Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Patterns of neuropsychological performance in multiple system atrophy compared to sporadic and hereditary olivopontocerebellar atrophy.

Although neuropsychological symptoms are associated with multiple system atrophy (MSA), sporadic olivopontocerebellar atrophy (sOPCA), and dominantly inherited olivopontocerebellar atrophy (dOPCA), the differences between these groups have not been explored. We compared 28 MSA patients on psychiatric rating scales and neuropsychological measures to 67 sOPCA patients, 42 dOPCA patients, and 30 normal controls. Patients with dOPCA, sOPCA, and MSA all exhibited significant deficits on motor-related tasks, as well as relatively mild deficits in cognitive functioning. Patients with MSA had greater neuropsychological dysfunction, particularly in memory and other "higher order" cognitive processes, than patients with either sOPCA or dOPCA.

Treatment of Wilson's disease with zinc XVI: treatment during the pediatric years.

The objectives were to evaluate appropriate doses of zinc acetate and its efficacy for the maintenance management of Wilson's disease in pediatric cases. Pediatric patients of 1 to 5 years of age were given 25 mg of zinc twice daily; patients of 6 to 15 years of age, if under 125 pounds body weight, were given 25 mg of zinc three times daily; and patients 16 years of age or older were given 50 mg of zinc three times daily. Patients were followed for efficacy (or over-treatment) until their 19th birthday by measuring levels of urine and plasma copper, urine and plasma zinc and through liver function tests and quantitative speech and neurologic scores. Patients were followed for toxicity by measures of blood counts, blood biochemistries, urinalysis, and clinical follow-up. Thirty-four patients, ranging in ages from 3.2 to 17.7 years of age, were included in the study. All doses met efficacy objectives of copper control, zinc levels, neurologic improvement, and maintenance of liver function except for episodes of poor compliance. No instance of over-treatment was encountered. Four patients exhibited mild and transient gastric disturbance from the zinc. Zinc therapy in pediatric patients appears to have a mildly adverse effect on the high-density lipoprotein/total cholesterol ratio, contrary to results of an earlier large study of primarily adults. In conclusion, zinc is effective and safe for the maintenance management of pediatric cases of Wilson's disease. Our data are strongest in children above 10 years of age. More work needs to be done in very young children, and the cholesterol observations need to be studied further.

Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy.

OBJECTIVE: To determine the percentage of sporadic olivopontocerebellar atrophy (sOPCA) patients who later develop multiple system atrophy (MSA). METHODS: Observations of the course of 51 sOPCA patients 20 years of age or older initially evaluated in an ataxia clinic over 14 years and followed at 3- to 6-month intervals for 3 months to 10 years (median 2.5 years, interquartile range 5 months to 4 years). RESULTS: Seventeen patients evolved to develop MSA, whereas the remaining 34 manifested only progressively worsening cerebellar ataxia. The features of the MSA cases included autonomic failure and parkinsonism in 10 patients, autonomic failure without parkinsonism in six, and parkinsonism without autonomic failure in one. Using survival analysis methods, the authors estimated that 24% of subjects in this population will evolve to MSA within 5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at onset of symptoms and a shorter time from onset of symptoms to first presentation in a neurology specialty clinic were both highly predictive of evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to 5 years after they had met diagnostic criteria for MSA. The estimated median survival time from time of transition was 3.5 years. In contrast, death occurred in only one of the 34 patients with sOPCA who did not evolve to MSA. Autopsy examination of all six patients with MSA who died confirmed the diagnosis. CONCLUSIONS: Approximately one-fourth of sporadic olivopontocerebellar atrophy patients will evolve to multiple system atrophy within 5 years, and this transition carries a poor prognosis for survival. Older age at onset of ataxia and earlier presentation in a neurologic specialty clinic predicted transition to MSA.

Treatment of Wilson's disease with zinc. XVII: treatment during pregnancy.

Therapy of Wilson's disease continues to evolve. In 1997, zinc acetate was added to the list of drugs approved by the Food and Drug Administration, which includes penicillamine and trientine. The mechanism of zinc's anticopper action is unique. It induces intestinal cell metallothionein, which binds copper and prevents its transfer into blood. As intestinal cells die and slough, the contained copper is eliminated in the stool. Thus, zinc prevents the intestinal absorption of copper. It is universally agreed that pregnant Wilson's disease patients should remain on anticopper therapy during pregnancy. There are numerous reports of such patients stopping penicillamine therapy to protect their fetus from teratogenicity, only to undergo serious deterioration and even death from renewed copper toxicity. Penicillamine and trientine have teratogenic effects in animals, and penicillamine has known teratogenic effects in humans. In this report we discuss the results of 26 pregnancies in 19 women who were on zinc therapy throughout their pregnancy. The evidence is good that zinc protects the health of the mother during pregnancy. Fetal outcomes were generally quite good, although one baby had a surgically correctable heart defect and one had microcephaly.

Decreased striatal monoaminergic terminals in multiple system atrophy detected with positron emission tomography.

We examined the density of striatal presynaptic monoaminergic terminals, using a ligand for the type 2 vesicular monoamine transporter, (+)-[11C]dihydrotetrabenazine, with positron emission tomography in 7 normal control subjects, 8 multiple system atrophy (MSA) patients with predominantly parkinsonian features (MSA-P), 8 MSA patients with principally cerebellar dysfunction (MSA-C), and 6 sporadic olivopontocerebellar atrophy (sOPCA) patients. The findings were correlated with the results of neurological evaluations and magnetic resonance imaging studies. Specific binding was significantly reduced in the putamen of all patient groups in the order MSA-P < MSA-C < sOPCA, compared with controls. Mean blood-to-brain ligand transport (K1) was significantly decreased in the putamen of all patient groups and in the cerebellar hemispheres of MSA-C and sOPCA but not MSA-P groups, compared with controls. Significant negative correlations were found between striatal binding and the intensity of parkinsonian features and between cerebellar K1 and the intensity of cerebellar dysfunction. The results suggest fundamental differences between MSA-P and MSA-C groups reflecting differential severity of degeneration of nigrostriatal and cerebellar systems in these two forms of MSA. The findings also show that some sOPCA patients have subclinical nigrostriatal dysfunction and are at risk of developing MSA with disease progression.

Treatment of Wilson's disease with zinc: XV long-term follow-up studies.

Wilson's disease is an inherited disease of copper accumulation caused by a failure of biliary excretion of excess copper. Accumulated copper causes liver disease in these patients, and in perhaps two thirds of patients, it causes brain damage leading to clinical neurologic or psychiatric dysfunction. Maintenance treatment involves reversing the positive copper balance. The earliest approaches have used chelators, such as penicillamine or trientine, which increase the urinary excretion of copper. A more recent approach has used zinc, which blocks the absorption of copper and increases copper excretion in the stool. Because of the high level of endogenously secreted copper in alimentary secretions, the reabsorption of which is partially blocked by zinc therapy, zinc acts to remove accumulated copper from the body as well as prevent its reaccumulation. In the present article we present data on the long-term follow-up (up to 10 years) of maintenance zinc treatment of 141 patients with Wilson's disease. The data presented document that zinc is effective as a sole therapy in the long-term maintenance treatment of Wilson's disease and that it has a low toxicity. The results demonstrate the efficacy of zinc therapy in treating the presymptomatic patient from the beginning of therapy. We also present limited data on the use of zinc in the treatment of pregnant patients and children who have Wilson's disease; these data also indicate efficacy and low toxicity. The median follow-up period for the group as a whole is 4.8 years; for the presymptomatic patients it is 6.5 years; for the children it is 3.6 years.

Decreased striatal monoaminergic terminals in severe chronic alcoholism demonstrated with (+)[11C]dihydrotetrabenazine and positron emission tomography.

We used (+)[11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter, with positron emission tomography to study striatal monoaminergic presynaptic terminals in 7 male severe chronic alcoholic subjects without Wernicke-Korsakoff disease compared with 7 male normal controls of similar ages. We found reduced specific binding in the caudate nucleus and putamen in the alcoholic group, and the difference reached significance in the putamen. Specific binding was not decreased in the thalamus, which was examined as a reference structure. We also detected deficits in blood-to-brain transfer rate, K1, in the same regions of the alcoholic group, with a significant difference in the putamen. K1 was unchanged in the thalamus. The finding of reduced striatal VMAT2 in severe chronic alcoholic patients suggests that nigrostriatal monoaminergic terminals are reduced, with or without loss of neurons from the substantia nigra. The findings suggest that the damaging effects of severe chronic alcoholism on the central nervous system are more extensive than previously considered.

Absence of normal activation of the left anterior fusiform gyrus during naming in left temporal lobe epilepsy.

Patients with left temporal lobe epilepsy (TLE) often have impaired naming. We studied 13 patients with left TLE and 10 healthy control subjects with [(15)O]H2O PET during visual confrontation naming. Statistical mapping detected multiple regions of significant cerebral blood flow increases within individuals. The left fusiform gyrus was activated in nine healthy subjects, but only in two patients with TLE (a significant difference, p < 0.001). Other activation sites were more variable in healthy subjects and those with TLE. Impaired naming ability may be associated with a lack of increased cerebral blood flow in the left fusiform gyrus in TLE.

The significance of family history status in relation to neuropsychological test performance and cerebral glucose metabolism studied with positron emission tomography in older alcoholic patients.

Patients with severe chronic alcoholism have decreased rates of glucose metabolism in the medial frontal lobe and correlated abnormalities of neuropsychological functioning. The potential influence of family history of alcoholism has not been examined in these patients. In a retrospective study, we used neuropsychological tests and neuroimaging employing [18F]fluorodeoxyglucose with positron emission tomography to study 48 older subjects who had histories of severe, chronic alcohol dependence. These patients were divided into two groups: 27 with a first-degree relative with chronic alcoholism and 21 patients without first-degree relative with chronic alcoholism. No differences were found between groups on either neuropsychological or neuroimaging tests. These results suggest that a family history of alcoholism does not moderate the damaging effects of severe chronic alcoholism on the functioning of the medial frontal lobe.

Effects of abstinence and relapse upon neuropsychological function and cerebral glucose metabolism in severe chronic alcoholism.

Prolonged excessive consumption of alcohol has been associated with a variety of cognitive disorders accompanied by neuropathological and neurochemical abnormalities of the brain, particularly in the frontal lobes. Studies with positron emission tomography (PET) have shown decreased local cerebral metabolic rates for glucose (lCMRglc) in frontal regions, with correlated abnormalities on neuropsychological tests sensitive to executive functioning. This investigation was designed as a pilot study to examine the effects of abstinence and relapse in patients with severe chronic alcoholism studied longitudinally with PET and with neuropsychological evaluation to assess both general and executive functioning. Six patients, including 4 who remained relatively abstinent and 2 who relapsed following their initial evaluation, were studied twice, with inter-evaluation intervals ranging from 10 to 32 months. The patients who remained abstinent or who had minimal alcohol use showed partial recovery of lCMRglc in two of three divisions of the frontal lobes and improvement on neuropsychological tests of general cognitive and executive functioning, whereas the patients who relapsed had further declines in these areas. These results, although based upon a relatively small number of subjects, provide preliminary support for at least partial recovery of metabolic and cognitive functioning in individual patients who abstain from alcohol.

Impaired upper limb coordination in alcoholic cerebellar degeneration.

BACKGROUND: Alcoholic cerebellar degeneration (ACD) is a disorder resulting from severe chronic alcoholism and malnutrition and is characterized by cognitive disturbances, ataxia of gait, and truncal instability, with generally preserved coordination of the upper extremities. OBJECTIVES: To determine whether cognitive deficits in patients with ACD are the same as those seen in patients with severe chronic alcoholism without ACD and to determine whether upper limb motor coordination is different in the 2 groups. DESIGN: We examined cognitive function and upper limb coordination in 56 patients with severe chronic alcoholism, 13 with ACD and 43 without ACD, who had comparable levels of total alcohol intake. Neuropsychological and motor function was measured using an expanded Halstead-Reitan Neuropsychological Test Battery, including the Tactual Performance Test and Grooved Pegboard Test. RESULTS: Neither group had impaired coordination of upper limb function on clinical neurological examination. Both groups had impaired performance on neuropsychological tests involving executive function, but the patients with ACD had greater impairment of upper limb coordination than the patients without ACD as measured by the Tactual Performance Test and Grooved Pegboard Test. CONCLUSIONS: The findings suggest that these 2 groups have similar cognitive deficits but that upper extremity motor functions are more significantly impaired in the ACD group and that quantitative tasks of motor function reveal these impairments.

Effects of disulfiram on positron emission tomography and neuropsychological studies in severe chronic alcoholism.

Disulfiram is an aldehyde dehydrogenase inhibitor that is widely used as an adjunctive agent in the treatment of patients with severe chronic alcoholism. Recent positron emission tomography (PET) studies of local cerebral metabolic rates for glucose (ICMRglc) and benzodiazepine receptor binding in alcoholic patients have shown regional cerebral abnormalities; however, some of the patients were studied while receiving disulfiram, which could influence the biochemical processes under investigation. In a retrospective investigation, we examined the influence of disulfiram administration on the results of PET studies of ICMRglc and benzodiazepine receptor binding and neuropsychological tests of cognition and executive function in patients with severe chronic alcoholism. [18F]Fluorodeoxyglucose was used to measure ICMRglc in 48 male patients, including 11 receiving and 37 not receiving disulfiram in therapeutic doses. [11C]Flumazenil was used to measure benzodiazepine receptor binding in 17 male patients, including 3 receiving and 14 not receiving disulfiram. All patients studied with FMZ were also examined with fluorodeoxyglucose. PET studies of ICMRglc revealed significantly decreased global values in the patients receiving disulfiram compared with those not receiving disulfiram. PET studies of benzodiazepine receptor binding revealed decreased flumazenil influx and distribution volume in patients receiving disulfiram. The neuropsychological tests demonstrated no differences between the two groups of subjects. The findings suggest that disulfiram may influence the results of PET studies of glucose metabolism and benzodiazepine receptor binding.

Treatment of Wilson disease with ammonium tetrathiomolybdate. II. Initial therapy in 33 neurologically affected patients and follow-up with zinc therapy.

OBJECTIVE: To test the efficacy and toxic effects of ammonium tetrathiomolybdate in the initial treatment of a relatively large series of patients with neurologic symptoms and signs caused by Wilson disease. Two key aspects of efficacy are to preserve the neurologic function present at the onset of therapy and to maximize the opportunity for long-term recovery. DESIGN: An open study of 33 patients treated for 8 weeks each, including further follow-up data on the original 17 patients. Neurologic function was evaluated by frequent quantitative neurologic and speech pathology examinations. Several copper-related variables were studied to evaluate the effect of the drug on copper, and several biochemical and clinical variables were studied to evaluate potential toxic effects. Patients were then followed up at yearly intervals, with follow-up periods of 1 to 8 years reported. SETTING: A university hospital referral setting. INTERVENTION: Patients were generally treated for 8 weeks with tetrathiomolybdate, followed by zinc maintenance therapy. MAIN OUTCOME MEASURES: Neurologic function was evaluated by quantitative neurologic and motor speech examinations and magnetic resonance imaging scans of the brain. RESULTS: During the 8 weeks of tetrathiomolybdate administration, only 1 of the 33 patients showed deterioration in neurologic function. Copper status and potential further toxic effects were generally well controlled quickly. Evaluation of data from individual patients revealed evidence of a toxic side effect in only 1 patient, who exhibited reversible anemia. During the ensuing period of follow-up of 1 to 6 years, neurologic recovery in most patients was good to excellent. CONCLUSIONS: Tetrathiomolybdate appears to be an excellent form of initial treatment in patients with Wilson disease who present with neurologic symptoms and signs. In contrast to penicillamine therapy, initial treatment with tetrathiomolybdate rarely allows further, often irreversible, neurologic deterioration.

Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics.

Positron emission tomography was used with [11C]flumazenil (FMZ) and [18F]fluorodeoxyglucose to study GABA type A/benzodiazepine (GA-BA-A/BDZ) receptors and cerebral metabolic rates for glucose (1CMRg1c) in 17 male patients with severe chronic alcoholism (ALC), 8 with (ACD) and 9 without alcoholic cerebellar degeneration (non-ACD). In comparison with male normal controls of similar ages, the ALC group had significantly reduced FMZ ligand influx (K1), FMZ distribution volume (DV), and 1CMRg1c bilaterally in the medial frontal lobes, including superior frontal gyrus and rostral cingulate gyrus; the ACD group had significant reductions of K1, DV, and 1CMRg1c bilaterally in the same distribution, and also in the superior cerebellar vermis; and the non-ACD group had significant reductions of K1, DV, and 1CMRg1c bilaterally in the same regions of the frontal lobes but not in the superior cerebellar vermis. When compared with the non-ACD group, the ACD group had significant reductions of K1, and DV bilaterally in the superior cerebellar vermis. The results suggest that severe chronic alcoholism damages neurons containing GA-BA-A/BDZ receptors in the superior medial aspects of the frontal lobes, and in patients with clinical signs of ACD, neurons containing GABA-A/BDZ receptors in the superior cerebellar vermis.

Dysphagia in elderly men with myasthenia gravis.

Eight elderly men whose primary symptoms of myasthenia gravis were decreased speech and swallowing ability were seen for speech pathology evaluations and videofluoroscopic swallow studies. All patients had fatigable flaccid dysarthria and greater than expected pharyngeal phase dysphagia on videofluoroscopy; eight had decreased pharyngeal motility as demonstrated by residual material in the valleculae and pyriform sinuses bilaterally; seven had episodes of laryngeal penetration secondary to overflow of residual material; and five experienced silent aspiration despite gag reflexes and the ability to cough to command. Five patients required feeding tubes because their dysphagia responded poorly to treatment. Videofluoroscopic swallow studies revealed a common swallowing profile with pharyngeal phase dysphagia greater than expected from patient symptoms. Dysphagia did not improve at the same rate as other manifestations of myasthenia gravis.

Characteristics of the dysarthria of multiple system atrophy.

OBJECTIVE: To characterize the dysarthria in patients with multiple system atrophy (MSA). DESIGN: Motor speech examinations, consisting of oral motor, oral agility, and perceptual speech analysis, were performed on 46 patients with MSA. SETTING: University department of neurology referral center. RESULTS: All patients had dysarthria with combinations of hypokinesia, ataxia, or spasticity. Thirty-two patients had all 3 components, 13 had 2 components, and 1 had only 1 component. In most patients the hypokinetic components were the most severe. Hypokinetic components predominated in 22 patients (48%), whereas ataxic components predominated in 16 (35%), and spastic components in 5 (11%). In 1 patient (2%) the hypokinetic and spastic components were equal and greater than the ataxic components, and in 1 patient (2%) the hypokinetic and ataxic components were equal and greater than the spastic components. One patient (2%) had only ataxic dysarthria. The predominant type of dysarthria corresponded well to the subtype of MSA. CONCLUSIONS: The finding of a mixed dysarthria with combinations of hypokinetic, ataxic, and spastic components is consistent with both the overall clinical and the neuropathologic changes in MSA. Motor speech examination can provide helpful information in evaluating patients who might have MSA.

Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions.

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological disorder characterized by neuronal degeneration and reactive gliosis in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns. Multiple system atrophy is a sporadic progressive neurological disorder with degeneration and gliosis in the basal ganglia, cerebellum, brainstem, and spinal autonomic nuclei, and with argyrophilic glial cytoplasmic inclusions. We describe 4 members of a family with the SCA1 mutation and a dominantly inherited progressive ataxia in which autopsy examination of 1 member showed neuropathological changes typical of multiple system atrophy, including glial cytoplasmic inclusions. In this patient, magnetic resonance imaging revealed marked brainstem and cerebellar volume loss and mild supratentorial generalized volume loss. Positron emission tomography with [18F]fluorodeoxyglucose revealed widespread hypometabolism in a pattern found in sporadic multiple system atrophy and not in dominantly inherited olivopontocerebellar atrophy. Positron emission tomography with [11C]flumazenil revealed normal benzodiazepine receptor distribution volumes, similar to those seen in sporadic multiple system atrophy. Two other family members still living had similar changes in the imaging studies. The findings in this family suggest that the SCA1 gene mutation can result in a disorder similar to multiple system atrophy, both clinically and neuropathologically.