Design Prospective study.
Setting The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months).
Participants Eight hundred four subjects with early PD enrolled in the PRECEPT study.
Main Outcome Measures The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123–labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([123I]β-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects.
Results The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [123I]β-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43).
Conclusions These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD.
Trial Registration clinicaltrials.gov Identifier:
Published online Apr 14, 2008 (doi:10.1001/archneur.2008.65.6.nct70003).
]]>Objective To assess whether prior use of AP drugs is related to outcome following intravenous tissue plasminogen activator therapy in patients with ischemic stroke.
Design, Setting, and Patients A single-center prospective observational cohort study of the relation between prior AP therapy, occurrence of SICH, and functional outcome of consecutive patients with ischemic stroke undergoing intravenous thrombolysis with tissue plasminogen activator in a university hospital between April 1, 2002, and November 30, 2006.
Main Outcome Measures The occurrence of SICH and favorable outcome reflecting independence defined as a modified Rankin Scale score of 2 or lower at 3 months.
Results Of the 301 patients who received intravenous tissue plasminogen activator, 89 used AP drugs prior to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 12 patients (13.5%; 95% confidence interval, 7.8%-22.3%) who had received AP drugs and in 6 patients (2.8%; 95% confidence interval, 1.2%-6.2%) without prior AP therapy (P = .001). Multivariate analysis revealed that prior AP therapy was an independent predictor of SICH (odds ratio, 6.0; 95% confidence interval, 2.0-17.1). Nonetheless, prior AP therapy was independently associated with a favorable outcome (odds ratio, 2.0; 95% confidence interval, 1.0-4.3).
Conclusion Despite a higher incidence of SICH, the net benefit of intravenous tissue plasminogen activator therapy for acute ischemic stroke was greater in patients using AP drugs.
Published online March 10, 2008 (doi:10.1001/archneur.65.5.noc70077).
]]>Design We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset ≤50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband.
Setting Tertiary care movement disorders center.
Patients Cases, controls, and their first-degree relatives were enrolled in the GEPD study.
Main Outcome Measures Estimated age-specific penetrance in first-degree relatives.
Results Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52).
Conclusions The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study.
]]>Objective To investigate possible changes in insulin sensitivity and secretion, major determinants of glucose homeostasis, in a group of consecutive normoglycemic patients with HD.
Design Metabolic investigations.
Participants Twenty-nine untreated, nondiabetic patients with HD and 22 control participants matched by age, sex, and socioeconomic background.
Main Outcome Measures Glucose tolerance, assessed by means of the glucose curve during oral glucose challenge; insulin sensitivity, assessed using homeostasis model assessment and minimal model analysis based on frequent sampling of plasma glucose and plasma insulin during the intravenous glucose tolerance test; and insulin secretion, determined by means of the acute insulin response and the insulinogenic index.
Results The evaluation of insulin sensitivity using homeostasis model assessment demonstrated higher homeostasis model assessment insulin resistance indices, and a lower sensitivity index when the minimal model approach was used, in patients with HD compared with controls (P = .03 and P = .003, respectively). In the assessment of early-phase insulin secretion, the acute insulin response and the insulinogenic index were lower in patients with HD compared with controls (P = .02). The number of CAG repeats correlated significantly only with acute insulin response (P = .003).
Conclusions Besides impairment in insulin secretion capacity, a simultaneous decrease in insulin sensitivity, with an increase in the insulin resistance level, was found in normoglycemic patients with HD compared with controls. These data imply that progression of the insulin secretion defect in HD may lead to a failure to compensate for insulin resistance.
]]>Objective To evaluate the HD sleep-wake phenotype (including abnormal motor activity during sleep) in patients with various HD stages and the length of CAG repeats. Because a mild hypocretin deficiency has been found in the brains of some patients with HD (hereinafter referred to as HD patients), we also tested the HD patients for narcolepsy.
Design and Patients Twenty-five HD patients (including 2 premanifest carriers) underwent clinical interview, nighttime video and sleep monitoring, and daytime multiple sleep latency tests. Their results were compared with those of patients with narcolepsy and control patients.
Results The HD patients had frequent insomnia, earlier sleep onset, lower sleep efficiency, increased stage 1 sleep, delayed and shortened rapid eye movement (REM) sleep, and increased periodic leg movements. Three HD patients (12%) had REM sleep behavior disorders. No sleep abnormality correlated with CAG repeat length. Reduced REM sleep duration (but not REM sleep behavior disorders) was present in premanifest carriers and patients with very mild HD and worsened with disease severity. In contrast to narcoleptic patients, HD patients had no cataplexy, hypnagogic hallucinations, or sleep paralysis. Four HD patients had abnormally low (< 8 minutes) daytime sleep latencies, but none had multiple sleep-onset REM periods.
Conclusions The sleep phenotype of HD includes insomnia, advanced sleep phase, periodic leg movements, REM sleep behavior disorders, and reduced REM sleep but not narcolepsy. Reduced REM sleep may precede chorea. Mutant huntingtin may exert an effect on REM sleep and motor control during sleep.
]]>Objective To search for disease-causing mutations in SCN1A in patients with cryptogenic epileptic syndromes (ie, syndromes with an unknown cause).
Design Clinical characterization and molecular genetic analysis of a cohort of patients.
Setting University hospitals, rehabilitation centers, and molecular biology laboratories.
Patients Sixty unrelated patients with cryptogenic epileptic syndromes.
Main Outcome Measures Samples of DNA were analyzed for mutations and for large heterozygous deletions encompassing the SCN1A gene. A search for microdeletions in the SCN1A gene was also performed in the subset of patients with SMEI/SMEI-borderland who had negative results at the point mutation screening.
Results No large deletions at the SCN1A locus were found in any of the patients analyzed. In contrast, 13 different point mutations were identified in 12 patients: 10 with SMEI, 1 with generalized epilepsy with febrile seizures plus, and 1 with cryptogenic focal epilepsy. An additional search for SCN1A intragenic microdeletions in the remaining patients with SMEI/SMEI-borderland and no point mutations was also negative.
Conclusions These results confirm the role of the SCN1A gene in different types of epilepsy, including cryptogenic epileptic syndromes. However, large deletions encompassing SCN1A were not common disease-causing rearrangements in this group of epilepsies.
]]>Methods We performed nerve conduction studies in 16 male carriers with FXTAS, 11 non-FXTAS carriers, and 11 control subjects and assessed the outcomes with respect to the fragile X mental retardation 1 genotype (FMR1) (Online Mendelian Inheritance in Man [OMIM]
Results Men with FXTAS had slower tibial nerve conduction velocities and prolonged F-wave latencies compared with controls (z = 2.06, P = .04; and z = 2.73, P = .005) and unaffected premutation males (z = 1.98, P = .04; and z = 2.00, P = .04). Compound muscle action potential amplitudes were smaller in the FXTAS group relative to controls. Sural nerve action potential amplitudes were reduced in the FXTAS group compared with controls. After controlling for age, there was a significant relationship between the longer CGG repeat number and tibial nerve conduction velocity slowing (r = –0.42, P = .04) and between elevated messenger RNA levels and reduction of the tibial compound muscle action potential velocity (r = –0.52, P = .01) in the permutation group.
Conclusions Male premutation carriers had significant conduction abnormalities of motor and sensory nerves that correlated with molecular measures, suggesting that the premutation FMR1 genotype is a causal factor. There was also evidence of nerve conduction abnormalities in non-FXTAS carriers compared with controls, which suggests that the neuropathy can occur without the full clinical presentation of FXTAS.
]]>Objective To describe features of 1 Swedish and 1 American family with the previously reported Arctic APP mutation.
Design, Setting, and Participants Affected and nonaffected carriers of the Arctic APP mutation from the Swedish and American families were investigated clinically. In addition, 1 brain from each family was investigated neuropathologically.
Results The clinical picture, with age at disease onset in the sixth to seventh decade of life and dysfunction in multiple cognitive areas, is indicative of Alzheimer disease and similar to the phenotype for other Alzheimer disease APP mutations. Several affected mutation carriers displayed general brain atrophy and reduced blood flow of the parietal lobe as demonstrated by magnetic resonance imaging and single-photon emission computed tomography. One Swedish case and 1 American case with the Arctic APP mutation came to autopsy, and both showed no signs of hemorrhage but revealed severe congophilic angiopathy, region-specific neurofibrillary tangle pathological findings, and abundant amyloid plaques. Intriguingly, most plaques from both of these cases had a characteristic ringlike character.
Conclusions Overall, our findings corroborate that the Arctic APP mutation causes a clinical and neuropathological picture compatible with Alzheimer disease.
]]>Design Case series.
Patients A large British kindred (DRC255) with a PGRN mutation was assessed. Affected individuals presented with a mean age of 57.8 years (range, 54-67 years) and a mean disease duration of 6.1 years (range, 2-11 years).
Results All patients exhibited a clinical and radiologic phenotype compatible with frontotemporal lobar degeneration based on current consensus criteria. However, unlike sporadic frontotemporal lobar degeneration, parietal deficits, consisting of dyscalculia, visuoperceptual /visuospatial dysfunction, and/or limb apraxia, were a common feature, and brain imaging showed posterior extension of frontotemporal atrophy to involve the parietal lobes. Other common clinical features included language output impairment with either dynamic aphasia or nonfluent aphasia and a behavioral syndrome dominated by apathy.
Conclusion We suggest that parietal deficits may be a prominent feature of PGRN mutations and that these deficits may be caused by disruption of frontoparietal functional pathways.
]]>Objective To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA.
Design Four-generation family study.
Setting Academic research.
Patients We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.
Main Outcome Measures We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.
Results Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated -synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients.
Conclusions Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated -synuclein in the brains of patients.
]]>Objective To determine whether the truncated spartin protein is present or absent in cells derived from patients with Troyer syndrome.
Design Case report.
Setting Academic research.
Patients We describe a new family with Troyer syndrome due to the 1110delA mutation.
Main Outcome Measures We cultured primary fibroblasts and generated lymphoblasts from affected individuals, carriers, and control subjects and subjected these cells to immunoblot analyses.
Results Spartin protein is undetectable in several cell lines derived from patients with Troyer syndrome.
Conclusions Our data suggest that Troyer syndrome results from complete loss of spartin protein rather than from the predicted partly functional fragment. This may reflect increased protein degradation or impaired translation.
]]>Design Machado-Joseph disease is a common autosomal dominant cerebellar ataxia caused by an unstable CAG trinucleotide repeat expansion. Muscle cramps and fasciculations are frequent and sometimes disabling manifestations. However, their frequency and pathophysiological mechanisms remain largely unknown. Symptomatic patients with MJD (hereinafter MJD patients) with molecular confirmation were assessed prospectively. A standard questionnaire addressing clinical features of muscle cramps and fasciculations was used. The Cramps Disability Scale was used to quantify cramps-related disability. Patients underwent neurophysiological testing with routine techniques. F waves of the right median nerves were obtained, and persistence indexes were calculated. Four muscles (deltoid, first dorsal interossei, tibialis anterior, and vastus lateralis) were examined by needle electromyography. A semiquantitative scale (from 0 [no activity] to 4 [continuous activity]) was used to determine the frequency of rest fasciculations in each muscle.
Results Fifty MJD patients (29 men) were included in the study. Their mean age at examination was 46.3 years, their mean age at onset of the disease was 35 years, and the mean duration of disease was 11.2 years. Abnormal CAGn varied from 59 to 75 repeats. Forty-one patients presented with muscle cramps; in 10, this was their first symptom. The frequency of cramps varied between 1 and 90 episodes a week. For 15 patients, cramps were the chief complaint, frequently disturbing sleep or work (Cramps Disability Scale score, 2 or 3). Lower limbs were affected in 37 individuals, but unusual regions, such as the face and abdominal muscles, were also involved. Fasciculations were found in 25 individuals; in 8 patients, they included facial muscles. However, fasciculations were not a significant complaint for any of these patients. The clinical and neurophysiological profile of MJD patients with and without cramps was not significantly different. However, MJD patients with fasciculations had more severe damage to their peripheral nerves.
Conclusions Muscle excitability abnormalities were found in 41 MJD patients (82%), and they were the presenting complaint in 10 (20%). They are related to altered excitability of peripheral motor axons, but mechanisms underlying cramps and fasciculations are possibly distinct in MJD patients.
]]>Objective To identify early abnormalities of ocular motor function in individuals who have the spinocerebellar ataxia type 6 (SCA6) gene (CACNA1A) but no clinical symptoms.
Design Physiological techniques were used to record and analyze eye movements and postural sway.
Patients Four presymptomatic and 5 ataxic patients with SCA6, genetically identified, and 10 healthy controls.
Results Presymptomatic individuals had normal postural sway but definite ocular motor abnormalities. Two had a low-amplitude horizontal gaze–evoked nystagmus, 1 of whom had a significantly decreased eye velocity for upward saccades and an abnormal frequency of square-wave jerks. Another had abnormal square-wave jerks and a fourth had a reduced gain for pursuit tracking. Not all of the presymptomatic patients had the same findings, but a multivariate analysis discriminated the presymptomatic patients, as a group, from healthy controls and the ataxic patients.
Conclusions Among the earliest functional deficits in SCA6 are eye movement abnormalities, including impaired saccade velocity, saccade metrics, and pursuit gain. This suggests that early functional impairments are caused by cellular dysfunction and/or loss in the posterior cerebellar vermis and flocculus. These findings might help to determine the timing of a treatment and to define variables that could be used as outcome measures for the efficacy of therapeutic trials.
]]>Objective To describe the occurrence of single-gene neurogenetic disorders in a group of elderly patients.
Design Retrospective review of neurogenetic cases in an academic medical center.
Setting Academic university and Veterans Affairs medical centers.
Patients Eight elderly patients with single-gene neurogenetic diseases were studied. These patients included an 87-year-old man and an 85-year-old man with Huntington disease, an 84-year-old woman with limb-girdle muscular dystrophy type 2A, a 78-year-old man with spinocerebellar ataxia type 14, an 86-year-old man with spinocerebellar ataxia type 5, an 85-year-old man with a presenilin 1 familial Alzheimer disease mutation, an 87-year-old man with autosomal dominant hereditary neuropathy, and a 78-year-old man with spinocerebellar ataxia type 6. Three patients had no family history of neurologic disease.
Main Outcome Measures Medical histories, physical examination results, and genetic testing results.
Conclusions Single-gene mendelian neurogenetic diseases can be found in the oldest old population (> 85 years). Such cases are currently underrecognized and will become more commonly observed in the future. This phenomenon is a result of (1) the aging of the general population, (2) better recognition of the highly variable ages at onset of genetic diseases, and (3) the availability of specific DNA-based genetic testing.
]]>Design, Setting, and Patients Positron emission tomography with 11C-PiB and magnetic resonance imaging were performed for 2 patients, 49-year-old and 60-year-old siblings with APP locus duplication, with hereditary Alzheimer disease and cerebral amyloid angiopathy.
Main Outcome Measure Change in 11C-PiB uptake.
Results Uptake of 11C-PiB was increased especially in the striatum (caudate nucleus to 225% and 280% of the control mean and putamen to 166% and 185% of the control mean) and in the posterior cingulate (to 168% and 198% of the control mean), and it was marginally increased in other cortical brain areas. The pattern of increased 11C-PiB uptake was different from that seen in sporadic Alzheimer disease.
Conclusions Amyloid imaging with 11C-PiB positron emission tomography is a useful tool for detecting in vivo amyloid accumulation in patients with hereditary cerebral amyloid angiopathy. However, the pattern of 11C-PiB accumulation differs between patients with typical AD and patients with APP locus duplication.
]]>Objective To determine whether multisequence MRI of the brain can show thalamic alterations and establish pathoradiologic correlations in a patient with familial fatal insomnia.
Design Radioclinical prospective study. We describe a patient with fatal familial insomnia and normal MRI images. Because the MRI study was performed only 4 days before the patient's death, we were able to compare radiological data with the lesions observed at the neuropathologic level.
Patient A 55-year-old man with familial fatal insomnia.
Main Outcome Measure Magnetic resonance spectroscopy combined with the measurement of apparent diffusion coefficient of water in different brain areas.
Results The neuroradiological study showed, in the thalamus but not in the other brain regions studied, an increase of apparent diffusion coefficient of water and a metabolic pattern indicating gliosis. These alterations closely correlated with neuropathologic data showing an almost pure gliosis that was restricted to the thalami.
Conclusion Considering fatal familial insomnia as a model of thalamic-restricted gliosis, this case demonstrates that multisequences of magnetic resonance can detect prion-induced gliosis in vivo, as confirmed by a neuropathologic examination performed only a few days after radiological examination.
]]>Design Fluorescence in situ hybridization and array comparative genomic hybridization were used to map the locations of chromosomal translocation breakpoints.
Results SLC4A10 (OMIM
Conclusion SLC4A10 is the third SLC4 base transporter family member to be implicated in human cognition and epilepsy.
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