iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates.

Young-onset Parkinson's disease (YOPD), defined by onset at <50 years, accounts for approximately 10% of all Parkinson's disease cases and, while some cases are associated with known genetic mutations, most are not. Here induced pluripotent stem cells were generated from control individuals and from patients with YOPD with no known mutations. Following differentiation into cultures containing dopamine neurons, induced pluripotent stem cells from patients with YOPD showed increased accumulation of soluble α-synuclein protein and phosphorylated protein kinase Cα, as well as reduced abundance of lysosomal membrane proteins such as LAMP1. Testing activators of lysosomal function showed that specific phorbol esters, such as PEP005, reduced α-synuclein and phosphorylated protein kinase Cα levels while increasing LAMP1 abundance. Interestingly, the reduction in α-synuclein occurred through proteasomal degradation. PEP005 delivery to mouse striatum also decreased α-synuclein production in vivo. Induced pluripotent stem cell-derived dopaminergic cultures reveal a signature in patients with YOPD who have no known Parkinson's disease-related mutations, suggesting that there might be other genetic contributions to this disorder. This signature was normalized by specific phorbol esters, making them promising therapeutic candidates.

The role of Personal KinetiGraph™ fluctuator score in quantifying the progression of motor fluctuations in Parkinson's disease.

Motor fluctuations (MF) are important determinants of quality of life in Parkinson's disease (PD). To determine whether the Personal Kineti Graph (PKG), a wearable motion tracking device, can define MF progression, we correlated PKG fluctuator scores (FS) with clinical motor fluctuator profiles in a case-control cohort study. 54 subjects completed a 6-day PKG trial and completed a standardized motor diary. We distinguished non-fluctuators (NF), early (EF), moderate (MF) and troublesome fluctuators (TF), based on Wearing Off Questionnaire and Movement Disorders Society-Unified Parkinson's Disease Rating Scale scores. PKG FS significantly differentiated EF and TF, as well as dyskinetic and non-dyskinetic subjects. Motor diaries could not distinguish the four study groups on the basis of average OFF time, while average time with dyskinesia distinguished NF and MF. In conclusion, PKG FS can distinguish EF from TF, as well as dyskinetic from non-dyskinetic patients, but cannot discriminate subtler MF. PKG may provide objective MF measures for routine PD management and clinical trials.

Subthalamic deep brain stimulation and impulse control in Parkinson's disease.

BACKGROUND AND PURPOSE: Experimental studies suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) induces impulsivity in patients with Parkinson's disease (PD). The purpose of this study was to assess various measures of impulse control in PD patients with STN DBS in comparison to patients receiving medical therapy. METHODS: In a cross-sectional evaluation, 53 consecutively eligible patients were assessed for impulsivity with the Barratt Impulsiveness Scale, for impulse control disorders (ICDs) using the Minnesota Impulsive Disorders Interview, and for obsessive-compulsive symptoms using the Maudsley Obsessional-Compulsive Inventory. RESULTS: Independent samples t-tests revealed that compulsivity scores were not different between DBS patients and patients without DBS. However, impulsivity scores were significantly higher in DBS patients. Additionally, ICDs were observed in 3 of 16 (19%) DBS patients and in 3 of 37 (8%) medically treated patients. No association was found between the use of dopamine agonists and impulsivity in DBS patients. CONCLUSIONS: Our data suggest that screening for impulsivity and ICDs should be performed prior to DBS, and that patients should be monitored for these problems during follow-up. Prospective trials are needed to confirm the findings of this exploratory study and to elucidate the reasons of a possible induction of impulsivity by STN DBS.

Sixty hertz pallidal deep brain stimulation for primary torsion dystonia.

OBJECTIVE: To evaluate the safety and efficacy of 60 Hz deep brain stimulation (DBS) of the globus pallidus internus (GPi) in 15 consecutive patients with primary dystonia. METHODS: We conducted a retrospective analysis of clinic charts relative to 15 consecutive patients with medically refractory primary dystonia who underwent stereotactic implantation of DBS leads within the GPi. Twelve had the DYT1 gene mutation. Frame-based MRI and intraoperative microelectrode recording were employed for targeting. All patients were treated exclusively with stimulation at 60 Hz from therapy outset. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) served as the primary measure of symptom severity at baseline and 1, 3, 6, and 12 months after treatment. RESULTS: All patients tolerated DBS treatment well and showed a progressive median improvement of their BFMDRS motor subscores from 38% at 1 month to 89% at 1 year (p < 0.001, Wilcoxon rank sum test). The disability subscores were similarly improved. The clinical response to DBS allowed seven patients to completely discontinue their medications; six additional patients had reduced their medications by at least 50%. Surgical complications were limited to two superficial infections, which were treated successfully. CONCLUSIONS: Stimulation of the internal globus pallidus at 60 Hz is safe and effective for treating medically refractory primary dystonia.

Emergence of restless legs syndrome during subthalamic stimulation for Parkinson disease.

The authors systematically studied the emergence of restless legs syndrome (RLS) after subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson disease (PD). Postoperatively, 11 of 195 patients with STN DBS reported new problematic symptoms of RLS. The mean reduction in antiparkinsonian medication was 74%. The mean RLS score at diagnosis was 15 (+/-5.9) of a possible 24 points and after symptomatic drug therapy 4.3 (+/-3.1) points. Reduction of antiparkinsonian medication during STN DBS may unmask symptoms of RLS and complicate therapy of both RLS and PD.

Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study.

BACKGROUND: The histopathology of AIDS-associated myelopathy (AM) closely resembles that of myelopathies due to cobalamin or folate deficiency, with white matter vacuolization in the spinal cord. The pathogenesis of AM appears unrelated to direct HIV infection of the spinal cord. There is abnormal trans-methylation metabolism in AM, with decreased availability of the methyl group donor S-adenosyl-methionine (SAM). The authors hypothesized that treatment with l-methionine, the direct metabolic precursor of SAM, might improve AM. OBJECTIVE: To determine the safety and efficacy of l-methionine treatment in AM. METHODS: Fifty-six patients with clinical diagnosis of AM were randomized to a Phase II, double-blind, placebo-controlled study comparing the effect of l-methionine 6 g/day in two divided doses with that of placebo. Study duration was 12 weeks. All patients had somatosensory evoked potentials with prolonged central conduction time (CCT) at entry. Change in CCT was the primary endpoint of the study. Frequency of adverse events (AEs) was used to assess safety. Secondary endpoints were strength, spasticity, and urinary function. Biochemical measurements included serum methionine and homocysteine and CSF SAM. RESULTS: There were no significant differences in AEs between the two groups. Serum homocysteine increased in l-methionine-treated patients from 7.2 (+/-5.2 SD) to 12.6 (+/-6.15 SD) micromol/L. The mean CCT at baseline was 25.9 milliseconds (+/-7.3 SD) for the treatment group and 24.1 milliseconds (+/-7.0 SD) for the placebo group. At completion, it was 3.0 milliseconds (+/-6.1 SD) for the treatment group and 23.6 milliseconds (+/-5.5 SD) for the placebo group (p = 0.17). In a subset of 15 patients with CSF studies, SAM levels increased in the l-methionine but not in the placebo group (p = 0.07). There was no significant effect of treatment on strength, spasticity, or urinary function. CONCLUSIONS: l-methionine was safe and well tolerated although in some patients induced an increase of serum homocysteine. There was a nonsignificant improvement in CCT in treated patients but no benefit in any of the clinical measures.

Intraoperative microelectrode recording equipment: what features are necessary?

Intraoperative neurophysiologic methods for localizing targets deep in the brain require the use of specialized monitoring and recording equipment, including stimulators, neurophysiologic recording devices, and image manipulation tools. When using microelectrode recording devices there are some specifications that are more important than others, such as signal-to-noise ratios and amplifier impedance. As more companies develop tools to be used in the operating room, the end users have more choices. Some of the more important specifications are discussed and a comparison is made of the five major brands on the market today.

A major locus for myoclonus-dystonia maps to chromosome 7q in eight families.

Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported in another. We performed genetic studies, using eight additional families with M-D, to assess these two loci. No evidence for linkage was found for 11q markers. However, all eight of these families showed linkage to chromosome 7 markers, with a combined multipoint LOD score of 11.71. Recombination events in the families define the disease gene within a 14-cM interval flanked by D7S2212 and D7S821. These data provide evidence for a major locus for M-D on chromosome 7q21.

AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid.

The pathogenesis of AIDS-associated myelopathy is unknown. Elevated HIV-1 viral load in CSF has been associated with cognitive impairment. The authors investigated if a similar association exists in patients with myelopathy. The authors evaluated levels of HIV-1 RNA in the CSF of 16 individuals with AIDS myelopathy and in 16 nonmyelopathic HIV-infected control subjects. There was no correlation between levels of HIV-1 RNA and the presence or severity of myelopathy.

The role of somatosensory evoked potentials in the diagnosis of AIDS-associated myelopathy.

BACKGROUND: Although AIDS-associated vacuolar myelopathy is detected in >50% of autopsy cases, it is often unrecognized during life. The clinical assessment is often difficult because of concurrent peripheral neuropathy and lack of specific diagnostic markers. Somatosensory evoked potentials (SEPs) have been successfully used to evaluate central conduction in a number of diseases involving the spinal cord. OBJECTIVES: To assess the diagnostic yield of SEPs in AIDS-associated myelopathy. METHODS: We recorded tibial and median nerve SEPs in 69 HIV-infected subjects referred for evaluation of lower extremity neurologic abnormalities. Stimulation of the peroneal nerve at the popliteal fossa was performed in patients with absent response to ankle stimulation. RESULTS: HIV-infected subjects had significantly delayed latencies of both peripheral and central potentials, suggesting a combination of peripheral and CNS abnormalities. Analysis of peripheral and central latencies allowed us to discriminate between neuropathy and myelopathy in individual patients. Abnormalities of tibial central conduction time (CCT) correlated with clinical diagnosis of myelopathy. There was no significant difference in median CCTs between patients and controls, suggesting that conduction abnormalities were restricted to the thoracolumbar spinal cord. A derived spinal conduction time was a sensitive indicator of central conduction abnormalities in AIDS patients with myelopathy. CONCLUSIONS: The combination of median, posterior tibial, and peroneal SEPs is a valuable tool in the diagnosis of AIDS-associated myelopathy, particularly when myelopathy and peripheral neuropathy coexist. The use of a derived spinal conduction time improves the diagnostic yield of SEPs in AIDS-associated myelopathy.

MR findings in AIDS-associated myelopathy.

BACKGROUND AND PURPOSE: The most common cause of spinal cord disease among patients with AIDS or those infected with HIV-1 is AIDS-associated myelopathy. The purpose of this study was to determine the MR characteristics of the spinal cord in this patient population and to correlate these findings with the clinical severity of myelopathy. METHODS: MR images of the spinal cord in 21 patients with documented HIV-1 infection or AIDS and a clinical diagnosis of AIDS-associated myelopathy were assessed retrospectively for atrophy, intrinsic signal abnormality, and abnormal enhancement. The clinical severity of myelopathy was graded by a neurologist on the basis of physical examination, and a qualitative correlation was made with the MR findings. RESULTS: MR findings were abnormal in 18 of the 21 patients. The most common feature was spinal cord atrophy (n = 15), typically involving the thoracic cord with or without cervical cord involvement, followed by intrinsic cord signal abnormality (n = 6), and normal-appearing cord (n = 3). Three patients had both cord atrophy and intrinsic cord signal abnormality. The cord signal abnormality was diffuse, without predilection for any specific distribution pattern. Enhancement was not seen in any of the 10 patients who received intravenous contrast material. Only one of 16 patients with moderate to severe myelopathy had normal MR findings, as compared with two of five patients with mild myelopathy. CONCLUSION: MR findings in the spinal cord are abnormal in the majority of patients with AIDS-associated myelopathy, typically showing spinal cord atrophy, with or without intrinsic cord signal abnormality. Patients with moderate to severe myelopathy have an increased frequency of spinal cord abnormalities, but a definite correlation between clinical severity of myelopathy and extent of MR abnormalities remains to be established.

Hip prothesis: an in vitro wear protocol based on a comparison between gravimetric and profilometric analysis.

Ultra high molecular weight polyethylene acetabular cups were analysed by means of a shadowgraph method (using a profile projector) to measure linear wear. The results were compared with those of previous wear tests performed on a hip joint simulator. Twelve polyethylene acetabular cups were analysed. The specimens were evaluated visually for evidence of polyethylene wear. Examination of the polyethylene inner surface did not reveal evidence of surface failure such as delamination, fatigue cracks or scratches. Volumetric wear was calculated using a formula based on dimensional change due to the penetration of the femoral head in the acetabular cup. It was found to be of the same order of magnitude as the wear obtained in in vitro experimental tests.

A mixed D1 and D2 antagonist does not replay pattern electroretinogram alterations observed with a selective D2 antagonist in normal humans: relationship with Parkinson's disease pattern electroretinogram alterations.

The human retina produces a tuned response to stimuli of increasing spatial frequency reversed at a steady state. The peak amplitude response, at medium spatial frequencies, is decreased in Parkinson's disease and in normal subjects (n = 18) treated with a D2 dopaminergic antagonist (l-sulpiride). Here, we report that a mixed D1-D2 receptor antagonist (haloperidol) in normal subjects (n = 18) does not produce an amplitude decrease of medium spatial frequencies (SFs) responses but it decreases low-frequency response. It could argued that the increased dopamine release produced by the presynaptic D2 antagonistic action of haloperidol is subsequently counteracted at postsynaptic level by its D1 antagonistic effect, producing a net counterbalance at medium SFs. These data suggest that the two dopamine receptors may play different roles in the retinal function and in the origin of visual alterations in Parkinson's disease.

Peripheral nerve function in HIV infection: clinical, electrophysiologic, and laboratory findings.

OBJECTIVE: To determine the effects of immunodeficiency, nutritional status, and concurrent systemic disease on peripheral nerve function in acquired immunodeficiency syndrome. DESIGN: Survey of subjects infected with human immunodeficiency virus (HIV), recruited as part of a prospective study of neuromuscular complications of HIV infection. SETTING: A neuro-acquired immunodeficiency syndrome outpatient clinic in a university medical center. PATIENTS: A consecutive sample of 251 HIV-infected individuals. Primary care providers referred subjects to the study for evaluation of neurologic symptoms or for prospective neurologic assessment. MAIN OUTCOME MEASURES: Standardized history and neurologic examination, laboratory tests (complete blood cell count, serum albumin level, vitamin B12 level, and T-lymphocyte subsets), and electrophysiologic testing of sural, tibial, and ulnar nerves. RESULTS: The most frequent neurologic diagnosis was distal symmetrical polyneuropathy (DSP) (38%). The most common clinical features were nonpainful paresthesias (71%), abnormalities of pain and temperature perception (71%), and reduced or absent ankle reflexes (66%). Patients with DSP were significantly older (P=.009), and had lower CD4 lymphocyte cell counts (P=.004) and lower hemoglobin levels (P=.004) than those without DSP. Deterioration of values on nerve conduction studies, irrespective of the clinical diagnosis of DSP, was significantly correlated with low CD4 counts, aging, abnormal serum albumin and hemoglobin levels, and weight loss. Most of these factors co-correlated, and, with the exception of age, no single variable significantly accounted for changes in results of nerve conduction studies when the influence of other factors was eliminated. CONCLUSION: The combination of several factors, including age, immunosuppression, nutritional status, and chronic disease, contributes to distal peripheral nerve dysfunction in HIV infection.

A pilot study of L-methionine for the treatment of AIDS-associated myelopathy.

The pathogenesis of AIDS-associated vacuolar myelopathy (VM) may be related to abnormality of transmethylation mechanisms in the nervous system. To evaluate the safety and potential efficacy of the methyl-group donor L-methionine in AIDS-associated VM, we conducted a pilot clinical trial in 12 patients with VM. Seven of the nine patients who completed the study had clinical and electrophysiologic improvement. Controlled studies may be indicated to assess the efficacy and safety of L-methionine in AIDS-associated VM.

D1 agonist CY208-243 attenuates the pattern electroretinogram to low spatial frequency stimuli in the monkey.

We investigated whether or not the D1 agonist, CY 208-243, affects the spatial tuning function of pattern electroretinogram (PERG). Two lightly anaesthetised monkeys were studied before and after CY 208-243 or placebo administration. The results show that the PERG response to 0.5 cycles/degree (c/d; coarse), but not to 2.3 c/d (medium) spatial frequency stimuli disappears following systemic administration of this drug. Since previous results show that D2 blockers attenuate the PERG only above 2.3 c/d, foremost the peak of the normal spatial frequency response function, the current results suggest that dopamine itself, via D1 receptors, may be responsible for the low spatial frequency decline of normal spatial PERG tuning function. We infer that the synergistic activation of D1 and D2 receptors is needed to shape the spatially tuned primate ERG.

Cerebellar degeneration associated with human immunodeficiency virus infection.

Cerebellar disorders associated with HIV infection are typically the result of discrete cerebellar lesions resulting from opportunistic infections such as toxoplasmosis and progressive multifocal leukoencephalopathy or primary CNS lymphoma. Clinical symptoms and pathologic abnormalities related to the cerebellum may also be observed with HIV dementia. A primary cerebellar degeneration with HIV has not previously been reported. Ten patients were identified over an 8-year period at five medical centers. All patients had clinical, laboratory, and radiologic evaluations, and three had neuropathologic examinations. Patients presented with progressively unsteady gait, slurred speech, and limb clumsiness. Examination revealed gait ataxia, impaired limb coordination, dysarthria, and abnormal eye movements. Cognition, strength, and sensory function remained normal. CD4 lymphocyte counts varied between 10 and 437 cells/mm3. Neuroimaging studies showed prominent cerebellar atrophy. Neuropathology showed focal degeneration of the cerebellar granular cell layer and unusual focal axonal swellings in the brainstem and spinal cord. Cultures, histopathology, and immunochemical studies showed no conclusive evidence of infection. We report a syndrome of unexplained degeneration of the cerebellum occurring in association with HIV infection.