Measurement of gray and white matter atrophy in dementia with Lewy bodies using diffeomorphic anatomic registration through exponentiated lie algebra: A comparison with conventional voxel-based morphometry.

BACKGROUND AND PURPOSE: DLB is recognized as the second major form of dementia in the elderly. The regional pattern of GM atrophy in DLB highly overlaps that in AD. The aim of this study was to identify the critical pattern of atrophy in DLB by using DARTEL, which provides improved registration accuracy compared with that of conventional VBM. MATERIALS AND METHODS: We evaluated 51 patients with probable AD, 43 patients with probable DLB, and 40 age-matched healthy controls. The pattern of GM atrophy in each group was compared by using conventional VBM and VBM-DARTEL. RESULTS: Regional patterns of atrophy identified by using conventional VBM differed significantly from those identified by using VBM-DARTEL. A decrease in GM volume in the MTLs in both AD and DLB was identified with VBM-DARTEL; the decrease was greater in patients with AD than in those with DLB. Comparisons with healthy controls revealed that the WM volume of the whole brain was preserved in patients with DLB. In contrast, a severe bilateral decrease in WM in the MTLs was detected in patients with AD. CONCLUSIONS: VBM-DARTEL provided more accurate results, and it enabled the identification of more localized morphologic alterations than did conventional VBM. Analysis of WM preservation in DLB could help to differentiate this condition from AD.

Intra-striatal phencyclidine inhibits N-methyl-D-aspartic acid-stimulated increase in glutamate levels of freely moving rats.

1. The authors investigated the effect of local phencyclidine (phenylcyclohexylpiperidine, PCP) on extracellular levels of glutamate and gamma-amino butyric acid (GABA) in rat striatum using in vivo microdialysis. 2. Intrastriatal infusion of PCP (1 mM) via a microdialysis probe did not alter the basal extracellular levels of either glutamate or GABA. Addition of N-methyl-D-aspartic acid (NMDA; 0.2, 0.5 and 1 mM) to the perfusion medium resulted in a dose-dependent increase in extracellular levels of glutamate. 3. Intrastriatal infusion of tetrodotoxin (0.1, 1, 10 microM), a highly selective blocker of voltage-dependent sodium channels, significantly attenuated the NMDA-stimulated release of glutamate, suggesting that NMDA-evoked release of glutamate originated from the neuronal pool and that the increase of striatal glutamate level was regulated indirectly via NMDA receptors. 4. The NMDA-induced release of glutamate was reduced significantly by pretreatment with local PCP (1 mM). Dizocilpine (MK801; 0.2 mM), a non-competitive NMDA antagonist, completely inhibited the NMDA-stimulated release of glutamate. 5. These results suggest that, in the striatum, PCP inhibits corticostriatal glutamatergic neurotransmission by inhibiting the release of glutamate probably via postsynaptic NMDA receptors.

Neurochemical and pathological alterations following infusion of leupeptin, a protease inhibitor, into the rat brain.

It is known that proteases participate in cellular protein turnover and eliminate abnormal and potentially toxic proteins. Disturbed proteolysis may be responsible for generating the pathological features of some neurodegenerative disorders. Alzheimer disease, for instance, is the most common neurodegenerative disorder and a condition in which proteins of the cell membrane and cytoskeleton are abnormally processed and accumulated in the brain. It is of interest to investigate the effect of protease inhibitors on neurons and neurotransmitter systems in the brain. We examined neurochemical and morphological neuronal changes in the rat brain following long-term intracerebroventricular infusion of leupeptin, a potent calcium-activated protease (calpain) inhibitor. Leupeptin (5 mg) was infused into the lateral ventricle using an osmotic minipump for 14 days. We found a significant reduction of regional choline acetyltransferase activities in the hippocampus, and of somatostatin concentrations in the hypothalamus and entorhinal cortex. Moreover, leupeptin caused a wide-spread, highly significant decrease in neuropeptide-Y concentrations. Leupeptin infusion produced severe degeneration of neuronal processes in both axons and dendrites, and accumulation of electron-dense bodies in the hippocampus. The results indicate that long-term intracerebroventricular infusion of leupeptin in the rat produces neurochemical and morphological changes resembling those of some neurodegenerative disease and aging. Abnormal proteolysis caused by either reduced protease or enhanced protease inhibitor activities might play an important role in these conditions.

[Manifestation of the symptoms in demented patients after the Great Hanshin Earthquake in Japan].

On Jan. 17, 1995, at 5:46 a.m., an earthquake measuring 7.2 on the Richter scale shook southern area of Hyogo prefecture of Japan, including Kobe city. By this earthquake referred as the Great Hanshin Earthquake later, over 6,000 people were killed, 150,000 buildings and houses were destroyed and more than 300,000 people were temporally evacuated. Over a half of victims were reported to be elderly. We reported five survivors with senile dementia of the Alzheimer's type, who showed exacerbation or manifestation of their dementia symptoms after the quake. None of them had been injured and none of their close relatives had been killed or injured. They had been living in the downtown of Kobe for over 30 years before the disaster. Most of them had lived by themselves. Their severity of dementation were mild to moderate. They had been living without any problems and functioning fairly well. Their sons and daughters did not realize that their fathers or mothers had dementia before the earthquake. They had to move to and live with their son's or daughter's families, since their residences were destroyed by the earthquake. Shortly after that, they showed exacerbation or manifestation of their symptoms and developed delusion that their money and valuables were stolen by their daughters or daughters-in-law. We concluded that: they had been living without any problems and functioning fairly well, although they had had mild dementia symptoms; their living by themselves in communities familiar to them prevented manifestation of dementia symptoms; living together with son's or daughter's family easily promoted the development of delusion that their property was stolen by their close relatives, especially daughters or daughters-in-law in demented people.

Low cerebrospinal fluid concentrations of peptide histidine valine and somatostatin-28 in Alzheimer's disease: altered processing of prepro-vasoactive intestinal peptide and prepro-somatostatin.

Recent studies have indicated that deposition of beta amyloid peptide in the brains of patients with senile dementia of the Alzheimer type (SDAT) is a consequence of abnormal processing of the beta amyloid protein precursor. In addition, reduced concentrations of various peptides have been measured in post-mortem brain tissue and cerebrospinal fluid (CSF) of patients with SDAT. We determined concentrations of the peptides derived from prepro-vasoactive intestinal peptide (VIP)--peptide histidine methionine-27 (PHM-27), peptide histidine valine (PHV) and VIP--and peptides derived from prepro-somatostatin (prepro-SS), SS-14 and SS-28, in CSF of patients with SDAT by radioimmunoassay combined with high performance liquid chromatography. We found significantly reduced levels of total PHM-immunoreactivity (IR) and PHV, and unaltered levels of PHM-27 and VIP in SDAT, compared with those in controls. Total SS-IR and SS-28 concentrations were significantly reduced in SDAT, while SS-14 levels did not differ from those of controls. These results suggest that an altered processing of the prepro-peptides of VIP and SS may occur in SDAT and that these alterations might have a significant role in the pathogenesis of SDAT.

Drug-induced oral dyskinesias in rats after traditional and new neuroleptics.

Tardive dyskinesia (TD) is a serious human side effect of neuroleptic treatment in psychotic disorders. Although the etiology is clear (i.e. chronic neuroleptic drugs), its pathophysiology has not yet been satisfactorily explained. This is important not only theoretically but also to inform drug development, allowing the introduction of antipsychotic compounds without TD liability. The development of an animal condition which putatively models these delayed onset dyskinesias, has provided a technique to differentiate between neuroleptic drug effect and dyskinesia correlates. We report here the development of oral dyskinesias in rats in response to a number of different neuroleptics, which have a range of neurochemical and clinical characteristics. Traditional neuroleptics (e.g. haloperidol) produced rat oral dyskinesias, in an open-cage environment. Clozapine, while it produced an increased rate of oral movements, showed a significantly decreased potency in this model. SCH23390 (D1 antagonist) neither produced the oral movements nor modified their onset by coadministration with raclopride. These data replicate and extend other similar studies in the literature. They suggest that clozapine differs from traditional neuroleptics with respect to motor side effects.

Clozapine in tardive dyskinesia: observations from human and animal model studies.

Clozapine has long been considered a useful treatment in patients who have schizophrenia with the neuroleptic-induced delayed-onset side effect tardive dyskinesia. We present data in support of the clinical impression using both an animal model of the disorder and dyskinetic patients themselves. Clozapine produces a lower rate of oral dyskinesia in laboratory rats after 6 months of chronic treatment than does haloperidol (8.6 +/- 1.3 vs. 13.6 +/- 1.4 vacuous chewing movements every 5 minutes, respectively), suggesting a lower propensity to cause tardive dyskinesia. In the human, when clozapine was compared with haloperidol in the treatment of patients with tardive dyskinesia, clozapine produced significantly greater benefit for motor symptoms after 12 months of treatment than did haloperidol (p < .001). Moreover, the dyskinesia rebound, which occurred equally in both drug groups at the beginning of the study, was sustained in the haloperidol group but lost in the clozapine-treated patients. These data suggest that dyskinetic patients lose their symptoms of tardive dyskinesia, along with dopaminergic hypersensitivity, with long-term clozapine treatment.

Tiagabine inhibits haloperidol-induced oral dyskinesias in rats.

Chronic administration of haloperidol to male Sprague Dawley rats for 6 months at a dosage of 1.5 mg/kg/day produces oral dyskinesias in a significant percent of the treated group. This has been used as an animal model of tardive dyskinesia in several laboratories, because the rat movements display characteristics reminiscent of the human dyskinetic condition. Previously, we have reported a reduction in these haloperidol-induced oral dyskinesias with the coadministration of a direct acting GABA agonist progabide. Here, we have tested an indirect acting GABA agonist, tiagabine, coadministered with haloperidol, for its effect on the oral dyskinesias. At a dosage of 75 mg/kg/day tiagabine significantly inhibited the onset of vacuous chewing movements (VCMs), decreasing the average movement severity from 11.2 +/- 2.0 to 4.4 +/- 1.4, compared with a placebo rate of 1.3 +/- 0.5 (VCMs/5 min). These data support the proposition that an effective, potent GABAmimetic coadministered with haloperidol, will block the onset of rat oral dyskinesias. This conclusion has important implications for the treatment and prevention of tardive dyskinesia in humans.

Effect of serotonergic agents on regional concentrations of somatostatin- and neuropeptide Y-like immunoreactivities in rat brain.

A possible role for neuropeptides in affective disorders is suggested by many investigators. Somatostatin-like immunoreactivity (SS-LI) and neuropeptide Y-like immunoreactivity (NPY-LI) concentrations are demonstrated to be reduced in cerebrospinal fluid from depressed patients. We have shown that long-term treatment with serotonin uptake inhibitors, clomipramine and zimelidine, reduce brain SS-LI concentrations in the rat. We have studied the effect of serotonergic agents on regional brain SS-LI and NPY-LI concentrations in rats. Long-term treatment with 5-hydroxytryptamine (5-HTP), a serotonin precursor, caused reductions in SS- and NPY-LI levels in the hypothalamus. SS- and NPY-LI concentrations in the brain were markedly elevated by treatment with p-chlorophenylalanine, a serotonin synthesis inhibitor. Intracerebroventricular administration of 5,7-dihydroxytryptamine, a serotonin neurotoxin, resulted in elevations of both peptides in the brain. These results suggest a inhibitory role for the serotonergic system in the brain in the regulation of SS and NPY.

Repeated administration of antidepressant drugs reduces regional somatostatin concentrations in rat brain.

A possible role for somatostatin in affective disorders is suggested by its low concentration in cerebrospinal fluid of patients with depression. Therefore, we studied the regional effects of antidepressant drugs and antimanic agents on somatostatin concentrations in rat brain. Repeated, but not acute, administration of clomipramine, a specific serotonin uptake inhibitor, caused a highly significant, widespread reduction in somatostatin levels. Somatostatin content was similarly reduced in the hypothalamus, and midbrain and thalamus following repeated administration of zimelidine, another specific serotonin uptake inhibitor. Repeated administration of either imipramine, maprotiline, mianserin, carbamazepine or zotepine were without effect on somatostatin levels. These results suggest that somatostatin in the brain might be involved in therapeutic effects of some of antidepressant drugs.

The effect of intracerebroventricular administration of somatostatin on prolactin and TSH release in rats.

We investigated the effect of intracerebroventricular (icv) administration of somatostatin (SRIF) on prolactin (PRL) and thyroid-stimulating hormone (TSH) release in freely moving rats chronically cannulated with an atrial catheter. The plasma PRL levels were significantly elevated following the icv administration of 0.5 microgram SRIF. No further increase in PRL following the icv administration of SRIF were found in the rats in the course of repeated intravenous of injection of 5.0 mg/kg sulpiride, a specific D2 receptor antagonist. On the other hand, the injection of 5.0 micrograms SRIF resulted in no significant change in the plasma TSH levels. These results suggest that the effect of SRIF on PRL release was exerted through brain D2 receptors.

Elevated urinary free cortisol in patients with dementia.

Urinary free cortisol (UFC), 17-hydroxycorticosteroids (17-OHCS) in urine and dexamethasone suppression test (DST) were examined in patients with dementia of Alzheimer type (DAT) and multi-infarct dementia (MID), and nondemented elderly. Eight of 19 patients (42.1%) were DST nonsuppressor. UFC was significantly elevated in patients with dementia, compared with that in nondemented elderly. There was no difference in UFC levels between DAT and MID. The UFC level correlated with post-DST plasma cortisol level at 1600 in demented patients. The mean level of 17-OHCS in demented patients was increased, although the difference was not significant statistically. In demented patients, UFC levels, not 17-OHCS levels in urine were correlated with Mini-Mental State Examination scores. These results suggest that a hypothalamo-pituitary-adrenal axis function is activated in demented patients and that this activation relates generally to dementation itself, not to an etiology of dementia. Measurement of UFC might be a biological marker of dementia and may have a value in diagnosis of dementia.