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J S Perlmutter

Publications and source records attributed to J S Perlmutter.

At least 37 records · Page 2Linked to original sources
PubMed2001

Template images for nonhuman primate neuroimaging: 2. Macaque.

Neuroimaging studies are increasingly performed in macaque species, including the pig-tailed macaque (Macaca nemestrina). At times experimental questions can be answered by analysis of functional images in individual subjects and reference to a structural image in that subject. However, coregistration of functional brain images across many subjects offers the experimental advantage of enabling voxel-based analysis over multiple subjects and is therefore widely used in human studies. Voxel-based coregistration methods require a high-quality 3D template image. We created such templates, derived from T1-weighted MRI and blood-flow PET images from 12 nemestrina monkeys. We designed the macaque templates to be maximally compatible with the baboon template images described in a companion paper, to facilitate cross-species comparison of functional imaging data. Here we present data showing the reliability and validity of automatic image registration to the template. Alignment of selected internal fiducial points was accurate to within 1.9 mm overall (mean) even across species. The template images, along with copies aligned to the UCLA nemestrina brain atlas, are available on the Internet (purl.org/net/kbmd/n2k) and can be used as targets with any image registration software.

Animals↗
PubMed2000

The behavioral complications of pallidal stimulation: a case report.

We report a case of recurrent manic episodes associated with chronic deep brain stimulation (DBS) targeting globus pallidus (GP) in the treatment of Parkinson's disease (PD). Cardinal PD symptoms and dyskinesia improved with DBS, and neuropsychological testing found improvements in visuospatial measures associated with left DBS and in verbal memory with right DBS when compared to the patient's preoperative baseline. Under conditions of right, left, and bilateral DBS, the patient experienced bouts of mania and hypomania lasting several days at a time. Positron emission tomography (PET) with (15)O-labeled water was performed after his first manic episode under four conditions: no stimulation, right DBS, left DBS, and bilateral DBS. Although no manic switch occurred during the course of the PET study, all three DBS conditions were associated with decreases in regional flow in the left parahippocampus and hippocampus and right mid-cingulate gyrus. Increases in flow in left inferior frontal area, bilateral insula, dorsolateral prefrontal cortex, and cuneus were common to all DBS conditions. GP stimulation in PD may be associated with behavioral and cognitive effects. Distributed blood flow changes observed with pallidal DBS support a role for the pallidum in cognition and affective regulation.

Adult↗
PubMed2000

Dopa-induced blood flow responses in nonhuman primates.

Initially, treatment with the dopamine precursor levodopa provides substantial symptomatic relief for patients with Parkinson's disease (PD). However, as the disease progresses, side effects such as involuntary movements or psychosis may accompany the response to medication. The mechanisms underlying these actions of levodopa remain unclear. To develop methodology for longitudinal studies of the effects of PD and levodopa treatment in living nonhuman primates, we first studied the effects of an acute dose of levodopa on regional brain activity in sedated baboons using positron emission tomography. We found that levodopa significantly decreased regional cerebral blood flow (rCBF) bilaterally in putamen and right cingulate and increased rCBF in right lateral temporal cortex and bilateral frontal cortex. We then performed similar studies on a nemestrina in awake and sedated states to determine whether these responses were affected by sedation. Interestingly, the directions of the rCBF responses in the putamen and temporal cortex were reversed depending on the presence or absence of sedation. Specifically, responses were decreased in sedated animals, but increased dose-dependently in the awake nemestrina. These findings have important implications for the interpretation of studies that use anesthesia. The responses in the awake nemestrina were most similar to those reported in humans and thus may be the most useful model system. Future imaging studies using selective dopaminergic agents in awake animals may permit the identification of relatively specific agonist-mediated pathways and may help separate the mechanisms that mediate levodopa's benefit from those that produce its unwanted side effects.

Anesthetics, Dissociative↗
PubMed2000

Dopamine D(1) agonist activates temporal lobe structures in primates.

Changes in the function of dopamine D(1)-influenced neuronal pathways may be important to the pathophysiology of several human diseases. We recently developed methods for averaging functional imaging data across nonhuman primate subjects; in this study, we apply this method for the first time to map brain responses to experimental dopamine agonists in vivo. Here we report the use of positron emission tomography (PET) in seven normal baboons to measure the regional cerebral blood flow (rCBF) responses produced by an acute dose of the dopamine D(1) full agonist SKF82958. The most significant rCBF increases were in bilateral temporal lobe, including amygdala and superior temporal sulcus (6-17%, P < 0.001). Blood flow decreased in thalamus, pallidum, and pons (4-7%, P = 0.001). Furthermore the rCBF responses were dose-dependent and had a half-life of approximately 30 min, similar to that reported for the drug's antiparkinsonian effects. Absolute whole-brain blood flow did not change, suggesting that these local changes in rCBF reflect neuronal rather than direct vascular effects of the agonist. The prominent temporal lobe response to a D(1) agonist supports and extends our recent observations that levodopa produces prominent amygdala activation both in humans and in other primates. We speculate that levodopa may exert its known effects on mood in humans through increased amygdala activity, mediated in part by D(1) receptors.

Animals↗
PubMed1999

Evaluation of a screening questionnaire for genetic studies of Parkinson's disease.

A screening questionnaire with high sensitivity for detection of Parkinson's disease would make it easier to identify undiagnosed, yet affected, family members for genetic research. We assessed the validity of a screening questionnaire developed by Duarte et al. [1995: Mov Disord 10:643-649] with reported high specificity and sensitivity for Parkinson's disease (PD). We applied the questionnaire to 78 asymptomatic members of families that had at least two people diagnosed with PD. These families were participating in a linkage study of Parkinson's disease. Examination of these 78 revealed that 53 were normal (normal controls) and 25 were classified ("undiagnosed" PD defined) as possible, probable, or clinically definite PD based on standardized criteria. We compared these results with 123 patients with clinically definite PD ("diagnosed" PD). There were significant differences among the mean scores on the questionnaire for normal controls (4.4), subjects with undiagnosed PD (9.8), and patients with diagnosed PD (42.1; p<0.000001) and a significant difference between undiagnosed PD and normals (p<0.01). The questionnaire had only 4% sensitivity for detection of parkinsonism in undiagnosed PD using the original criteria [Duarte et al., 1995]. Revising the criteria increased the sensitivity from 4 to 48% in the undiagnosed group. The positive predictive value was 39% and the negative predictive value was 72%. Prospective application of these revised criteria is necessary to confirm the improved sensitivity. However, we conclude that this screening questionnaire has inadequate sensitivity for detection of mild parkinsonism and direct examination is still critical for accurate classification for genetic studies.

Adult↗
PubMed1999

Diminished regional cerebral blood flow response to vibration in patients with blepharospasm.

OBJECTIVE: To determine whether patients with blepharospasm have abnormal sensorimotor processing similar to patients with writer's cramp. BACKGROUND: Blepharospasm is a focal dystonia manifest by involuntary, excessive blinking and squeezing of the eyes. Altered sensorimotor processing may contribute to the development of dystonic movements. Previously the authors demonstrated decreased vibration-induced cortical blood flow responses in hand primary sensorimotor area (PSA) in patients with hand dystonia. METHODS: In this prospective, case-control study, seven patients with blepharospasm were compared with seven normal subjects. PET measurements of regional blood flow were obtained using bolus administration of H(2)15O at rest or during sequential vibration of either the left or the right hand or side of the mouth. RESULTS: PSA activation decreased significantly in the patients with blepharospasm both ipsilateral (-68%; p = 0.0004) and contralateral to the side of facial stimulation (-56%; p = 0.0009). Patients had a 31% lower mean contralateral PSA response to hand vibration and a 51% smaller right supplementary motor area response to left-hand vibration than normal subjects, but these differences did not reach statistical significance. CONCLUSIONS: Patients with blepharospasm have abnormal sensorimotor processing in response to lower face vibration. They may also have abnormal brain responses to stimulation of clinically uninvolved parts of the body, but this requires confirmation.

Aged↗
PubMed1999

Convergence insufficiency in idiopathic Parkinson's disease responsive to levodopa.

We report a patient with pathologically proven idiopathic Parkinson's disease (IPD) who developed diplopia secondary to convergence insufficiency during his motor "off" periods. Diplopia resolved with onset of motor benefit from levodopa. Neuro-ophthalmologic examination demonstrated convergence insufficiency during motor "off" periods that was alleviated after onset of motor benefit from levodopa. This is the first reported case of convergence insufficiency in IPD responsive to levodopa.

Antiparkinson Agents↗
PubMed1999

PET measurements of dopaminergic pathways in the brain.

Positron emission tomography (PET) measurements of dopaminergic pathways have revealed several new insights into the role of dopamine in the pathophysiology and pharmacology of brain diseases such as Parkinson's disease (PD), dystonia and schizophrenia. PET studies of regional blood flow or metabolism identifies sites of regional pathology. Drug-induced changes in flow or metabolism indicate the function of dopamine-mediated pathways. Measurements of radioligand binding in vivo with PET reveals abnormalities associated with specific diseases and the actions of various drugs that affect the dopaminergic system. Finally, PET measurements of the uptake of analogues of levodopa provide clues to the function of dopamine pathways potentially important for diagnosis and treatment of disease like PD.

Adrenergic Fibers↗
PubMed1998

Altered thalamic response to levodopa in Parkinson's patients with dopa-induced dyskinesias.

Parkinson's disease (PD) is a progressive neurologic condition characterized by tremor, slowness, stiffness, and unstable posture. Degeneration of dopamine-producing neurons in the substantia nigra causes PD. Treatment with levodopa, a precursor of dopamine, initially ameliorates the clinical manifestations of PD. However, chronic levodopa treatment can produce severe involuntary movements (so-called dopa-induced dyskinesias or DID), limiting treatment. Pallidotomy, placement of a surgical lesion in the internal segment of the globus pallidus, reduces DID. Because this result is inconsistent with current theories of both basal ganglia function and DID, it prompted us to investigate the brain's response to levodopa. We measured regional cerebral blood flow response to levodopa with positron-emission tomography in 6 PD patients with DID, 10 chronically treated PD patients without DID, 17 dopa-naïve PD patients, and 11 normals. The dose of levodopa was chosen to produce clinical benefit without inducing DID. This strategy allowed us to examine the brain response to levodopa across groups without the confounding effect of differences in motor behavior. We found that the DID group had a significantly greater response in ventrolateral thalamus than the other groups. This was associated with decreased activity in primary motor cortex. These findings are consistent with increased inhibitory output from the internal segment of the globus pallidus to thalamus after levodopa administration. They provide a physiological explanation for the clinical efficacy of pallidotomy and new insights into the physiology of the basal ganglia.

Adult↗
PubMed1998

Mutational and biochemical analysis of dopamine in dystonia: evidence for decreased dopamine D2 receptor inhibition.

The dystonias are a group of serious movement disorders characterized by involuntary muscle spasms of different parts of the body. We recently proposed that hypofunction of dopamine D2 receptor-mediated inhibition of the indirect output pathway of the basal ganglia can result in dystonia. In this review, we discuss the results of a variety of genetic and biochemical studies in light of this hypothesis. Several forms of early-onset dystonia show distinct autosomal dominant, recessive, or X-linked genetic transmission patterns. Late onset forms of dystonia, though not showing clear Mendelian transmission patterns, also appear to be highly familial. Recently, several genetic-linkage locations have been identified for early-onset dystonia and for two of these loci, mutations decreasing dopamine synthesis have been demonstrated. Biochemical studies of monkeys and man also demonstrate that several types of dystonia occur in a dopamine-deficiency state. Similarly, mice strains developed to be deficient in several dopamine-pathway components have motor abnormalities consistent with dystonia. Hypofunction of the dopamine D2 receptor-mediated inhibition of the indirect output pathway of the putamen may be a common feature of many of these heritable and secondary dystonic syndromes.

Animals↗
PubMed1998

Levodopa responsive parkinsonism in an adult with Huntington's disease.

A patient is reported on with Huntington's disease who, as an adult, first developed severe parkinsonism with bradykinesia, rigidity, postural instability and festinating gait. His clinical signs were similar to those of the Westphal variant of Huntington's disease except that he also had resting tremor and a supranuclear gaze palsy. Magnetic resonance imaging showed caudate and putamen atrophy. Genetic analysis disclosed 49 triple CAG repeats in allele 1 and 17 in allele 2 confirming the diagnosis of Huntington's disease. Treatment with levodopa produced substantial functional motor improvement with a 17 point reduction in the unified Parkinson's disease rating scale (UPDRS) motor subscale including reduction of tremor, bradykinesia, and postural instability. This is the first report of a patient with adult onset Huntington's disease with parkinsonism responsive to levodopa.

Adult↗
PubMed1998

Changes in brain activity during motor learning measured with PET: effects of hand of performance and practice.

The aim of this study is to assess brain activity measured during continuous performance of design tracing tasks. Three issues were addressed: identification of brain areas involved in performing maze and square tracing tasks, investigation of differences and similarities in these areas related to dominant and nondominant hand performance, and most importantly, examination of the effects of practice in these areas. A total of 32 normal, right-handed subjects were instructed to move a pen with the dominant right hand (16 subjects) or nondominant left hand (16 subjects) continuously through cut-out maze and square patterns with their eyes closed during a 40-s positron emission tomography (PET) scan to measure regional blood flow. There were six conditions: 1) holding the pen on a writing tablet without moving it (rest condition); 2) tracing a maze without practice; 3) tracing the same maze after 10 min of practice; 4) tracing a novel maze; and tracing an easily learned square design at 5) high or 6) low speed. To identify brain areas generally related to continuous tracing, data analyses were performed on the combined data acquired during the five tracing scans minus rest conditions. Areas activated included: primary and secondary motor areas, somatosensory, parietal, and inferior frontal cortex, thalamus, and several cerebellar regions. Then comparisons were made between right- and left-hand performance. There were no significant differences in performance. As for brain activations, only primary motor cortex and anterior cerebellum showed activations that switched with hand of performance. All other areas, with the exception of the midbrain, showed activations that were common for both right- and left-hand performance. These areas were further analyzed for significant conditional effects. We found patterns of activation related to velocity in the contralateral primary motor cortex, related to unskilled performance in right premotor and parietal areas and left cerebellum, related to skilled performance in supplementary motor area (SMA), and related to the level of capacity at which subjects were performing in left premotor cortex, ipsilateral anterior cerebellum, right posterior cerebellum and right dentate nucleus. These findings demonstrate two important principles: 1) practice produces a shift in activity from one set of areas to a different area and 2) practice-related activations appeared in the same hemisphere regardless of the hand used, suggesting that some of the areas related to maze learning must code information at an abstract level that is distinct from the motor performance of the task itself.

Adult↗
PubMed1998

Putamen volume in idiopathic focal dystonia.

OBJECTIVE: To determine whether the volume of the putamen is abnormal in patients with idiopathic focal dystonia. BACKGROUND: The cause of adult-onset focal dystonia is unknown, but substantial evidence suggests that the putamen may be abnormal in this condition. Cell loss and gliosis have been suggested. We hypothesized that this might be reflected as abnormal putamen volume on MRI. DESIGN AND METHODS: A high-resolution MRI was acquired in 13 adults with cranial or hand dystonia and 13 normal individuals matched for age and sex. Putamen volume was measured using a stereologic method (Study 1). In a replication study, another rater measured putamen volume using manual tracing and direct voxel count (Study 2). Neither rater was aware of the diagnosis, and the order of measurement was random in each study. RESULTS: In Study 1, putamen measurements were reasonably accurate (coefficient of error, approximately 6%). The putamen was 13% larger in patients, both in absolute terms (p = 0.03) and after covarying total brain volume (p = 0.02). In Study 2, putamen volumes correlated with those measured in Study 1 (intraclass correlation coefficient, 0.68 to 0.83). The putamen was 8% larger in patients (p = 0.06) and was larger in the patient than in the matched control subject in 10 of 13 pairs (p = 0.046). CONCLUSION: We find no evidence of putaminal atrophy or degeneration in adult-onset idiopathic focal dystonia. In fact, in this group, the putamen is about 10% larger in patients than in matched control subjects. This finding may reflect a response to the dystonia or may relate to its cause.

Adult↗
PubMed1998

Mutation, sequence analysis, and association studies of alpha-synuclein in Parkinson's disease.

A mutation within the alpha-synuclein gene on human chromosome 4 has been reported to segregate with PD in an Italian family. We screened a sample of familial cases of PD for mutation in the alpha-synuclein gene. None of the familial cases of PD carried a mutation within the alpha-synuclein gene, and no association was detected between PD and alleles of a dinucleotide repeat marker within the alpha-synuclein gene. We conclude that variation within the alpha-synuclein gene does not play a significant role in the risk for PD in our sample.

Aged↗
PubMed1998

Preoperative treatment with botulinum toxin to facilitate cervical fusion in dystonic cerebral palsy. Report of two cases.

The authors report the use of high-dose botulinum toxin A for muscle relaxation prior to surgery for cervical spine fixation in two patients with dystonic cerebral palsy that included severe cervical dystonia. Both patients had recently developed progressive cervical myelopathy and surgery was planned to halt the insidious progressive weakness. However, marked dystonic posturing of the neck would have compromised their tolerance of halo fixation and subsequently impeded postoperative fusion. Preoperative chemodenervation of selected cervical muscles with injections of high-dose botulinum toxin A eliminated all involuntary neck movements, permitting the patients to tolerate halo fixation and facilitating postoperative spinal fusion. It is concluded that botulinum toxin A can be used safely and effectively in the preoperative management of patients with cervical dystonia and cervical spondylitic myelopathy.

Adult↗