Alan N. Davison

Biochemical assessment of serotonergic and cholinergic dysfunction and cerebral atrophy in Alzheimer's disease.

Abstract: Markers of serotonin synapses in entire temporal lobe and frontal and temporal neocortex were examined for changes in Alzheimers disease by use of both neurosurgical and autopsy samples. Uptake of [3H]sero‐tonin, binding of [3H]imipramine, and content of indola‐mines were all significantly reduced, indicating that serotonin nerve terminals are affected. Binding of [3H]serotonin was also reduced, whereas that of [3H]qui‐nuclidinyl benzilate, [3H]muscimol, and [3H]dihydroal‐prenolol were unaltered. When the Alzheimers samples were subdivided according to age, the reduction in [3H]serotonin binding was a feature of only autopsy samples from younger patients. In contrast, presynaptic cholinergic activity was reduced in all groups of Alzheimers samples, including neurosurgical specimens. Five markers, thought to reflect cerebral atrophy, cytoplasm, nerve cell membrane, and neuronal perikarya were measured in the entire temporal lobe. In Alzheimers disease the reductions (mean 25%, range 20–35%) were thought to be too large to be due only to loss of structures associated with the presumed cholinergic perikarya in the basal forebrain and monoamine neurones in the brain stem.

Presynaptic Cholinergic Dysfunction in Patients with Dementia

Abstract: Indices of presynaptic cholinergic nerve endings were assayed in neocortical biopsy samples from patients with presenile dementia. For those patients in whom Alzheimers disease was histologically confirmed, [14C]acetylcholine synthesis, choline acetyltransferase activity and choline uptake were all found to be markedly reduced (at least 40%) below mean control values. The changes occurred in samples from both the frontal and temporal lobes and for [14C]acetylcholine synthesis the decrease was similar under conditions of high and low neuronal activity (as assessed by incubations in 31 mM and 5 mM K+ respectively). Samples from other demented patients, in whom the histological features of Alzheimers disease were not detected, produced values for all three biochemical parameters which were similar to controls. For the total group of patients with presenile dementia there were correlations between values for the three markers of presynaptic cholinergic nerve endings suggestive of a loss of functional activity at these sites in Alzheimers disease.

Accelerated ageing or selective neuronal loss as an important cause of dementia

Extensive biochemical analysis of whole temporal lobe from cases of dementia and controls suggests that Alzheimers disease is a primary degenerative nerve-cell disorder and not the result of accelerated ageing. There is selective loss of neocortical cholinergic neurones. Transmitter systems apart from the cholinergic system appears to be affected, but to a lesser extent, and there are no significant changes in the caudate nucleus. The change in cholinergic neurones has been confirmed in biopsy samples.

Alzheimer's disease: a correlative study.

In a study of 17 patients with histologically proven Alzheimers disease the relationship between psychological, pathological and chemical measures of disorder was examined. Severity of dementia, determined by mental test performance, correlated highly with pathological change in large cortical neurons (cell loss and reduction in nuclear and nucleolar volume and cytoplasmic RNA content), to a lesser extent with cortical senile plaque and neurofibrillary tangle frequency and reduction in acetylcholine (ACh) synthesis, and not with reduction in choline acetyltransferase (CAT) activity. A strongly significant relationship was demonstrated between cell loss and reductions in nuclear and nucleolar volume and cytoplasmic RNA content. Reduction in CAT activity and senile plaque frequency were significantly correlated, thereby linking changes in the sub-cortical projection system of the nucleus basalis with the cortical pathology. The pattern of correlations suggests that the dementia of Alzheimers disease is largely a reflection of the state of large cortical neurons, and it is argued that abnormalities in the latter may not be directly related to primary loss of cholinergic neurons in the subcortex.

Biochemical Evidence of Selective Nerve Cell Changes in the Normal Ageing Human and Rat Brain

Abstract: Atrophy with ageing of human whole brain, entire temporal lobe, and caudate nucleus was assessed in autopsy specimens, by biochemical techniques. Only the caudate nucleus showed changes. Markers for several neurotransmitter systems were also examined for changes with age. In neocortex and temporal lobe of human brain, small decreases were detected in markers of cholinergic nerve terminals, whereas a large decrease (79%) occurred in the caudate nucleus. Findings were similar in striatum from 3–33‐month‐old rats. No change occurred in binding of [3H]quinuclidinyl benzilate by human samples. Markers of serotonergic terminals were also unchanged in human and rat brain. By contrast, binding of [3H]lysergic acid diethylamide and [3H]serotonin was decreased (32–81%) in human neocortex and temporal lobe, but not in caudate nucleus. A 43% loss of a marker of γ‐aminobutyrate terminals occurred in human neocortex, while [3H]muscimol binding increased (179%). No changes were detected in markers of catecholamine synapses in temporal lobe or rat striatum. Hence, with human ageing there appears to be a loss of markers of γ‐aminobutyrate neurones intrinsic to neocortex and acetylcholine cells intrinsic to the caudate nucleus, as well as a change in postsynaptic serotonin receptors in neocortex. These losses are accompanied by relative preservation of markers of ascending projections from basal forebrain and brain stem.

Metabolic Processes in Alzheimer's Disease: Adenine Nucleotide Content and Production of 14CO2 from [U‐14C]Glucose In Vitro in Human Neocortex

Abstract: Samples of neocortex removed at diagnostic craniotomy from patients with Alzheimers disease and incubated in vitro showed an increased production of 14CO2 from [U‐14C]glucose compared with neurosurgical controls. This was a feature of incubations in the presence of both 5 mM K+ (142% control) and 31 mM K + (126%). Specific labelling of the amino acid pool was unaltered, suggesting that the apparent increase of CO2 production was not merely a reflection of changes in dilution of the radiolabel from glucose. The content of adenine nucleotides was significantly less than control values in the tissue from patients with Alzheimers disease after in vitro incubations but the adenylate energy charge was unchanged, indicating that normal energy metabolism was not grossly impaired in these preparations.

The effects of cadmium, manganese and aluminium on sodium-potassium-activated and magnesium-activated adenosine triphosphatase activity and choline uptake in rat brain synaptosomes

The effects of Cd2+, Mn2+ and Al3+ on rat brain synaptosomal sodium-potassium-activated and magnesium-activated adenosine triphosphatase (Na-K-ATPase and Mg-ATPase) activity and choline uptake were studied. All three types of metal ions inhibited Na-K-ATPase activity more markedly than Mg-ATPase activity. The rank order of inhibition of Na-K-ATPase was: Cd2+ (ic50 = 5.4 μM) > Mn2+ (ic50 = 955 μm) > Al3+ (ic50 = 8.3 mM). The rank order of inhibition of Mg- was:Cd2+ (ic50 = 316 μM > Mn2+ (ic50 = 5.5 mM > Al3+ (ic50 = 21.9 mM). Al3+ was most potent in inhibiting synaptosomal choline uptake (ic50 = 24μM in the absence of Ca2+ and 123 μ.M in the presence of 1 mM Ca2+). Cd2+ (ic50 = 363 μM) was a more effective inhibitor of choline uptake than Mn2+(ic50 = 1.2−1.5 mM) . The presence of 1 mM Ca2+ did not alter choline uptake, nor did it antagonize the inhibitory actions of the three metals. Our observations that Cd2+ and Al3+ inhibited synaptosomal choline uptake, but did not show parallel inhibitory effects on Na-K-ATPase activity directly contradicts the ionic gradient hypothesis. These results are also discussed in relation to the in vivo neurotoxicity of cadmium, manganese and aluminium.

Amino acid release from biopsy samples of temporal neocortex from patients with Alzheimer's disease

Tissue prisms prepared from neurosurgical samples of temporal neocortex of Alzheimer and control patients, upon depolarization preferentially released aspartate, glutamate and gamma-aminobutyrate (GABA). The Alzheimer and control samples did not significantly differ in the pattern of amino acid release, although acetylcholine synthesis by the Alzheimer tissue prisms was greatly reduced. There was no correlation between the efflux of any amino and acetylcholine synthesis. These observations suggest that in Alzheimers disease there are no major changes in the extracellular concentrations of these putative amino acid transmitters.

Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia.

Concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy indoleacetic acid (5-HIAA) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) from control subjects and patients of both presenile and senile age with histologically verified Alzheimers dementia. CSF HVA increased with age in control but not in Alzheimer patients. HVA and 5-HIAA in the CSF of presenile Alzheimer patients was lower than that of age matched control subjects.

Immunosuppression by cyclosporin a of experimental allergic encephalomyelitis

Cyclosporin A (CsA), an immunosuppressant which acts selectively on antigen-responding T cells, was tried in the treatment of experimental allergic encephalomyelitis (EAE). The drug was highly effective in preventing the appearance of clinical and pathological signs of EAE in rats, guinea pigs and monkeys. Treatment of the established disease also reduced the incidence and severity of symptoms, and significantly reduced the number of inflammatory lesions in the central nervous system.