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.

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.

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.

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.

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.

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.

Linkage to the Huntington's disease locus in a family with unusual clinical and pathological features.

We used the anonymous DNA probe, D4S10 (G8), known to be linked to the Huntington's disease (HD) locus, to confirm inheritance at that locus in a family in whom most affected individuals had atypical clinical and pathological features. Their clinical features were similar to the Westphal variant (usually seen in juvenile-onset HD) but they had onset in adult life, and in contrast to juvenile-onset HD, their course of illness was prolonged. Most family members had been repeatedly misdiagnosed during life because of the absence of chorea and prominence of long-tract signs. In 2 patients who died, neuropathological examination at autopsy revealed prominent involvement of brainstem and spinal cord structures, and in 1, mild neostriatal atrophy relative to duration of the disease. The study demonstrates the usefulness of genetic linkage analysis as a diagnostic tool in families with atypical forms of HD. This method allows study of phenotypic variations that can be inherited at or near the HD locus and implies either multiple alleles at the locus gene, modifiers of a single allele, or another locus in the same region causing a dominantly inherited neurodegenerative disease.

The pedunculopontine nucleus in Parkinson's disease.

This study demonstrated a significant loss of neurons within the lateral part of the pedunculopontine nucleus pars compacta in individuals with idiopathic Parkinson's disease and in individuals with combined Parkinson's and Alzheimer's disease. We also examined the extent of neuronal loss within the substantia nigra pars compacta, locus ceruleus, dorsal raphe nucleus, and nucleus basalis of Meynert. The number of pedunculopontine nucleus pars compacta neurons in the patients with Parkinson's or Parkinson's and Alzheimer's disease was reduced (average, 40%) in comparison with the number in control subjects or patients with Alzheimer's disease (p less than 0.01). This finding correlated significantly with the extent of loss of substantia nigra pars compacta neurons (p less than 0.01).

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.

Neuropathology of aminergic nuclei in Alzheimer's disease.

In order to comprehensively evaluate pathological involvement of the locus coeruleus (LC) and cortically projecting raphe nuclei in Alzheimer's disease (AD), we have recently completed a study (Zweig, et al., 1988) in which numbers of neurons containing neuromelanin within the LC and large nucleolus-containing neurons within the dorsal raphe nucleus (DR) and the central superior (raphe) nucleus (CSN) were determined in 25 cases of AD and 12 age-matched controls. Numbers of neurofibrillary tangles (NFTs) within these regions were also counted. Pathological results were compared with clinical data, including psychiatric evaluations, available for 21 of the AD cases. Neuronal loss in AD cases was most severe within LC at mid level (p less than .01) and within DR, caudally (p less than .05). Counts of NFTs within LC were also highest at mid level (p less than .05) in comparison with caudal level). Neuronal loss was not demonstrated within CSN, although NFTs were abundant within this nucleus. At individual levels, neuronal and NFT counts did not correlate. Relative severity of neuronal loss or NFTs was usually consistent from level to level within nuclei; internuclear correlations were weaker. Cases of AD complicated by depression had significantly fewer neurons at mid LC and rostral CSN levels than nondepressed cases (p less than .05). There was also a trend (nonsignificant) suggesting increased neuronal loss at all levels of LC and DR in depressed cases. Neuronal loss correlated negatively with age, particularly within LC. NFT counts correlated negatively with duration of illness, particularly within DR. As all but 3 individuals had severe dementia, NFT counts may reflect rate of progression of disease. Neuronal loss and NFTs frequently occur in the LC and cortically projecting raphe nuclei in AD (Curcio and Kemper, 1984, Hirano and Zimmermann, 1962, Ishii, 1966, Marcynuik et al., 1986, Yamamoto and Hirano, 1985, Bondareff and Mountjoy, 1986, Iverson et al., 1983, Mann et al., 1985, Tabaton et al., 1986). We have recently completed a comprehensive evaluation of pathological involvement of the LC, the DR, and the CSN in a series of aged controls and AD patients for whom detailed clinical information, including psychiatric evaluations, were available (Zweig et al., 1988). This report summarizes the findings of that 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.

The neuropathology of aminergic nuclei in Alzheimer's disease.

Neuronal loss and the presence of neurofibrillary tangles (NFTs) within aminergic nuclei were examined in a series of patients with Alzheimer's disease (AD). Neuromelanin-containing neurons within the locus ceruleus and large nucleolus-containing neurons within the dorsal raphe nucleus and the central superior (raphe) nucleus were counted in 25 patients with AD and in 12 age-matched control subjects. Numbers of NFTs were quantified in the same regions. Counts were compared with clinical data, including psychiatric evaluations, available for 21 of the patients with AD. Within the locus ceruleus in the patients with AD, abnormalities were more severe at mid level than at caudal or rostral levels (p less than 0.01). Within the dorsal raphe nucleus, neuronal loss was most severe caudally (p less than 0.05). NFTs, but not neuronal loss, were demonstrated within the central superior nucleus. Neuronal and NFT counts did not correlate at individual levels; the relative severity of both pathological processes was consistent from level to level within nuclei but was less consistent between nuclei. Neuronal loss correlated inversely with age, particularly within the locus ceruleus. Duration of disease correlated inversely with counts of NFTs, particularly within the dorsal raphe nucleus, implying a correlation between NFT counts and rate of progression of disease as all but 3 patients had severe dementia. Significantly, patients with AD complicated by major depression had fewer neurons at the mid level of the locus ceruleus and at the rostral level of the central superior nucleus in comparison with nondepressed patients. There was a trend suggesting greater loss of neurons at all levels of the locus ceruleus and dorsal raphe nucleus in depressed individuals.

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.

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.

Aminergic systems in Alzheimer's disease and Parkinson's disease.

Biochemical markers for serotoninergic and catecholaminergic neurons in frontal and temporal poles were examined post mortem in brains of patients with Alzheimer's disease, Parkinson's disease, and the two combined. Binding of [3H] citalopram to serotoninergic uptake sites and levels of serotonin were decreased by 40 to 50% in brains of persons in each disease category. In contrast, significant reductions of catecholaminergic markers were not detected. In all three disease groups, the choline acetyltransferase activity was reduced by 50 to 60%. Binding sites for adenosine (A1), muscarinic cholinergic, phencyclidine, beta-adrenergic, and calcium antagonist receptors were unchanged. We conclude that substantial damage to serotoninergic neurons occurs in persons with Parkinson's and Alzheimer's diseases.