F. Owen

Pick's disease is associated with mutations in the tau gene

Recently, mutations within the tau gene have been associated with some familial forms of frontotemporal dementia. To investigate whether tau gene mutations are also associated with Picks disease, we analyzed the tau gene in 30 cases of pathologically confirmed Picks disease. Two coding mutations were identified in separate cases of Picks disease. A glycine‐to‐arginine mutation at codon 389 was detected in 1 case and a lysine‐to‐threonine mutation at codon 257 was identified in another. Analysis of dephosphorylated tau from the brain of the patient with the codon 389 mutation revealed a prominent band representing tau, with four microtubule‐binding domains and no amino terminal inserts. This is in contrast to Picks disease without any tau gene mutations, which consist of tau with mainly three microtubule‐binding domains and only a trace of tau, with four microtubule‐binding domains. Functional analysis of tau with these two mutations demonstrated a reduced ability of tau to promote microtubule assembly. Surprisingly, these mutations increased taus susceptibility to calpain I digestion, suggesting that this feature may be related to the formation of a Pick type of histology. Moreover, these data suggest that Picks disease is not a separate entity but part of the frontotemporal dementia disease spectrum. Ann Neurol 2000;48:859–867

Studies on possible mechanisms of action of electroconvulsive therapy; effects of repeated electrically induced seizures on rat brain receptors for monoamines and other neurotransmitters

There is evidence that repeated electroconvulsive shocks (ECS) in rats potentiate dopamine (DA)-, serotonin (5HT)- and α-noradrenergic (α-NA)-mediated drug-induced behaviour and reduce opiate-induced behaviours. These studies suggest changes at the level of the receptor or beyond. However, high affinity in vitro 3H-ligand binding studies in brain membranes from ECS-treated control rats failed to demonstrate generalized ECS-induced changes in 5HT, DA, α-NA or opiate receptor binding. Binding of the β-receptor ligand dihydroalprenolol (3H-DHA) was significantly reduced in ECS-treated rat brain membranes. This may be secondary to effects on NA neurones since ECS-induced reduction of 3H-DHA binding did not occur in animals with 6-hydroxydopamine-induced depletion of cortical noradrenaline. In conjunction with other studies, the results suggest that electroconvulsive therapy may have a noradrenergic mechanism of action.

Diagnosis of Gerstmann-Straussler syndrome in familial dementia with prion protein gene analysis.

The polymerase chain reaction was used to screen DNA samples from 12 unrelated individuals with various familial dementias and ataxias for mutation in part of the prion protein (PrP) gene, an abnormality that occurs in individuals with the spongiform encephalopathies, Gerstmann-Sträussler syndrome (GSS) and Creutzfeldt-Jakob disease. 2 members of a family in whom GSS was not previously suspected had a 0.15 kb insertion of similar size to that found in another kindred with pathologically proven spongiform encephalopathy. GSS may be more common than is currently realised; PrP gene analysis is potentially useful for diagnosis and genetic counselling in familial dementias and ataxias.

[3H]R05-4864 and [3H]flunitrazepam binding in kainate-lesioned rat striatum and in temporal cortex of brains from patients with senile dementia of the Alzheimer type

In agreement with other workers we report increased [3H]R05-4864 binding in kainate-lesioned rat striatum. [3H]R05-4864 binding, a possible glial marker, was also increased in temporal cortex obtained post-mortem from patients with Alzheimers disease. [3H]Flunitrazepam binding was decreased in these brain samples, possibly indicative of neuronal cell loss. It is suggested that the poor binding characteristics of [3H]R05-4864 in human brain samples may limit its usefulness in assessing gliosis.

Abnormal involuntary movements in schizophrenia: are they related to the disease process or its treatment? Are they associated with changes in dopamine receptors?

Abnormal involuntary movements indistinguishable from those now described as tardive dyskinesia were reported in schizophrenic patients by Kraepelin long before the introduction of neuroleptic drugs. Two large surveys of mental hospital patients including patients who had never received neuroleptics also revealed involuntary movements; indeed, the incidence was not substantially different from that in drug-treated patients. This fact casts doubt on the widely held assumption that these movements are persistent and irreversible effects of neuroleptic drugs. In an animal model of dyskinesia, abnormal movements were seen after administration of a phenothiazine and a thioxanthene but not after haloperidol. The syndrome appeared to be unrelated to dopamine receptor blockade or to changes in dopamine receptors. In postmortem striatal tissue from patients with schizophrenia, ligand binding to D-1 and D-2 dopamine receptors was not increased in patients who had been found to have abnormal involuntary movements in comparison with those who did not have such movements; as previously reported, binding to D-2 receptors was increased in patients with schizophrenia in comparison with controls. It is concluded that dyskinetic changes occur as a consequence of the process of schizophrenia and perhaps other diseases. Whether or not persistent and irreversible changes can be caused either in animals or humans by neuroleptic administration has yet to be clearly established. Whether they occur as a manifestation of the disease process or a consequence of drug administration, such dyskinesias are unassociated with changes in D-1 or D-2 receptors.

Preferential deposition of amyloid β protein (Aβ) in the form Aβ40 in Alzheimer's disease is associated with a gene dosage effect of the apolipoprotein E E4 allele

Abstract The effect of apolipoprotein E (ApoE) genotype on the deposition of amyloid β protein (A β ) was examined in 54 patients with Alzheimers disease. No difference in the amount of A β deposited as A β 42(43) was seen between genotype groups with no, one or two E4 alleles. However, the amount of A β 40 deposited increased according to the copy number of E4 alleles with patients possessing one E4 allele containing more than twice, and those with two E4 alleles, four times, the amount of A β 40 in their brains compared to patients without an E4 allele. The increase in total A β deposited within the tissue (i.e. A β 40 plus A β 42(43) loads) in the presence of an E4 allele is therefore due entirely to an enhanced deposition of A β 40 . These data are consistent with the suggestion that the presence of E4 within pre-existing A β 42(43) containing plaques may lower the threshold to fibrilization of A β 40 thereby promoting its subsequent deposition. Thus, although the total amount of A β initially deposited in the brain as A β 42(43) is not affected by the binding of any one particular ApoE isoform this does influence the subsequent maturation of plaques with a greater proportion transforming into A β 40 containing cored plaques when the E4 isoform is present.

Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration

Abstract Rats were treated with haloperidol (1.5mg/kg/day) in their drinking water for 9 months, with or without a subsequent withdrawal period of 7–10 days. Compared with controls, spontaneous locomotion and apomorphine-induced stereotypy were reduced in rats maintained on haloperidol whereas both behaviours were increased after the withdrawal period. Maximum specific 3 H-spiperone binding to striatal membrane preparations was increased (about 65%) in drug-treated rats with or without a withdrawal period. The dissociation constant for 3 H-spiperone binding was significantly increased only in those rats maintained on haloperidol with no withdrawal period. The increase in maximum binding of 3 H-spiperone was larger than that reported after less prolonged administration of neuroleptics. The size of the change should be taken into account in assessing the increased ligand binding reported in post-mortem brains of schizophrenics.

A dementing illness associated with a novel insertion in the prion protein gene

Following our previous report of an 144-bp insertion in the open reading frame of the prion protein (PrP) gene, we have now identified a larger, 216-bp, insertion in the gene. The insertion which is in frame encodes 9 extra octapeptide repeat sequences in addition to the 5 repeats normally present and represents the largest insertion so far detected in the PrP gene.

Reduced high affinity cholecystokinin binding in hippocampus and frontal cortex of schizophrenic patients

Cholecystokinin (CCK) binding sites were assessed in post-mortem brain membrane preparations from controls and schizophrenic patients. 125I-BH CCK33 specific binding was reduced by 40% (p less than 0.02) in the hippocampus and by 20% (p less than 0.01) in the frontal cortex of schizophrenic patients compared with controls. There were no differences in 125I-BH CCK33 binding between the two groups in the amygdala, temporal cortex or caudate nucleus.

GAMMA-AMINOBUTYRIC ACID IN THE BRAIN IN SCHIZOPHRENIA

SIR,-Focal brain lesions and cerebral granulomas associated with central-nervous-system cryptococcis 1,2 are nothing like as common as cryptococcal meningitis.2,3 Cryptococcal meningitis can be successfully managed by chemotherapy alone, but no intracranial focal lesion associated with cryptococcosis has been reported to be cured in this way.3 Successful surgical excision, with or without subsequent chemotherapy, has been described but the mortality-rate may exceed 50% 1, 4-8. We have seen a patient with cryptococcal meningitis and an intracranial focal lesion detected by computerised axid tomography (C.A.T.). After treatment with amphotericin B without surgery the focal lesion disappeared. A 61-year-old male alcoholic was brought to the Wadsworth