Imbalance of a serotonergic system in frontotemporal dementia: implication for pharmacotherapy.

RATIONALE: Information is sparse on neurotransmitter deficiencies in frontotemporal dementia (FTD), in particular with reference to distinct histological subgroups and Alzheimer's disease (AD). OBJECTIVES: To evaluate in FTD with the major histologies, and compare with AD and controls, neurotransmission indices, as these may help in developing treatment. MATERIALS AND METHODS: Post-mortem grey matter from Brodmann Area 21, 9 and 7 of 51 brains was assayed for ten neurochemical parameters indexing neurotransmission. Repeated measures analyses of variance were carried out for each parameter comparing groups (FTD vs AD vs control) at each anatomical site. RESULTS: In FTD only the indices of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, serotonin (5-HT)(1A) and 5-HT(2A) receptors were significantly reduced from control values. Of the ten parameters only 5-HT(1A) receptors showed significant group x site interaction. This reflected disproportionate reduction in frontal and temporal compared to parietal cortex. In FTD three other receptors (muscarinic, M(1), N-methyl-D: -aspartate, NMDA, and kainate), choline acetyltransferase (ChAT) activity, 5-HT and 5-hydroxyindoleacetic acid content and 5-HT reuptake site values were not significantly reduced from control values. Only 5-HT, 5-HT reuptake site and ChAT values were significantly higher in FTD than AD. NMDA receptor and ChAT values were significantly reduced from control only in AD. CONCLUSIONS: Neurochemical results in FTD indicate degeneration and loss of pyramidal neurones in frontotemporal neocortex, yet 5-HT afferents and 5-HT concentration, which are inhibitory on pyramidal neurones, were relatively preserved. This could lead to an excess of extraneural 5-HT causing underactivity of surviving pyramidal neurones. Pharmacotherapy with a 5-HT(1A) receptor antagonist may be indicated.

Neurochemical features of frontotemporal dementia.

This study examines neurochemical measures of cholinergic, serotonergic and glutamatergic innervation in frontal temporal and parietal cerebral cortex from 16 subjects with frontotemporal dementia (FTD) including 10 subjects with Pick pathology and 6 with dementia of frontal lobe type (DFT) together with 9 subjects with Alzheimer's disease, and 28 matched controls. In both forms of FTD there was not evidence of any cholinergic abnormality, unlike the situation in AD. Serotonin receptors were lost from frontal and temporal cortex in FTD and from temporal and parietal cortex in AD. In FTD there was no loss of kainate receptors but loss of AMPA receptors from both temporal and frontal lobes. Loss of AMPA receptors differentiated Pick-type FTD from DFT. These results are interpreted to indicate selective losses of subpopulations of cortical pyramidal neurones.

Neurochemical correlates of dementia.

Studies of the neurochemical pathology of AD have indicated that early in the course of the disease, abnormalities of relatively few neurotransmitters are obvious. The most reliable and consistent changes are those seen in the cholinergic innervation of the cortex and the cortical pyramidal neurones. However, by the time of death there is usually considerable involvement of other neurones.

Postmortem brains reveal similar but not identical amyloid precursor protein-like immunoreactivity in Alzheimer compared with other dementias.

Concentrations of amyloid precursor protein (APP)-like immunoreactivity (APPLIR) have been determined by Western blotting in a soluble fraction and two membrane fractions of two areas of brain cortex from patients with Alzheimer's disease (AD) and other dementias. There were no significant differences between AD and other cases in species with the Kunitz protease inhibitor domain. However, the total soluble APPLIR was higher in AD and it was hypothesized that this relates to cholinergic hypoactivity.

Brain membrane serine protease activity in human cortex compared with rat: implication for Alzheimer's disease.

Cerebral cortex from humans and rats was extracted sequentially with detergent-containing and low-ionic-strength buffers. The resulting pellet was extracted with detergent/high-ionic-strength buffer to yield a soluble enzyme preparation. This was incubated with substrate prepared from rat cerebral cortical membranes containing amyloid precursor protein-like immunoreactivity (APPLIR) of 116 kD approximate apparent molecular mass. The effectiveness of various enzyme preparations to degrade APPLIR was: routine-post-mortem (pm)-delay human samples > rat pup > short-pm-delay human samples >> adult rat. In incubations with human samples only a 100-kD product accumulated. The activity in human brain was inhibited by phenylmethylsulphonylfluoride, insensitive to Ca2+, correlated with pyramidal neurone numbers but not those of astrocytes and was not significantly higher in Alzheimer's disease compared with controls. These data are discussed in terms of other approaches for studying proteolytic activity to explain the deposition of beta-amyloid protein in this disease.

The effects of Alzheimer's disease, other dementias, and premortem course on beta-amyloid precursor protein messenger RNA in frontal cortex.

There are conflicting data regarding alterations in beta-amyloid precursor protein (APP) mRNAs in Alzheimer's disease (AD). This may be due partly to variables such as agonal state and choice of control group. We have used in situ hybridization histochemistry to study expression of APP mRNAs, with and without the domain encoding the Kunitz protease inhibitor, in a way that overcomes some of the limitations of the current data. Tissue from frontal cortex was collected at rapid autopsy from patients with AD or other cognitive impairments whose terminal phase was prospectively assessed. There were three main findings. Firstly, the amount of APP mRNAs correlated strongly with glutamate decarboxylase activity and was reduced in association with terminal pyrexia. These correlations suggest that agonal state affects APP mRNA and, therefore, that differences in premortem course may contribute to the varying changes in APP transcript abundance reported in AD. Secondly, a reduction of both forms of APP mRNA, normalized to polyadenylated mRNA, was found in AD compared with normal controls and with non-AD dementias. This supports findings that the APP-related pathology of AD is not due to overexpression of APP mRNA or an altered proportion of Kunitz protease inhibitor-containing isoforms. Thirdly, the amount of APP mRNA correlated inversely with that of heat-shock protein (hsx70) mRNA. This relationship was unexpected given current theories that APP expression occurs as part of a stress response, and suggests that other factors predominate in determining neocortical APP mRNA content in neurodegenerative disorders.

beta-Amyloid precursor protein isoforms show correlations with neurones but not with glia of demented subjects.

Post-mortem cerebral cortex from 15 demented patients was specially collected to minimise autolysis and two membrane fractions and one soluble fraction were quantitatively examined for the major species of beta-amyloid precursor protein (APP) of high apparent molecular mass (> or = 80 kDa) together with the major mRNA species encoding APP isoforms. The number of pyramidal neurones and astrocytes, putative biochemical indices of interneurones and pyramidal neurones, and choline acetyl transferase activity were also determined. Multiple regression analysis has been used to investigate intercorrelations of APP species with biochemical and morphometric measures, free of any effects of confounding demographic variables. Subjects with Alzheimer's disease showed a loss of cholinergic activity and D-aspartate uptake compared with patients with other causes of dementia. The major finding of the study is that measures of neurones rather than astrocytes most closely correlate with the concentration of APP. Pyramidal cell numbers were positively correlated with mRNA for APP695. APP in the soluble fraction showed a negative correlation with pyramidal cell numbers and cholinergic activity. These results indicate that neurones within the cerebral cortex are the major source of APP, and that secretion of APP is dependent upon cortical pyramidal neuronal activity and cholinergic activity.

An aspect of Alzheimer neuropathology after suicide transport damage.

Concentrations of APP-like immunoreactivity have been determined by western blotting in a soluble fraction and two membrane fractions of brain cortex from demented patients (14 with Alzheimer's disease and 8 with other diagnoses). The concentration of APP in the soluble fraction correlated with the number of pyramidal neurones but not astrocytes or indices of interneurones. Experimental lesions in rats and quantitative autoradiography were used to investigate the cellular localisation of receptors. Lesions were produced by intrastriatal or intracortical injections of volkensin to destroy corticofugal and corticortical pyramidal neurons respectively. Volkensin treatment caused significant loss of pyramidal neurones which was accompanied by reduced binding to muscarinic cholinergic m1 receptors. [3H] 8-OH-DPAT (serotonin 1A receptors) binding was reduced only following intrastriatal volkensin. Results from the human and rat investigations are discussed in terms of the biology of cortical pyramidal neurones and drugs for the treatment of Alzheimer's disease.

Neurotransmitters and second messengers in aging and Alzheimer's disease.

A substantial loss of cortical cholinergic nerve endings, along with a much more circumscribed cortical degeneration of pyramidal neurons, almost certainly causes glutamatergic hypoactivity in live Alzheimer's patients. These selective pathologies are discussed in terms of therapy. An additional effect of some proposed treatments is emerging as there is evidence that processing pathways for beta-amyloid precursor proteins in cortical pyramidal neurons, a target cell for acetylcholine, are affected by neuronal activity.

Preliminary neurochemical findings in non-Alzheimer dementia due to lobar atrophy.

Non-Alzheimer's dementia due to lobar atrophy had choline acetyltransferase activities comparable with control rather than Alzheimer's disease values, based on 3 autopsy proven cases on Pick's disease and biopsies from 3 examples of dementia of frontal lobe type. Muscarinic cholinergic receptors were relatively spared only in Alzheimer's disease. Serotonin receptors were markedly reduced (based on Pick cases) whereas measures that reflected presynaptic serotonergic activity were either not affected or increased. Cerebrospinal fluid and brain tissue measurements suggested that inhibitory interneurones and dopamine release were relatively spared. There was no in vitro evidence of hypometabolism.

Heat shock protein (hsx70) mRNA expression in human brain: effects of neurodegenerative disease and agonal state.

Heat shock proteins (hsps) are involved in the response by cells to stress including hyperthermia, hypoxia and injury. Previous work has demonstrated expression of messenger RNA (mRNA) encoding 70 kDa hsps (hsp70) in animal brain in response to stimuli such as these. We have used in situ hybridization histochemistry to assess the distribution and quantity of a specific hsp70 (called hsx70) mRNA in frontal cortex and cerebellum from normal and demented patients whose pre-mortem course had been documented. In cortex, hsx70 mRNA was concentrated over pia mater and glia but was also present over neurons; in cerebellum, hsx70 mRNA was prominent over granule cells but absent from Purkinje cells. Detection of hsx70 mRNA did not correlate with pre-mortem factors such as pyrexia or coma. Increased hsx70 mRNA was found in frontal cortex white matter in Alzheimer's disease and in a mixed group of other neurodegenerative disorders. No changes occurred in cerebellum. The data provide further evidence for altered hsp gene expression in dementia, and support the existence of a stress response occurring in brains affected by such diseases.

Antemortem measurements of neurotransmission: possible implications for pharmacotherapy of Alzheimer's disease and depression.

Aspartic acid, 5-hydroxyindoleacetic acid, glutamic acid, homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol was determined in samples of ventricular fluid from 82 subjects. Laminar distribution of the total number (Bmax value) of serotonin 1A receptors was determined on seven neurosurgical samples of neocortex. Apart from an association in a small subgroup of subjects between homovanillate concentration and corticosteroid medication, no complicating influences of treatment preceding operation were found. The content of the serotonin metabolite alone was significantly reduced in intractable depressive illness (bipolar and major depressive disorders) compared with neurological conditions subdivided into Alzheimer's disease, other dementias and other conditions. There was no other significant difference between these groups for the compounds measured. The total number of serotonin 1A receptors was highest in the superficial layers, being considerably higher than in the rat, irrespective of cortical layer. This part of the study indicated that these receptors are important for regulating activity of human corticocortical glutamatergic neurons. The results are discussed in relation to treating depression with serotonergic agents and targeting corticocortical glutamatergic neurons as well as acetylcholine in Alzheimer's disease.

Serotonergic pathology is not widespread in Alzheimer patients without prominent aggressive symptoms.

Behavioural symptoms of Alzheimer's disease, such as aggression, may determine the care patients required. Most postmortem neurochemical studies have been of institutionalized patients and conclusions drawn from these may not be valid for all patients. We have shown that serotonin 2 receptors are not lost from 12 of the 13 areas of cerebral cortex examined in the patients assessed to be free of aggressive symptoms. This has been interpreted as representing the relative preservation of cortical interneurones. In contrast choline acetyltransferase activity was reduced in all areas whereas serotonin content was reduced in only 2 of the 4 areas examined.