in DAT patients than the age-matched controls. There was no significant difference in AChE activity and Ch levels between early-onset (less than or equal to 65 years) patients and late-onset (greater than 65 years) patients. However, the AChE activity was significantly lower in early-onset patients compared with their age-matched controls but no difference was observed in late-onset patients compared with their age-matched controls. None of the biological measures (AChE, Ch) were significantly correlated with the degree of cognitive impairment, duration of the illness or the sex of these patients.

Mortality of demented patients in a geriatric institution

A group of 237 elderly patients with dementia of Alzheimer type (DAT) or multi-infarct dementia (MID) was randomly selected in a large geriatric institution in Milan. Mean age of the sample was 78.9 years, 160 (67.5%) were DAT patients and 77 (32.5%) were MID patients. Half of the sample had low levels of autonomy and after 4 years 183 (77.2%) patients were dead. Predictors of mortality, according to a univariate analysis, were age, level of autonomy and type of diagnosis (DAT vs. MID). Mortality rate after 4 years was significantly higher ( p<0.001) in DAT (86.9%) than in MID (57.1%) patients.

Diagnosis and treatment of depression in the elderly.

Depression and suicide are significant problems in the elderly, both in terms of their severity and their prevalence. It is particularly difficult to distinguish depression from early dementia, since elderly depressed patients often deny mood disorder and focus on their memory problems. This differential diagnostic dilemma is further complicated by the fact that 20 percent of Alzheimer-type dementia patients have moderate to severe depression. An even higher prevalence of depression can be seen in elderly patients with stroke or Parkinson's disease. Most all of the depressive disorders of the elderly are amenable to one form or combination of therapies: pharmacologic, electro-convulsive, or psychotherapy. Tricyclic antidepressants are often associated with adverse drug reactions in the elderly, so alternatives such as MAO inhibitors, alprazolam, bupropion and psychostimulants are currently being explored in this patient population.

Calbindin neurones in the nucleus basalis of Meynert in Alzheimer-type dementia

In the monkey brain, the neurones on nucleus basalis of Meynert (nbM) have been reported to be calbindin immunoreactive (CaBP-Ir) (Celio and Norman, 1985), so that it was of considerable interest, because of the involvement of these neurones in the pathology of Alzheimer-type dementia (ATD), to see if the nbM neurones of the human brain were also CaBP-Ir. In this study, CaBP and choline acetyltransferase (CHAT) immunohistochemistry was performed in the human nbM. Parvalbmin (PVA) was also studied in the same area. Postmortem brains from three control patients (mean age 77.7+S.D. 6.1) and five pathologically diagnosed ATD patients (82.8 + 7.3) were used for this study. In order to visualize CaBP immunoreactivity, peroxidase-antiperoxidase (PAP) and/or immunofluorescence techniques were used. ChAT monoclonal antibody (Boeringer) was used according to the manufacturer. ChAT immunoreactivity was detected with PAP technique. Counts and size of CaBP-Ir neurones were made with the aid of an image analyser (Ichimiya et al., 1988). In the controls, almost all the large neurones and their processes in the nbM were CaBP-Ir, and some CaBP-Ir neurones were also ChAT immunoreactive (Fig. 1). Compared to the controls, the number and mean size of CaBP-Ir nbM neurones were reduced in the ATDs [number: control, mean 870 4S.D. 23.3/ATD, 222 445.3; mean size (gm 2) : control, 778.6 435.5/ATD, 647.3 + 69.6]. These findings suggest that CaBP might co-exist, at least partially, in the nbM cholinergic neurones, and CaBP-Ir neurones are damaged in ATD.

Vasopressin levels in CSF of Alzheimer patients: Correlations with monoamine metabolites and neuropsychological test performance

Concentrations of vasopressin (AVP) and monoamine metabolites (HVA, 5-HIAA, MHPG) in cerebrospinal fluid (CSF) were measured and compared with memory functions in patients with dementia of Alzheimer type (DAT) and control subjects. CSF concentrations did not differ between the DAT patients and the controls, or between patients with different degrees of dementia. There were no correlations between concentrations of vasopressin and monoamine metabolites in CSF or between the CSF measures and psychological test scores, except for a correlation between CSF HVA and immediate and delayed story recall. These data suggest that probable damage to the vasopressinergic and monoaminergic systems in DAT is not reflected in the CSF of patients in early stages of the disease, nor is a deficit in these systems or their interaction the primary cause of cognitive impairment in DAT.

Platelet MAO-B activity and the psychopathology of Parkinson's disease, senile dementia and multi-infarct dementia.

Monoamine oxidase-B (MAO-B) activity of platelets of an age- and sex-matched group of controls was compared with several groups of inpatients having non-familial dementia of Alzheimer type (DAT), Parkinson's disease (PD), multi-infarct dementia (MID), mixed types of these 3 diseases and a group of other central nervous system (CNS) organic disorders. All patients were subjected to several psychometric tests, including the Sandoz Clinical Assessment--Geriatric Scale, Hamilton Rating Scale for Depression, Mini-Mental State Examination and the Organic mental Disorder Scale (OMDS). A statistically significant enhancement of MAO-B activity could be observed in DAT patients and in PD patients, whereas the MID group showed a mean activity similar to that of the control group and the group with other organic CNS disorders. In DAT patients the degree of dementia in the OMDS test and the enhancement of MAO activity were positively correlated, but PD did not show such a correlation. It is concluded that the increase of MAO activity in PD and in DAT might be due to a disease-related enhanced affinity to oxygen and to such oxygen-derived radicals as superoxide or hydroxyl radicals. However, a possible drug-induced enhancement of MAO activity in PD cannot be excluded. Furthermore, the MAO-B activity values in platelets of individual patients or controls are not indicative of diagnosis or prognosis of any of these diseases and are of no disease-related specificity.

Differential modification of muscarinic cholinergic receptors in the hippocampus of patients with Alzheimer's disease: an autoradiographic study

We have used quantitative light microscopic autoradiographic techniques to analyze changes in muscarinic cholinergic receptors in the hippocampus in Alzheimer type dementia (ATD). The density and distribution of muscarinic cholinergic receptors has been correlated with the density of neurons, neuritic plaques and neurofibrillary tangles in the CA1 subfield of the hippocampus of control and ATD patients. The number of pyramidal cells per mm 2 in the CA1 sector was significantly decreased in ATD cases as compared to controls, although there were large variations among cases. The most marked reductions in cell counts were observed in patients with a history of profound dementia. The densities of muscarinic receptors, as well as the proportions of M 1 and M 2 subtypes, in the CA1 sector and dentate gyrus were not significantly different between ATD and old non-demented patients. Neuritic plaques, even in high numbers, did not affect the density of muscarinic receptors; moreover, the densities of receptors over the neuritic plaques did not differ from the surrounding neuropil. However, in some ATD cases there was a marked decrease in the concentration of these receptors in the CA1 sector and subiculum, with no change in the proportions of muscarinic receptor subtypes. These patients exhibited frequent extracellular remnants of neurofibrillary tangles (ghost tangles), but scarce neuritic plaques, and were those showing severe losses of pyramidal cells. There was a significant positive correlation between the total concentration of muscarinic receptors in the CA1 and the density of pyramidal cells, suggesting that decreases in receptor concentration result from a severe neuronal loss. We observed that the ratio of muscarinic receptors per pyramidal cell was significantly increased in ATD patients. This might indicate a possible upregulatory mechanism for muscarinic receptors in the population of remaining neurons in ATD. However, decreases of receptor numbers following severe neuronal fall out suggest that compensatory mechanisms are no longer possible in such cases. The question is raised whether these differences between cases reflect different diseases or different stages of the same disease.

Regional difference in the kinetics of choline acetyltransferase in brains of neurologically normal elderly people and those with Alzheimer-type dementia

In order to clarify the biochemical changes which occur in the brains of patients suffering from Alzheimer-type dementia (ATD), the kinetics of choline acetyltransferase (ChAT) were measured in 8 or 11 regions of post-mortem brains of 6 patients with non-neurological diseases (control subjects) and 8 patients with ATD. In the control subjects, Michaelis constants (K m) of ChAT for choline were lower in the caudate nucleus and putamen than in other regions examined, whereas K m values for acetyl-CoA in these two regions were higher. Maximal velocities (V max) for the control subjects were higher in the caudate nucleus and putamen than in the other regions studied. K m values for choline of ATD patients were higher than those of control subjects in all regions except the amygdala and substantia innominata (innominate); however, K m values for acetyl-CoA of ATD patients were higher than those of control subjects only in the caudate nucleus, putamen and thalamus. V max values of ATD patients were lower than those of control subjects in all the regions of brains with ATD. These results suggest that the binding site of ChAT for choline is sensitive to the pathological process of ATD, whereas the binding site for acetyl-CoA is resistant. Based on the presence or absence of variations of K m values, we have classified brain regions into 3 types: highly sensitive, somewhat sensitive or resistant to the pathological process of ATD.

Cortisol, ACTH, and dexamethasone concentrations in a psychogeriatric population

Cortisol and adrenocorticotrophic hormone (ACTH) were measured at 2 time points before the administration of 1 mg of dexamethasone (day 1) and 1 time point on the following day (day 2). Thirteen severely depressed elderly patients, 15 patients with Alzheimer-type dementia (ATD), and 16 normal controls were studied. Cortisol was markedly elevated in depressed patients compared with the other subjects in day 1 samples. Following dexamethasone, both the depressed and ATD patients showed a similar elevation of cortisol compared with controls. ACTH concentrations were not significantly different between the groups before dexamethasone, but were significantly higher in both depressed and ATD patients after dexamethasone. More depressed patients than ATD patients exhibited hypersecretion of ACTH after dexamethasone. This implies that ACTH is less responsive to glucocorticoid feedback in elderly depressed patients, which may be a factor in causing hypercortisolemia.

Unaltered platelet [3H]-imipramine binding in dementia of the Alzheimer type.

High-affinity [3H]-imipramine binding to platelets was evaluated in 11 patients suffering from dementia of Alzheimer type (DAT) in comparison to 12 normal controls. The [3H]-imipramine binding values (Bmax and Kd) did not differ between the DAT patients and the controls. Previous studies have demonstrated hypofunction of central serotonergic system in this disease, including reduced imipramine binding to brain. Thus, it seems that the low imipramine binding in DAT is confined to the brain tissue and not reflected in the platelets.

The effect of concurrent articulation on memory span in Alzheimer-type dementia.

This study explored the effects of concurrent articulation on memory-span performance, comparing patients with early Alzheimer-type dementia (AD) and matched controls. Reduction in memory span due to concurrent articulation was the same in AD patients as controls, supporting the notion that the contribution of articulatory rehearsal to memory-span performance is undiminished in early AD.

Sodium dependent d-[ 3H]aspartate binding in cerebral cortex in patients with Alzheimer's and Parkinson's diseases

The sodium dependent binding of d-[ 3H]aspartate to the high-affinity glutamate uptake system was used as a marker of glutamate-releasing terminals in the cerebral cortex of brains from patients with Alzheimer-type dementia (ATD) and Parkinson's disease (PD). Sodium-dependent d-[ 3H]aspartate binding was reduced in the ATD patients but not in the PD patients. Within the PD patients no association was observed between sodium-dependent d-[ 3H]aspartate binding and the presence of dementia. In contrast choline acetyltransferase activity was reduced in both the ATD and the PD patients. The present results suggest that changes in the cortical cholinergic system can occur independently of the cortical glutamate system. The glutamatergic deficit in ATD may contribute to some of the clinical differences between the dementia of ATD and PD.

Falls and Fractures in Patients With Alzheimer-Type Dementia

The prevention of fall-related injuries in patients with Alzheimer-type dementia (ATD) is hampered by an incomplete understanding of their causes. We studied falls and fractures in 157 ATD patients, including 117 with three-year follow-up. Initially all but one patient could walk; 31% reported falls. During follow-up, 50% either fell or became unable to walk. The fracture rate during follow-up (69/1000/y) was more than three times the age- and sex-adjusted fracture rate in the general population. Features of both ATD and comorbid conditions contributed to the risk of falls and fractures. In particular, patients who experienced toxic reactions to drugs on entry into the study were more likely to report they had fallen prior to entry (odds ratio, 4.9; 95% confidence interval, 1.78 to 13.3), and patients who wandered were more likely to sustain fractures (odds ratio, 3.6; 95% confidence interval, 1.25 to 10.4) during the follow-up period, including hip fractures for which the odds ratio of 6.9 (95% confidence interval, 1.66 to 28.6) was unexpectedly high. Preventive measures may be possible, including controlling wandering, avoiding toxic reactions to drugs, and treating comorbid illnesses.

Articulatory rehearsal in Alzheimer type dementia

This study investigated the relationship between articulation rate and memory span in a sample of 21 patients with early Alzheimer type dementia (AD), comparing their performance with 21 matched controls. Memory span was measured using auditorily and visually presented digits. The AD patients were moderately impaired in both conditions. Articulation rate was measured either by requiring subjects to read lists of random digits or repeatedly count from 1 to 10. The AD patients were able to read the digits as fast as the controls but were slower in the counting task. The measures of memory span and articulation rate correlated significantly for the controls but not for the AD patients, indicating that the normal association between articulation and memory span is disrupted. These results are discussed in relation to previous results and suggest that articulatory rehearsal processes in primary memory are unimpaired at the early stages of AD.

Falls and fractures in patients with Alzheimer-type dementia

The prevention of fall-related injuries in patients with Alzheimer-type dementia (ATD) is hampered by an incomplete understanding of their causes. We studied falls and fractures in 157 ATD patients, including 117 with three-year follow-up. Initially all but one patient could walk; 31% reported falls. During follow-up, 50% either fell or became unable to walk. The fracture rate during follow-up (69/1000/y) was more than three times the age- and sex-adjusted fracture rate in the general population. Features of both ATD and comorbid conditions contributed to the risk of falls and fractures. In particular, patients who experienced toxic reactions to drugs on entry into the study were more likely to report they had fallen prior to entry (odds ratio, 4.9; 95% confidence interval, 1.78 to 13.3), and patients who wandered were more likely to sustain fractures (odds ratio, 3.6; 95% confidence interval, 1.25 to 10.4) during the follow-up period, including hip fractures for which the odds ratio of 6.9 (95% confidence interval, 1.66 to 28.6) was unexpectedly high. Preventive measures may be possible, including controlling wandering, avoiding toxic reactions to drugs, and treating comorbid illnesses. (JAMA1987;257:1492-1495)

Extrahypophyseal distribution of α-melanocyte stimulating hormone (α-MSH)-like immunoreactivity in postmortem brains from normal subjects and Alzheimer-type dementia patients

Using a sensitive double-antibody solid-phase enzyme immunoassay method α-melanocyte stimulating hormone-like immunoreactivity (α-MSH-LI) was measured in 21 regions of postmortem brains from 8 normal subjects and 5 patients with Alzheimer-type dementia (ATD). In the brains from the normal subjects, the highest concentration of α-MSH-LI was found in the hypothalamus. Relatively high concentration were also measured in the locus coeruleus, substantia innominata, substantia nigra, amygdala and medial nucleus of thalamus. α-MSH-LI in other regions was approximately1/100 of the hypothalamic content. This data is consistent with the existence of α-MSH in extrahypophyseal regions and indicates its regional distribution in the human brain. In the Alzheimer brains, although the temporal cortex and hippocampus had normal concentrations of α-MSH-LI, the cingulate cortex, caudate and substantia nigra showed significantly lower concentrations of α-MSH-LI than those of the control brains. This data suggests that further studies of α-MSH content in a larger number of ATD brains would be useful.

Molecular forms of cholinesterases in CSF of Alzheimer's disease/senile dementia of Alzheimer type patients and matched neurological controls

Acetylcholinesterase, pseudocholinesterase and their molecular forms were measured in the CSF of patients affected by Alzheimer's disease and of matched neurological controls. Three different molecular forms of ChE were found in the CSF of both groups of patients, but only two of them belonged to ‘true’ AChE. No differences were found between Alzheimer's disease patients and neurological controls in all the examined parameters.

The selectivity of the reduction of serotonin S2 receptors in Alzheimer-type dementia

The high-affinity binding of thirteen ligands to putative neurotransmitter receptors was studied in temporal cortex of control and Alzheimer-type dementia (ATD) patients. A selective reduction of serotonin S2 receptors was observed in the ATD patients, to 57% of controls with no change in S1 receptors. Of the other ligand binding sites studied, only 3H-flunitrazepam binding was significantly reduced, to 84% of controls. Ligand binding sites which were unchanged in ATD temporal cortex included those labelled by adrenergic, adenosine, histamine, opiate, GABA, benzodiazepine and cholinergic ligands.

Catecholamine metabolites and cyclic nucleotides in cerebrospinal fluid in dementia of Alzheimer type.

Three, 4-dihydroxyphenylacetic acid (DOPAC); 3-methoxy, 4-hydroxyphenylacetic acid (HVA); 3-methoxy; 4-hydroxyphenylglycol (MHPG); adenosine 3', 5'-cyclic monophosphate (cyclic AMP); and guanosine 3', 5'-cyclic monophosphate (cyclic GMP) were measured in cerebrospinal fluid (CSF) of patients with dementia of Alzheimer type (DAT) and controls. DOPAC levels were lower and HVA levels were higher in DAT patients than in controls. In the most rostral fractions of CSF from DAT patients there was a negative correlation between DOPAC and cyclic AMP levels. In addition, patients with onset of DAT symptoms before the age of 65 had lower DOPAC levels, a higher HVA/DOPAC ratio, and higher cyclic nucleotide levels than patients with late onset of DAT. By combining DOPAC and cyclic AMP levels, we could clearly distinguish these two groups.