Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques

Postmortem examination was performed on 137 residents (average age 85.5 years) of a skilled nursing facility whose mental status, memory, and functional status had been evaluated during life. Seventy-eight percent were demented using conservative criteria; 55% had characteristic Alzheimer's disease. Choline acetyltransferase and somatostatin were significantly reduced in the brains of patients with Alzheimer's disease as compared with age-matched nursing home control subjects, although the degree of the reduction was less severe than found in subjects less than 80 years of age. Ten subjects whose functional and cognitive performance was in the upper quintile of the nursing home residents, as good as or better than the performance of the upper quintile of residents without brain pathology (control subjects), showed the pathological features of mild Alzheimer's disease, with many neocortical plaques. Plaque counts were 80% of those of demented patients with Alzheimer's disease. Choline acetyltransferase and somatostatin levels were intermediate between controls and demented patients with Alzheimer's disease. The unexpected findings in these subjects were higher brain weights and greater number of neurons (greater than 90 micron 2 in a cross-sectional area in cerebral cortex) as compared to age-matched nursing home control subjects. These people may have had incipient Alzheimer's disease but escaped loss of large neurons, or alternatively, started with larger brains and more large neurons and thus might be said to have had a greater reserve.     

Neurotransmitter changes in early- and late-onset alzheimer-type dementia

Arai Heii., Yosuke Ichimiya, Kenji Kosaka, Takashi Noroji and Reiji Iizuka: Neurotransmitter Changes in Early- and Late-onset Alzheimer-type Dementia. Prog. Neuro-Psychophamacol. & Biol. Psychiat. 1992, 16(6):883–890.

1. 1. Neurotransmitter-related markers were examined in Alzheimer-type dementia (ATD) and studied whether or not there is biochemical difference between the early- and late-onset sub-groups.

2. 2. Postmortem brains were obtained from neuropathologically diagnosed ATD patients and control subjects with no clinico-neuropathological findings indicative of neuropsychiatric diseases.

3. 3. Neurochemical data in the early- and late-onset groups were compared to the age-matched younger and older control groups, respectively, and expressed as a percentage of the mean value in the respective controls.

4. 4. Choline acetyltransferase activity and concentrations of serotonin and noradrenaline were more severely depleted in the early-onset ATD group than in the late-onset ATD group.

5. 5. These findings indicative of heterogeneity of ATD patients were discussed from the pathogenetic and therapeutic viewpoints.

Acetylcholinesterase and butyrylcholinesterase in frontal cortex and cerebrospinal fluid of demented and non-demented patients with Parkinson's disease

The molecular forms of acetylcholinesterase (AChE) and butyrylcholinesterasse (BChE) were studied in frontal cortex (grey and white matter), postmortem, and in cerebrospinal fluid (CSF) of demented patients with Parkinson's diesease compared to controls and non-demented parkinsonians. In the frontal cortex, AChE activity decreased significantly in both demented and non-demented parkinsonian subjects compared to controls; the 10S form of the enzyme was significantly lower in demented parkinsonians than in the non-demented subjects. The decrease in AChE activity was correlated with a decrease in choline acetyltransferase activity thought to reflect lesion of cholinergic neurones in the substantia innominata which innervate the cerebral cortex. BChE activity decreased only in the non-demented parkinsonians; in the demented subjects, BChE activity was at control levels. Similar results were obtained with grey and white matter, although absolute levels of the two enzymes were different in the two types of tissue, suggesting that the enzymes were affected in the cholinergic neurones before transport to cortical nerve terminals. No decreases in AChE or BChE activity were observed in the CSF of the patients studied. On the contrary, AChE and BChE levels were significantly higher in demented parkinsonian patients compared to the non-demented subjects.     

A correlative study of calcium channel antagonist binding and local neuropathological features in the hippocampus in Alzheimer''s disease

[3H]PN200-110 binding sites were studied by means of quantitative autoradiography in hippocampal sections of patients with Alzheimer's disease and age-matched control subjects. Choline acetyltransferase activity, plaque, tangle and cell densities were also determined in the same tissue samples used for autoradiographic studies. Quantitative autoradiographic analysis of [3H]PN200-110 binding in control hippocampus revealed a heterogeneous pattern similar to that described in rodents, being particularly high in the dentate gyrus. In Alzheimer's disease, [3H]PN200-110 binding was markedly reduced in the subiculum (control = 9.85 +/- 1.41 pmol/g; Alzheimer = 3.41 +/- 0.54 pmol/g, mean +/- S.E.M., P less than 0.001). In the subiculum there was a disproportionate reduction of [3H]PN200-110 binding in comparison to cell loss in Alzheimer's disease. The activity of choline acetyltransferase in the hippocampus was markedly reduced in Alzheimer's disease (controls 6.9 +/- 1.0; Alzheimer 2.7 +/- 0.9 nmol/h/mg protein, mean +/- S.E.M., P less than 0.01). There was a strong correlation between choline acetyltransferase activity and [3H]PN200-110 binding in the subiculum. [3H]PN200-110 binding did not correlate with plaque density in the subiculum. The discrete reduction and preservation of [3H]PN200-110 binding in the present study is consistent with the pattern of selective cellular vulnerability in the hippocampal region in Alzheimer's disease.     

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.     

Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity

Ultrastructural studies of biopsied cortical tissue from the right frontal lobe of 8 patients with mild to moderate Alzheimer's disease (AD) revealed that the number of synapses in lamina III of Brodmann's area 9 was significantly decreased when compared with the number in age-matched control brains (n = 9; postmortem time, less than 13 hours). Further decline in synaptic number was seen in age-matched autopsied AD specimens. In the AD brains there was significant enlargement of the mean apposition length, which correlated with degree of synapse loss; as synapse density declined, synapse size increased. The enlargement of synapses, coupled with the decrease in synaptic number, allowed the total synaptic contact area per unit volume to remain stable in the patients who underwent biopsy. In autopsied subjects who had AD, there was no further enlargement of mean synaptic contact area. There was a significant correlation between synapse counts and scores on the Mini-Mental State examination in the patients who underwent biopsy. Lower mental status scores were associated with greater loss of synapses. Choline acetyltransferase activity was significantly decreased in the biopsied group and declined further in the autopsied specimens of AD. There was no relationship between choline acetyltransferase activity and scores on the Mini-Mental State examination or synapse number. There is evidence of neural plasticity in the AD neuropil; synaptic contact size increased in patients who had biopsy and possibly compensated for the numerical loss of synapses. But by end stage of the disease, the ability of the cortex to compensate was exceeded and both synapse number and synaptic contact area declined.(ABSTRACT TRUNCATED AT 250 WORDS)     

Risk of dementia in relatives of patients with Alzheimer's disease

Using a family history questionnaire, we investigated the occurrence of dementia among relatives of patients with a clinical diagnosis of Alzheimer's disease (AD) and among the relatives of age-matched control subjects. Cumulative lifetime risk of developing AD-type dementia was greater among relatives of AD probands and was consistent with an autosomal dominant genetic mode of transmission. Although the lifetime risk of AD-type dementia was similar among relatives of early-onset and late-onset AD probands, relatives of early-onset probands tended to have an earlier onset of dementia than did relatives of late-onset AD probands. This result raises the possibility that age at onset of dementia in AD may be genetically determined.     

Dopaminergic and cholinergic lesions in progressive supranuclear palsy

In 9 patients with progressive supranuclear palsy and in 27 controls, dopamine and homovanillic acid concentrations, choline acetyltransferase (CAT) activity, and the number of [3H]spiperone and [3H]quinuclidinyl benzilate binding sites were measured post mortem in the striatum (caudate nucleus, putamen, and nucleus accumbens), substantia innominata, and frontal cortex. Dopamine and homovanillic acid concentrations were reduced in the caudate nucleus and putamen but not in the nucleus accumbens or frontal cortex, indicating that the nigrostriatal dopaminergic system is lesioned in patients with progressive supranuclear palsy (as in those with Parkinson's disease) but not the mesocortical and mesolimbic dopaminergic systems, which are lesioned in parkinsonian patients. CAT activity and [3H]spiperone binding decreased in parallel fashion in all the structures. In the striatum, this suggests that the cholinergic neurons, which are target cells of the nigrostriatal system, also degenerate in this disease. This might explain the decrease in the number of dopamine receptors as well as the inefficacy of levodopa or anticholinergic therapy in these patients. The decrease in CAT activity in the substantia innominata and the frontal cortex indicates that the innominatocortical cholinergic system is lesioned in patients with progressive supranuclear palsy and may play a role in the intellectual deterioration observed. This lesion is also found in demented patients with Alzheimer's and Parkinson's diseases.     

Lack of cholinergic deficit in the neocortex in pick''s disease

1. 1. Choline acetyltransferase activity was decreased in the frontal cortex in Alzheimer's and Gerstmann-Straussler dementias but not in Pick's disease.

2. 2. Cortical somatostatin was only decreased in Alzheimer's dementia.

3. 3. Postsynaptic muscarinic binding sites appeared to be decreased in a subpopulation of Alzheimer's patients.

4. 4. Our data indicate that a loss of cholinergic innervation of the cortex is not common to all dementias.

THE NUCLEUS BASALIS IN ALZHEIMER'S DISEASE: CELL COUNTS AND CORTICAL BIOCHEMISTRY

The cell density in the Nucleus Basalis in six patients with clinical and histological evidence of Alzheimer's disease and reduced choline acetyltransferase activity in frontal and temporal cortex was found to be in approximately 50% of the cell count in five control subjects.     

Choline acetyltransferase and acetylcholinesterase abnormalities in senile dementia: Importance of biochemical measurements in human post-mortem brain specimens

Choline acetyltransferase and acetylcholinesterase have been assessed in human aging brains, in demented and agonal states. Choline acetyl transferase decreased during aging in normal brain when measured in the cerebral cortex. Choline acetyltransferase was also reduced in several other brain areas in patients with Alzheimer's disease and in one patient with Creutzfeldt-Jakob disease. Choline acetyltransferase was also reduced in bronchopneumonia and in some terminal conditions. On the contrary, the activity was not reduced in patients who died after cerebrovascular accidents. Acetylcholine esterase, although it followed the general trend of choline acetyltransferase, did not yield significant results.     

Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer's disease

Sodium-dependent, hemicholinium-sensitive choline transport was measured in purified synaptosomes prepared from fresh necropsy brain of patients with senile dementia of the Alzheimer type and from control subjects. Choline transport velocity was standardized in terms of the occluded lactate dehydrogenase activity of the various synaptosomal preparations, rather than in terms of the protein content, since this enzyme is more representative of the synaptosome content of the purified homogenates. A regional difference in high-affinity choline transport was observed in purified synaptosomes prepared from brains of mentally normal controls; the velocities of sodium-dependent and hemicholinium-sensitive choline uptake into synaptosomes from hippocampus were about twice as great as that into synaptosomes from frontal cortex, indicating a greater relative density of cholinergic innervation in the hippocampus. Hippocampal and neocortical cholinergic nerve cell endings, prepared as synaptosomes, from brains of patients with Alzheimer's disease, also accumulated choline by a high-affinity mechanism; however, the velocity of uptake into both brain areas was decreased in comparison with controls. Choline transport into synaptosomes from Alzheimer frontal cortex was reduced approximately 50%, while uptake into Alzheimer hippocampal synaptosomes represented only 20% of the control activity. The reduction in synaptosomal high-affinity choline transport in Alzheimer's disease could be indicative of degeneration of cholinergic nerve terminal boutons resulting from cholinergic nerve cell death, or could result from an overall decrease in the number of carrier sites per nerve terminal or in the carrier transport velocity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Choline acetyltransferase and acetylcholinesterase abnormalities in senile dementia: Importance of biochemical measurements in human post-mortem brain specimens

Choline acetyltransferase and acetylcholinesterase have been assessed in human aging brains, in demented and agonal states. Choline acetyl transferase decreased during aging in normal brain when measured in the cerebral cortex. Choline acetyltransferase was also reduced in several other brain areas in patients with Alzheimer's disease and in one patient with Creutzfeldt-Jakob disease. Choline acetyltransferase was also reduced in bronchopneumonia and in some terminal conditions. On the contrary, the activity was not reduced in patients who died after cerebrovascular accidents. Acetylcholine esterase, although it followed the general trend of choline acetyltransferase, did not yield significant results.

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Sommario L'attività degli enzimi colina-acetil-transferasi e acetil-colina-esterasi è stata studiata nell'encefalo umano durante l'invecchiamento, nella demenza e nelle patologie terminali. La colina-acetil-transferasi è risultata decrescere con l'età nella corteccia frontale e significativamente diminuita in varie regioni dell'encefalo di soggetti affetti da malattia di Alzheimer e di Creutzfeldt Jacob. Corrispondentemente l'attività della colinoacetil-transferasi è risultata significativamente compromessa anche nelle patologie terminali quali il coma e la broncopolmonite terminale. In contrasto a questi risultati nell'encefalo di soggetti deceduti per accidenti cerebrovascolari la attività enzimatica è risultata normale. In oltre l'attività della acetilcolina-esterasi non ha mostrato significative variazioni in alcuno dei gruppi studiati.

     

Cholinergic correlates of cognitive impairment in Parkinson''s disease: comparisons with Alzheimer''s disease.

Dementia in Parkinson's disease has previously been attributed to the presence in the cerebral cortex of Alzheimer-type neuropathological abnormalities. New evidence suggests, however, that dementia in this disease usually occurs in the absence of substantial Alzheimer-type changes in the cortex and may be related to abnormalities in the cortical cholinergic system. Thus, in Parkinsonian patients with dementia there were extensive reductions of choline acetyltransferase and less extensive reductions of acetylcholinesterase in all four cortical lobes. Choline acetyltransferase reductions in temporal neocortex correlated with the degree of mental impairment assessed by a test of memory and information but not with the extent of plaque or tangle formation. In Parkinson's but not Alzheimer's disease the decrease in neocortical (particularly temporal) choline acetyltransferase correlated with the number of neurons in the nucleus of Meynert suggesting that primary degeneration of these cholinergic neurons may be related, directly or indirectly, to declining cognitive function in Parkinson's disease.     

Amino acids, glutathione, and glutathione transferase activity in the brains of patients with Alzheimer's disease

We measured the contents of amino acids and related amino compounds in autopsied brain from 22 patients with Alzheimer's disease (AD) and in cortical biopsy specimens from 2 other patients. The diagnosis of AD was established neuropathologically in all 24 patients by the presence of both neurofibrillary tangles and neuritic plaques in neocortex. The mean contents of gamma-aminobutyric acid (GABA), and of the GABA dipeptide homocarnosine, were significantly reduced in frontal and occipital cortices and in hippocampus of the autopsied brains of AD patients compared to control patients without neurological disease. However, GABA contents were normal in frontal cortex in biopsy samples from 2 patients. Phosphoethanolamine contents were significantly reduced at autopsy in frontal and occipital cortex, and in the substantia innominata. We found no evidence of a deficiency of glutamate, aspartate, or taurine in AD brain, as has been claimed. Glutathione contents and glutathione transferase activities were normal in frontal cortex and substantia innominata. The mechanism of neuronal death in patients with AD is unlikely to involve either insufficient synthesis of glutathione or failure to conjugate free radicals with glutathione.     

Neuropeptides in Alzheimer type dementia

Five neuropeptides (cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP), somatostatin (SRIF), neurotensin (NT) and substance P (SP)) were measured in 14 brain areas (4 cortical areas, hippocampus, amygdala, 3 striatal areas, 2 thalamic areas and 3 subcortical areas-- septum, substantia innominata and hypothalamus) in 12 brains with neuropathologically confirmed Alzheimer type change and in 13 control brains. Choline acetyltransferase (CAT) activity was assessed in 6 of these areas. Levels of SRIF, but not those of the other peptides, were reduced in several cortical areas in Alzheimer-type dementia (ATD). The distribution and magnitude of the reduction in SRIF were less than that of CAT activity and the temporal cortex was the only region in which there was a significant relationship between CAT and SRIF deficits. Peptide levels were unchanged in hippocampus, amygdala, thalamus, hypothalamus and striatum (except for an increase in SP in the putamen). SRIF levels were increased in substantia innominata in ATD. NT and SRIF were significantly, and VIP and SP non-significantly, reduced in the septum in ATD. Thus, apart from these alterations in the septum, SRIF was the only neuropeptide for which major changes were identified and these did not follow either the pattern of neuropathological change (e.g. in amygdala and hippocampus) or of CAT deficits (e.g. in substantia innominata).     

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 (Km) of ChAT for choline were lower in the caudate nucleus and putamen than in other regions examined, whereas Km values for acetyl-CoA in these two regions were higher. Maximal velocities (Vmax) for the control subjects were higher in the caudate nucleus and putamen than in the other regions studied. Km values for choline of ATD patients were higher than those of control subjects in all regions except the amygdala and substantia innominata (innominate); however, Km values for acetyl-CoA of ATD patients were higher than those of control subjects only in the caudate nucleus, putamen and thalamus. Vmax 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 Km values, we have classified brain regions into 3 types: highly sensitive, somewhat sensitive or resistant to the pathological process of ATD.     

The distribution and origin of glutamate decarboxylase and choline acetyltransferase in ventral pallidum and other basal forebrain regions.

The distribution of choline acetyltransferase (ChAT) and glutamate decarboxylase (GAD), and the histochemical reaction for acetylcholinesterase have been studied in the basal forebrain and globus pallidus of unoperated rats and in rats with an electrolytic lesion of the nucleus accumbens. ChAT was highly concentrated in the substriatal region, the neostriatum and the lateral part of the rostral substantia innominata. The strongest intensity of staining for acetylcholinesterase was found in the substriatal grey and the neostriatum. Very high GAD activity was found in the substantia innominata, being even slightly higher than that in the pars reticulata of the substantia nigra. The lateral preoptic area, the bed nucleus of the stria terminalis and the globus pallidus also showed high activity of GAD. After lesions of the nucleus accumbens the activity of GAD decreased significantly in the substantia innominata and in a restricted part of the rostroventral globus pallidus, but not in the other regions studied. ChAT activity and acetylcholinesterase staining were unaffected in all regions. The results indicate that a dense GABAergic projection originates in the nucleus accumbens and terminates in the rostral substantia innominata and rostroventral part of the globus pallidus. The study gives neurochemical support to the suggestion that nucleus accumbens may be regarded as a ventral part of the neostriatum and that the rostral substantia innominata may be regarded as a ventral part of the globus pallidus.     

Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer's disease

Summary. Both monoamine oxidase (MAO) A and MAO B in the brain have been implicated in the etiology of Alzheimer's disease. MAO B is elevated in plaque-associated glia in Alzheimer brain. Elevations in MAO A in Alzheimer neurons have been linked to increases in neurotoxic metabolites and neuron loss. We investigated the relationship between cognitive function in Alzheimer patients and post-mortem prefrontal cortex MAO A and B activities. Prefrontal cortex tissue from 92 Alzheimer patients and 74 neurologically normal subjects was obtained at autopsy and analyzed for activities of MAO A and B by radioenzymatic methods. Mini Mental Status Exam was performed on Alzheimer patients within 1 year of death. Alzheimer brains were analyzed for Braak stage, tangles, plaques and choline acetyltransferase activity. Prefrontal cortex MAO B activity was significantly increased by 16% in Alzheimer patients versus normals, whereas MAO A activity was significantly decreased by 17% in these same patients. Neither MAO A nor MAO B activities correlated with cognitive function (MMSE score), choline acetyltransferase activity, plaques, neurofibrillary tangles, Braak stage, or age of disease onset in the Alzheimer patients. With increasing Alzheimer duration or increasing Braak stage, MMSE scores and choline acetyltransferase activity declined, but levels of MAO A and B in prefrontal cortex were unchanged. Patients in the upper quintile for MAO A or B activity did not differ significantly from those in the lowest quintile with respect to MMSE scores or age of Alzheimer disease onset. We conclude that the changes in MAO A and B in the prefrontal cortex occur very early in Alzheimer's disease and remain relatively constant as the disease progresses. Received December 16, 2002; accepted February 20, 2003 Published online April 22, 2003 Acknowledgements The authors wish to acknowledge the UCSD and Harvard Brain Banks for provision of prefrontal cortex samples. This work was supported by NIH grants AG5131, AG18440, AG10869 and RO1 (MH/NS31862-25). Authors' address: B. Kennedy, Ph.D., Department of Medicine, University of California, San Diego Medical Center, 200 W Arbor Dr., San Diego, CA 92103-8341, U.S.A., e-mail: bpkennedy@ucsd.edu     

Carnitine acetyltransferase activity in the human brain and its microvessels is decreased in Alzheimer's disease.

L-Carnitine and acetyl-L-carnitine facilitate mitochondrial beta-oxidation of fatty acids. In the brain, they may also have a role in acetylcholine synthesis. Carnitine acetyltransferase catalyzes the interchange between L-carnitine and acetyl-L-carnitine. Recently, acetyl-L-carnitine was reported to have a beneficial effect in patients with Alzheimer's disease. We therefore assessed carnitine acetyl-transferase activity in selected brain regions and in isolated cerebral microvessels obtained at autopsy from patients with Alzheimer's disease and from age-matched control subjects. We found a 25 to 40% decrease in carnitine acetyltransferase activity in patients with Alzheimer's disease, which attained statistical significance in most brain regions and in cerebral microvessels. These findings document another neurochemical abnormality in patients with Alzheimer's disease and provide a rationale for the use of acetyl-L-carnitine in the treatment of patients with Alzheimer's disease.