Significance of neurotransmitter abnormalities in Alzheimer's disease.
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Alzheimer Disease↗
Biomedical subjects
R Katzman
Publications and source records attributed to R Katzman.
Differential diagnosis of dementing illnesses.
Dementia is a symptom complex that may occur in over 60 disorders. The importance of the mental status test in the diagnosis of dementia is emphasized. A systemic approach to the differential diagnosis of the disorders that produce dementia is described.
Aged↗
Neuronotrophic factors: effects on central cholinergic regeneration in vivo.
To determine if neurotrophic factors (NTFs) which either support the survival (CNTF) or promote neuritic outgrowth (PNPF) of peripheral cholinergic neurons in vitro affect central cholinergic regeneration in vivo, NTFs were administered intracerebrally to rats after injury to septohippocampal fibers. Choline acetyltransferase activity within intrahippocampal iris implants was used as an index of cholinergic innervation. CNTF stimulated cholinergic sprouting while PNPF was ineffective under our experimental conditions, suggesting that the effects of other NTFs in vivo may be mediated by enhanced neuronal survival after injury rather than increased axonal sprouting.
Animals↗
Progressive dementia, visual deficits, amyotrophy, and microinfarcts.
Data from three patients and 22 previously reported cases suggest that cerebral microinfarction causes a recognizable clinical syndrome. All cases present with stroke, followed by progressive dementia and often with visual field deficits, peripheral vascular disease, and signs of motor neuron dysfunction. The average age at onset is 45, and most patients have been men. Many patients have had valvular or ischemic heart disease; in one of our cases, mitral stenosis caused embolic microinfarcts.
Adult↗
Enhancement of central cholinergic sprouting by prior injury: correlation with endogenous trophic content of hippocampus.
Injury to neural tissue elicits the release of neurotrophic substances which support the survival of cultured cholinergic neurons. The aim of the present report was to determine the effect of prior hippocampal injury on the sprouting of mature intrinsic cholinergic septal afferents in vivo. Levels of choline acetyltransferase (CAT) in intrahippocampal iris implants were used as an index of cholinergic regeneration. The results show that prelesioning the hippocampus 1 week prior to insertion of the iris increased CAT levels of implants left for 8 days in situ. Levels of iris CAT were correlated with the trophic content of the surrounding hippocampal tissue. These observations suggest that endogenous trophic factors released as a consequence of neural injury facilitate cholinergic sprouting in vivo.
Animals↗
Acquired immune deficiency syndrome and multiple tract degeneration in a homosexual man.
A 35-year-old homosexual man with acquired immune deficiency syndrome developed progressive dementia and spastic quadriparesis over a two-month period. Severe symmetrical, bilateral degeneration of the corticospinal and frontopontine fibers and cerebellar white matter were found postmortem. Several glial nodules in the brainstem and cerebellum suggested "smoldering" brainstem encephalitis. The possible association of the adenovirus that was isolated from the patient's cerebrospinal fluid to these obscure changes in the central nervous system is discussed.
Acquired Immunodeficiency Syndrome↗
Dementia and motor neuron disease: morphometric, biochemical, and Golgi studies.
In three patients dementia without neurofibrillary tangles or Pick bodies antedated amyotrophy by several years. The motor neuron disorder in two patients was characterized by terminal bulbar symptoms; in one it was similar to classic amyotrophic lateral sclerosis. In two patients, quantitative studies of selected regions of the cortex using a computerized image analyzer disclosed, as in patients with senile dementia of Alzheimer type, a marked reduction in the number of neurons, especially those larger than 90 mu 2. The findings differed from those in Alzheimer dementia, however, in that the cells in the substantia innominata were not reduced and the levels of choline acetyltransferase and somatostatin-like immunoreactivity, determined in one patient, were within normal limits. A variable degree of sponginess of the upper layers of the cortex was attributed to attrition of pyramidal cell dendrites, observed in the one patient in whom Golgi study was successful. Because of severe degeneration of the substantia nigra in all three, the disease in these patients may represent a subset of motor neuron disease or a multisystem atrophy.
Alzheimer Disease↗
Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
Alzheimer Disease↗
Heart conditioned medium elicits post-lesion muscarinic receptor recovery in vivo.
Intraseptal administration of heart conditioned medium (HCM) stimulates the growth of injured cholinergic fibers into iris implants placed in the anterodorsal hippocampus. The aims of the present report were to monitor muscarinic cholinergic receptor concentrations during denervation and central innervation of the peripheral tissue targets, and to evaluate the effect of HCM on these changes. For 0, 4, 8, 16 and 28 days after mechanical injury to septohippocampal axons, animals received either intraseptal injections of HCM or control vehicle. Binding of [3H]quinuclidinylbenzilate ([3H]QNB) within iris implants was used as an index of cholinergic muscarinic receptor concentration. The results indicate that within the iris implants: (1) a dramatic drop in the number of muscarinic receptors is observed 4 days after denervation; (2) under control conditions, central cholinergic innervation is not associated with muscarinic receptor recovery; and (3) after administration of HCM, muscarinic receptor levels begin to increase within two weeks and approach the pre-lesion endogenous concentration following 28 days of treatment. These results support the hypothesis that trophic factors may facilitate the restoration of effective, appropriate connections between nerve fibers and their targets.
Animals↗
Senile dementia of the Alzheimer type.
The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and paleocortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.
Aged↗
Validation of a short Orientation-Memory-Concentration Test of cognitive impairment.
A 6-item Orientation-Memory-Concentration Test has been validated as a measure of cognitive impairment. This test predicted the scores on a validated 26-item mental status questionnaire of two patient groups in a skilled nursing home, patients in a health-related facility, and in a senior citizens' center. There was a positive correlation between scores on the 6-item test and plaque counts obtained from the cerebral cortex of 38 subjects at autopsy. This test, which is easily administered by a nonphysician, has been shown to discriminate among mild, moderate, and severe cognitive deficits.
Aged↗
An electron microscope autoradiographic study of regenerating locus coeruleus fibers into iris tissue implants in the rat mesencephalon.
Following interruption, fibers from the locus coeruleus have been shown to undergo axonal regeneration and invade peripheral tissue implants in the rat brain. The aim of the present study was to analyze the ultrastructural features of this phenomenon using electron microscope autoradiography. For this, iris tissue implants were inserted in the region of the dorsal tegmental bundle (DTB) in the mesencephalon of unilaterally sympathectomized rats. Approximately 2 weeks later, rats were injected with [3H]-leucine in the ipsilateral locus coeruleus and sacrificed 2 days later. The tissue was prepared for EM autoradiography and studied after an incubation period of at least 12 weeks. The results showed that regenerating fibers from the locus coeruleus were most dense in regions of implant proximal to the DTB. Within the implants, less than one-half of regenerating axons present were labeled and, hence, of locus coeruleus origin. The labeled fibers were characteristically thin and unmyelinated. At this relatively short survival time, there was no evidence that the regenerating locus coeruleus axons formed synaptic specializations or contacts with the surrounding iris neuropil. Thus, while these observations confirm previous reports describing the regenerative capacity of central monoaminergic axons, they fail to provide anatomical evidence of the establishment of functional interactions between incoming fibers and the target tissue.
Afferent Pathways↗
Intrusions as a sign of Alzheimer dementia: chemical and pathological verification.
Word intrusions, a behavioral abnormality previously observed in experimental subjects receiving anticholinergic medication as well as in patients with Alzheimer dementia (Alz), were studied as a diagnostic indicator of Alz in 29 elderly nursing home residents who later came to autopsy. Those who intruded words from one portion of a mental status test to another tended to have low levels of choline acetyltransferase in the cerebral cortex (median, 104.33,p less than 0.05) and large numbers of cortical senile plaques (median, 16.0,p less than 0.01). Immediate perseverations and "guesses" on a memory test were not counted. In another group of 38 patients referred for clinical neurological examination for dementia, intrusions were associated with Alz in 84% of those who exhibited them and identified 90% of patients with this presumptive diagnosis. Word intrusion appears sufficiently characteristic of Alz to be helpful diagnostically. The association of this behavioral phenomenon with low choline acetyltransferase levels and large numbers of senile plaques suggests that these changes may be important in producing the characteristic behavioral deterioration of Alz.
Adult↗
Biopsy-proved Alzheimer disease presenting as a right parietal lobe syndrome.
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Alzheimer Disease↗
Dopamine mechanisms in the subthalamic nucleus and possible relationship to hemiballismus and other movement disorders.
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Adenylyl Cyclases↗
Heart conditioned medium promotes central cholinergic regeneration in vivo.
The aim of the present study was to evaluate the effect of a proposed cholinergic growth factor, heart conditioned medium (HCM), on the regeneration of the cholinergic septo-hippocampal pathway in rats. At 0, 4, 8 and 16 days after mechanical injury to septo-hippocampal axons, animals received either repeated intraseptal injections of HCM or control vehicles. Recovery of choline acetyltransferase (CAT) activity in iris implants placed in the hippocampus was used as an index of cholinergic regeneration. The results indicate that CAT activity in iris implants from animals receiving HCM was significantly greater than in control implants. Thus, this is the first report of the in vivo activity of heart conditioned medium as a cholinergic growth factor.
Animals↗
Immunological studies in senile dementia of the Alzheimer type: evidence for enhanced suppressor cell activity.
To examine immunological variables in senile dementia of the Alzheimer type (SDAT), we compared SDAT patients with elderly and young controls with regard to concanavalin A (Con A)-induced suppression, lymphocyte proliferation, interferon production, and serum immunoglobulin levels. The results showed exaggerated Con A suppression and reduced lymphocyte proliferation in SDAT patients compared to elderly control subjects. Interferon production after stimulation by Con A and immunoglobulin levels did not differ between SDAT and elderly control subjects. The results suggest impaired immunoregulatory mechanisms in patients with SDAT that may be related to the cause or course of SDAT. Alternatively, these immunological changes may be secondary to pathological changes in the central nervous system.
Adult↗