Soluble and membrane-bound forms of brain acetylcholinesterase in Alzheimer's disease.

In order to determine the effect of Alzheimer's disease on the relative distribution of soluble and membrane-bound molecular forms of acetylcholinesterase (AChE) in the brain, postmortem samples (delay interval less than 12 h) were obtained from parietal cortex (Brodmann area 40) and hippocampus as well as the areas containing their respective projection nuclei, i.e., substantia innominata and septal nucleus, in 9 patients with Alzheimer's disease (AD) and 4 normal controls. The monomer (G1), dimer (G2), and tetramer (G4) forms of AChE were examined. In AD compared to controls, significant changes occurred in area 40 and hippocampus but not in the areas containing projection nuclei, and included loss of mean total AChE activity, decrease in the relative percentage of membrane-bound G4, and increase in the relative percentage of soluble G1-G2. Percent of soluble G4 was unaffected in AD brain. In area 40 but not hippocampus a large increase in percent membrane-bound G1-G2 occurred. Thus, these results emphasize that the selective decrease in membrane-bound G4 accounts for the decrease in total G4 activity in AD brain.

Factors associated with suicide attempts by depressed older adults: a prospective study.

OBJECTIVE: This study sought to ascertain demographic, clinical, and interpersonal factors prospectively associated with suicide attempts by older adults with major depressive disorder. METHOD: Elderly inpatients diagnosed as having major depressive disorder according to the Research Diagnostic Criteria were administered a structured diagnostic interview and then followed up for 1 year. Factors bearing on the interpersonal context of depression, including the emotional adjustment of patients' spouses and adult children, interpersonal strains, and relatives' concerns related to the care of their depressed family members, were also ascertained at the time of the patients' hospital admission. The elderly patients who attempted suicide during the follow-up period were compared with the nonattempters across demographic, clinical, and interpersonal factors assessed during the initial interviews. RESULTS: A suicide attempt was made by 8.7% (N = 11) of the 126 elderly depressed patients within 1 year after hospital admission. Compared with the nonattempters, the attempters were of a higher socioeconomic status, evidenced more past suicide attempts and current suicidal behavior, and constituted a disproportionately large percentage of those patients who had never had a remission of their index depressive episodes. Notably, the spouses and adult children of patients who later attempted suicide evidenced more psychiatric symptoms, more strain in the relative-patient relationship, and more difficulties in caring for the patient than the relatives of nonattempters. CONCLUSIONS: The findings emphasize the need for careful attention to both clinical and interpersonal factors in the assessment of suicide risk in the elderly.

The familial occurrence of Parkinson's disease. Lack of evidence for maternal inheritance.

A questionnaire concerning the occurrence of Parkinson's disease in parents was administered for 252 patients with Parkinson's disease. Eleven fathers and five mothers of patients were reported to also have had this disease. These data fail to provide support for the hypothesis that Parkinson's disease is the result of maternal inheritance of an abnormal mitochondrial gene. This conclusion is further supported by a review of similar studies in the literature and an additional unpublished study, which revealed that of 922 patients with this disease, 37 fathers and 19 mothers were reportedly affected.

Reductions in acetylcholine and nicotine binding in several degenerative diseases.

Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are all characterized by loss of neurons in the basal forebrain cholinergic system and by associated reductions in cortical presynaptic cholinergic markers, such as choline acetyltransferase. In this report, we identify that a major cortical receptor alteration in these disorders is a reduction in nicotinic receptors measured using both tritiated acetylcholine and levorotatory tritiated nicotine binding.

Locus coeruleus involvement in Huntington's disease.

Numbers and areas of neuronal profiles from sections of brain stem at specific anatomic levels of the locus coeruleus and the dorsal raphe nucleus were measured in 33 patients with Huntington's disease and in 23 age-matched control subjects. Results from the Huntington's disease cases were correlated with severity of neostriatal atrophy and with systematically collected quantitative clinical data. Among the patients with Huntington's disease, lower locus coeruleus neuronal counts, reduced neuronal areas, and reduced locus coeruleus length (distance between rostral and caudal levels) were associated with features of advanced disease, including severity of neostriatal atrophy, severity of dementia, duration of illness, and severity of motor impairment and activities of daily living impairment. By contrast, there was no evidence of neuronal pathology within the dorsal raphe nucleus in Huntington's disease. Pathologic changes in the locus coeruleus may relate to some of the clinical manifestations of Huntington's disease.

A case of Alzheimer's disease and hippocampal sclerosis with normal cholinergic activity in basal forebrain, neocortex, and hippocampus.

A 76-year-old man without apparent dementia met pathologic criteria at autopsy for Alzheimer's disease, which included a maximum senile plaque density greater than 15 per square millimeter of neocortex. Despite hippocampal sclerosis, changes typical of Alzheimer's disease were not found in this region or in basal forebrain. Choline acetyltransferase activity in hippocampus, septum, and parietal cortex was normal.

The locus ceruleus and dementia in Parkinson's disease.

We compared numbers of neuronal profiles in the locus ceruleus (LC) from sections of brainstem in 13 patients with Parkinson's disease (PD) without concurrent Alzheimer's disease (AD) with counts from age-matched controls and from patients with PD and concurrent AD. We also evaluated the relationships between presence of dementia or LC neuronal loss and additional pathologic measures related to dementia in PD. Among patients with PD without concurrent AD, the presence of dementia was associated with significantly lower LC neuronal counts (at all anatomic levels); greater neuronal loss within the ventral tegmental area, nucleus basalis of Meynert, and possibly the medial (but not the lateral) substantia nigra pars compacta; and more Lewy bodies in the anterior cingulate gyrus. Correlations between lower LC neuronal counts and these other pathologic measures were generally positive and often significant. We conclude that dementia in PD is associated with pathologic involvement of multiple extranigral neuronal populations.

Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy.

Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.

Pathology in brainstem regions of individuals with primary dystonia.

Examination of brains from four individuals with the clinical diagnosis of primary dystonia revealed histopathologic abnormalities in two cases. A 29-year-old man with a 15-year history of dystonia musculorum deformans (DMD) had numerous neurofibrillary tangles (NFT) and mild neuronal loss within the locus ceruleus; occasional NFT were also recognized in the substantia nigra pars compacta, pedunculopontine nucleus, and dorsal raphe nucleus. A 68-year-old man with a 35-year history of Meige syndrome had moderate-to-severe neuronal loss in several brainstem nuclei, including the substantia nigra pars compacta, locus ceruleus, raphe nuclei, and pedunculopontine nucleus. Infrequent NFT were also noted in substantia nigra. An examination of these and other brain regions in a 10-year-old boy with a 6-year history of DMD and a 50-year-old woman with a 3-year history of spasmodic torticollis did not disclose similar abnormalities.

Treatment of supratentorial high grade gliomas with split course high fractional dose postoperative radiotherapy.

Ninety-two patients with malignant supratentorial gliomas diagnosed from 1977 to 1983 received split course external beam radiotherapy. The initial course of radiation consisted of 3000 cGy whole brain in ten fractions 5 days a week. After a 2-week rest, treatment was continued to a portal restricted to the computerized tomography scan demonstrated abnormality plus a margin for an additional 2100 cGy (total 5100 cGy/17 fx/36 days). The optic chiasm and hypothalamus were excluded from the high dose region. Following review of all pathologic specimens, three patients with grade II glioma, three lacking histologic confirmation, two unbiopsied and eleven not receiving the prescribed treatment were excluded from the survival analysis. No patients were lost to follow-up. Surviving patients were followed 85 months (median); range 68-125 months. All remaining patients were followed until death. The median actuarial survival for 73 grade III and IV patients was 12.5 months. The 5-year actuarial survival was 10%. The median survival for 54 grade IV patients was 10 months. The 5-year survival was 4%. For 19 grade III patients the median survival was 22.5 months. The 5-year survival was 26%. There was one long-term grade IV survivor (68 mos.) and four long-term grade III survivors (76, 85, 108, 125 mos). No patient developed optic nerve or chiasm injury. One patient, an 85 months survivor, had biopsy documented radionecrosis and hemiparesis. The incidence of necrosis among 62 patients alive 6 months or more (and therefore at risk of brain necrosis) is 1/62 (2%). The incidence among survivors is 1/5. The nominal standard dose for this regimen is 1749 ret. The predictive value of the "nominal standard dose" and "equivalent dose" formulae for brain necrosis is explored. We conclude (a) that this regimen provides a survival probability equivalent to conventional treatment for grade III and IV supratentorial gliomas, (b) that neither the equivalent nor nominal standard doses predicted the incidence of brain necrosis, (c) that the time dose schedule is well tolerated and has an acceptable risk-benefit ratio, (d) that its advantage to the patient is decreased time requirement and cost.

Mesopontine cholinergic and non-cholinergic neurons in schizophrenia.

Mesopontine cholinergic neurons influence midbrain dopaminergic neurons, and thalamic and cerebellar structures which have been implicated in the neuroanatomy of schizophrenia. It has been reported that there are approximately twice as many mesopontine cholinergic neurons in schizophrenics than in normals, using nicotinomide adenosine dinucleotide phosphatediaphorase histochemistry to identify the cholinergic neurons. The present study sought to replicate this finding by analysing mesopontine cholinergic neurons using an antibody against choline acetyltransferase. The mesopontine cholinergic neurons are located in the pars compacta and pars dissipata of the pedunculopontine nucleus, and in the laterodorsal tegmental nucleus. Quantitative computer imaging techniques were used to map the distribution of mesopontine cholinergic neurons. In addition, all medium-sized and large neurons in a region of interest containing the middle portion of the pedunculopontine nucleus pars compacta were counted in Nissl-stained sections. There was no difference between schizophrenic and normal brains in terms of: (i) the rostral-caudal length of the cholinergic cell complex, approximately 10 mm; (ii) the estimated total number of cholinergic neurons in the combined pedunculopontine nucleus and laterodorsal tegmental nucleus, approximately 20,000 cells unilaterally; and (iii) the combined number of cholinergic and non-cholinergic Nissl-stained neurons in the middle portion of the pedunculopontine nucleus. The present data do not support the previous observation of increased numbers of mesopontine cholinergic neurons in schizophrenia.

Quantification of cholinergic and select non-cholinergic mesopontine neuronal populations in the human brain.

The pars compacta and pars dissipata of the pedunculopontine nucleus contain cholinergic cell group Ch5, and the laterodorsal tegmental nucleus contains cholinergic cell group Ch6. The pedunculopontine nucleus has been implicated in a variety of functions, including mediation of rapid eye movement sleep and in extrapyramidal motor function, although the role of cholinergic and non-cholinergic neurons is unclear. Quantitative neuroanatomical techniques were used to map the distribution of cholinergic neurons in the mesopontine nuclei of the adult human brain. In addition, the number and distribution of comparably sized non-cholinergic neurons at selected anatomical levels were compared. An antibody raised against human choline acetyltransferase was used to stain immunohistochemically the mesopontine neurons in six brains, ranging in age from 28 to 60 years. The rostrocaudal length of the Cb5/Ch6 cell complex was approximately 10 mm. The estimated total number of cells was similar for all brains, and varied by less than 7%. The estimated average number of cholinergic cells in the combined pedunculopontine and laterodorsal tegmental nuclei was approximately 20,000, with 30% of the cells in the pedunculopontine nucleus pars compacta, 57% in the pedunculopontine nucleus pars dissipata and 13% in the laterodorsal tegmental nucleus. There was no correlation between cell number and age. Within areas of mesopontine tegmentum occupied by the Ch5 cholinergic neurons, there were often more noncholinergic neurons than comparably sized cholinergic neurons. The present study provides detailed maps of the distribution and number of mesopontine cholinergic neurons in the normal human brain. Many non-cholinergic neurons are intermixed with the cholinergic pedunculopontine neurons. One region of the pedunculopontine nucleus pars dissipata containing few cholinergic neurons, located adjacent to the ventral border of the pedunculopontine nucleus pars compacta, may correspond to the midbrain-extrapyramidal area as defined previously in rodent and in non-human primate. These data will be useful for quantitative neuropathological studies concerning the role of both cholinergic and non-cholinergic mesopontine neurons in diseases proposed to affect these neurons, including Parkinson's disease, schizophrenia and progressive supranuclear palsy.

Food deprivation and nicotine correct akinesia and freezing in Na(+) -leak current channel (NALCN)-deficient strains of Caenorhabditis elegans.

Mutations in various genes adversely affect locomotion in model organisms, and thus provide valuable clues about the complex processes that control movement. In Caenorhabditis elegans, loss-of-function mutations in the Na(+) leak current channel (NALCN) and associated proteins (UNC-79 and UNC-80) cause akinesia and fainting (abrupt freezing of movement during escape from touch). It is not known how defects in the NALCN induce these phenotypes or if they are chronic and irreversible. Here, we report that akinesia and freezing are state-dependent and reversible in NALCN-deficient mutants (nca-1;nca-2, unc-79 and unc-80) when additional cation channels substitute for this protein. Two main measures of locomotion were evaluated: spontaneous movement (traversal of >2 head lengths during a 5 second observation period) and the touch-freeze response (movement greater than three body bends in response to tail touch). Food deprivation for as little as 3 min stimulated spontaneous movement and corrected the touch-freeze response. Conversely, food-deprived animals that moved normally in the absence of bacteria rapidly reverted to uncoordinated movement when re-exposed to food. The effects of food deprivation were mimicked by nicotine, which suggested that acetylcholine mediated the response. Nicotine appeared to act on interneurons or motor neurons rather than directly at the neuromuscular junction because levamisole, which stimulates muscle contraction, did not correct movement. Neural circuits have been proposed to account for the effects of food deprivation and nicotine on spontaneous movement and freezing. The NALCN may play an unrecognized role in human movement disorders characterized by akinesia and freezing gait.

Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial.

OBJECTIVE: 6002-US-051 was a 12-week, double-blind study evaluating the safety and efficacy of istradefylline, a selective A(2A) adenosine receptor antagonist, as monotherapy in patients with Parkinson's disease (PD). METHODS: Patients with Hoehn-Yahr stages 1-2.5 who had not received dopaminergic drugs in the past 30 days or levodopa for >30 days at anytime were randomized to 40 mg/day istradefylline or placebo. The primary efficacy outcome was the change from Baseline to Endpoint in the Unified Parkinson's Disease Rating Scale (UPDRS) Subscale III score. Safety was assessed by physical examination, laboratory tests, electrocardiograms, and adverse event monitoring. RESULTS: 176 patients comprised the intent-to-treat population. Although istradefylline showed numerically greater improvements in UPDRS Subscale III at each time point and reached statistical significance at Week 2 (LS mean difference = -1.47), it did not show statistically significant improvement from placebo for the primary endpoint (least square [LS] mean difference = -1.11). Similar proportions of patients in each group experienced treatment-emergent adverse events (63% istradefylline, 65% placebo). CONCLUSIONS: Istradefylline, as monotherapy in patients with PD, is safe and well tolerated. However, efficacy in improving motor symptoms in early PD was not statistically demonstrated by this study.

Decrease in membrane-bound G4 form of acetylcholinesterase in postmortem Alzheimer brain.

Samples of left hippocampus, septal nucleus, parietal lobe (area 40), and nucleus basalis of Meynert (NBM) were removed from eight patients with pathologically confirmed Alzheimer's disease (AD), four controls, and three patients with non-Alzheimer's dementia. Extracts of these brain regions were assayed for choline acetyltransferase (ChAT) specific activity, acetylcholinesterase (AChE) specific activity, and AChE molecular form composition. Average specific activities of ChAT from hippocampus, septum, and area 40, but not NBM, were significantly lower (p less than 0.01) in the AD population than in the control group. The average AChE specific activity was significantly less (p less than 0.05) in hippocampus and area 40 when the AD group was compared with controls. The average percentage of total AChE activity represented by the globular tetrameric (G4) molecular form was decreased in all AD brain regions as compared to control or to non-Alzheimer's demented groups. The decrease in G4 was, in all cases, due to a selective decrease in the membrane-bound form of G4. The loss of percent membrane-bound G4 in the AD group was significant for hippocampus (p less than 0.05) and area 40 (p less than 0.001) when compared to controls. The percentages of total AChE present as G4 and as membrane-bound G4 in each brain region were correlated with the ChAT specific activities in that region. The correlations showed that AChE molecular form composition changed significantly only if ChAT activity fell below a certain consistent level. The human data agreed well with data from fornix-lesioned mice which strongly suggest the existence of a soluble factor that regulates production of membrane-bound G4.