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.

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.

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.

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.

HHV-8 and AIDS-related CNS lymphoma.

Human herpesvirus 8 (HHV-8), the Kaposi's sarcoma (KS)-associated herpesvirus, is closely related to the transforming Epstein-Barr virus (EBV) and may be detected in AIDS-related, EBV-containing, body-cavity-based lymphomas. Accordingly, we analyzed 27 EBV-positive, AIDS-related CNS lymphomas for HHV-8 sequences. Only one tumor yielded HHV-8 sequences; this tumor arose in a patient with concomitant systemic lymphoma and a history of KS. We conclude that HHV-8 is unlikely to have a major role in the pathogenesis of AIDS-related, EBV-associated CNS lymphomas.

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.

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.

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.

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.

Botulinum toxin type A in the treatment of upper extremity spasticity: a randomized, double-blind, placebo-controlled trial.

Spasticity is a disorder of excess muscle tone associated with CNS disease. We hypothesized that botulinum toxin, a neuromuscular blocking agent, would reduce tone in spastic muscles after stroke. This randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the safety and efficacy of botulinum toxin type A (BTXA) in the treatment of chronic upper limb spasticity after stroke. Thirty-nine patients received IM injections of a total dose of either 75, 150, or 300 units of BTXA or placebo into the biceps, flexor carpi radialis, and flexor carpi ulnaris muscles. At baseline, patients demonstrated a mean wrist flexor tone of 2.9 and elbow flexor tone of 2.6 on the Ashworth Scale (0 to 4). Treatment with the 300-unit BTXA dose resulted in a statistically and clinically significant mean decrease in wrist flexor tone of 1.2 (p = 0.028), 1.1 (p = 0.044), and 1.2 (p = 0.026) points and elbow flexor tone of 1.2 (p = 0.024), 1.2 (p = 0.028), and 1.1 (p = 0.199) at weeks 2, 4, and 6 postinjection. In the placebo group, tone reduction at the wrist was 0.3, 0.2, and 0.0 and at the elbow was 0.3, 0.3, and 0.6 at weeks 2, 4, and 6 postinjection. BTXA groups reported significant improvement on the physician and patient Global Assessment of Response to Treatment at weeks 4 and 6 postinjection. There were no serious adverse effects. In this 3-month study, BTXA safely reduced upper extremity muscle tone in patients with chronic spasticity after stroke.

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.

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.

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.

Spatial frequency tuning of the monkey pattern ERG depends on D2 receptor-linked action of dopamine.

The pattern electroretinogram (PERG) has been previously shown to be sensitive to dopaminergic manipulations in the monkey's retina. In order to study the role of retinal D2 receptors were recorded the PERG before and during the acute administration of l-sulpiride, a selective D2 blocker, in three monkeys. The stimuli were sinusoidal vertical gratings, with a contrast of 70% counterphase modulated at 7.5 Hz. The response to four different spatial frequencies (0.5, 1.1, 2.3 and 4.6 c/deg) was explored. PERGs were recorded before and after 20 min of i.m. administration of l-sulpiride. Two different doses (0.07 and 0.35 mg/kg) were administered in different sessions for each spatial frequency (SF). Baseline (before sulpiride) responses showed high intersession reproducibility, with a clear SF tuning. Both doses of the drug affected the PERG to the peak SF of the stimulus, but the higher one was more consistently effective in all of the three monkeys. Our results confirm previous studies which suggested that DA is involved in retinal processing in the primate and reveal the new information that D2 receptors are necessary for spatio-temporal tuning of pattern vision.

Increasing doses of l-sulpiride reveal dose- and spatial frequency-dependent effects of D2 selective blockade in the human electroretinogram.

The amplitude and phase of the second harmonic (15 Hz) of the electroretinographic responses to three different spatial frequency grating stimuli (0.25, 1 and 4 c/deg), reversed at 7.5 Hz, were studied i normal human subjects, before and 30 min after the systemic administration of three doses (0.071, 0.357 or 1.428 mg/kg) of a selective D2 blocker, l-sulpiride, to three populations of 18, 19, or 20 subjects. The effect of the drug on the pattern electroretinogram (PERG) was clearly dose-dependent, being greatest on the responses to 4 c/deg. The mean decrease in second harmonic amplitude was -13.8% after 0.071 mg/kg of l-sulpiride, -23.5% after 0.357 mg/kg and -28.5% after 1.428 mg/kg. The last two variations were significant at P < 0.01 and P < 0.01 respectively. These data suggest that a dose-dependent effect on the human retinal response to 4 c/deg stimuli exists, probably mediated by a coupling between l-sulpiride and D2 receptors. Lastly, our data suggest that D2 receptors may play an important role in the pathophysiology of visual dysfunction in Parkinson's disease, that has been described to be more significant at medium spatial frequency (2-5 c/deg).

Neurologic complications of AIDS: new concepts and treatments.

As patients progress from seroconversion to progressive HIV-1 disease, a variety of neurologic disorders may occur. These include diseases of the central and peripheral nervous systems as well as primary muscle disorders. This presentation focuses on clinical, laboratory, and pathologic features of these disorders. Theories of pathogenesis and currently available treatments are reviewed.

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 case of stroke associated with gonadotropin treatment in a young patient.

A case of ischemic stroke in a 40-year-old hypofertile man who was given a gonadotropin therapy for a short time is described. We discuss the possible causal relationship between treatment and cerebrovascular accident. A possible pathogenetic mechanism is also proposed.