Oren S. Cohen

Systemic administration of antioxidants does not protect mice against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)☆

We examined whether DA neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) can be prevented by combined systemic administration of antioxidants. C57 black mice were injected s.c. with MPTP (30 mg/kg), once daily for two days, alone, or with ascorbic acid (1 g/kg), alpha-tocopherol (100 mg/kg), or dimethylsulfoxide (50 microliters) i.p. for two days before, two days with and two days after MPTP, and decapitated 30 days later. MPTP once (30 mg/kg), alone, or with ascorbic acid (200 mg/kg) or cysteamine (75 mg/kg), two days before, one day with and 4 days after, and decapitated 10 days post-MPTP. MPTP once (15 mg/kg), alone, or with ascorbic acid (500 mg/kg, alpha-tocopherol (100 mg/kg), cysteamine (50 mg/kg) or sodium selenite (2.5 mg/kg), 90 min before and again 90 min after MPTP, and decapitated 7 days later. In all experiments, the marked striatal DA depletions produced by MPTP alone (by 40-70% from controls) were unchanged by cotreatments with the various antioxidants. Findings do not favor intraneuronal generation of superoxides and related cytotoxic free radicals as a major factor in the DA neurotoxicity of MPTP. They suggest that if natural Parkinsons disease is caused by an MPTP-like neurotoxin, early treatment with antioxidants is unlikely to protect nigrostriatal neurons and prevent disease progression.

Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations.

Autosomal‐recessive early‐onset Parkinsonism (AREP) due to PINK1 mutations is characterized by an early‐onset, slowly progressive disease, with a good response to levodopa. Psychiatric and cognitive disturbances associated with AREP have rarely been reported in the literature. We describe 2 brothers from a Jewish–Iraqi consanguineous family with a homozygous PINK1 nonsense mutation. Both patients presented with anxiety and dysphoria accompanied by a gait disturbance that developed subsequently into a clinical depression. During the course of the disease, both developed drug‐induced behavioral disturbances of the hedonistic homeostatic dysregulation type and 1 had drug‐induced psychosis. The first patient had been diagnosed with mild mental retardation and during the 22 years of disease had further deteriorated; the second developed frontal‐type dementia at an early age, 20 years after onset. Their father had a psychiatric disorder but no Parkinsonism. This report expands the phenotypic profile of PINK1‐related disease, presenting unique psychiatric and cognitive features as part of the clinical picture.

The leucine rich repeat kinase 2 (LRRK2) G2019S substitution mutation. Association with Parkinson disease, malignant melanoma and prevalence in ethnic groups in Israel.

BackgroundA single missense mutation (G2019S) in the leucine rich repeat kinase 2 (LRRK2) gene has been reported to be prevalent among Ashkenazi Jewish patients with Parkinson disease (PD). An association between malignant melanoma (MM) and PD was also recently reported. The nature of this association is still elusive.ObjectiveTo evaluate the rate of the G2019S* LRKK2 mutation among ethnically diverse, Jewish PD patients, MM patients, and Ashkenazi, Iraqi and Moroccan healthy controls.Patients and methodsOverall, 242 Jewish PD patients (155 Ashkenazim and 7 of mixed origin) and 169 Jewish MM patients (142 Ashkenazim) were genotyped for the G2019S mutation. In addition, 900 healthy ethnic Jewish controls (300 Ashkenazim, 300 Moroccans and 300 Iraqis) were similarly analyzed. Genotyping was performed using PCR amplification followed by restriction digest and gel electrophoresis. Statistical analysis was done using the Chi square test.ResultsOverall 19/242 (7.9 %) of the PD patients (16/155 of Ashkenazim, 10.3 %; 3/87 of non-Ashkenazim, 3.4 %) harbored the G2019S LRKK2 mutation. The age at diagnosis of PD in mutation carriers was 60.6 ± 10.9 years compared with an age at diagnosis of 61.1 ± 13.4 years in non-carriers (p = 0.87). Nine of 38 familial Ashkenazi PD patients (23.68 %) carried the mutation, as did 2/169 MM patients (1.2 %; 2/142, 1.4 % of the Ashkenazim). A single mutation carrier of Ashkenazi origin was detected among 900 controls (0.3 % of the Ashkenazi controls).ConclusionThe G2019S*LRKK2 mutation is significantly more prevalent in Ashkenazi PD patients than in controls (p = 1 × 10–6), it is less commonly detected in non-Ashkenazi affected individuals, and its contribution to MM predisposition in Jewish individuals needs to be explored further.

Plasma homocysteine levels and parkinson disease : Disease progression, carotid intima-media thickness and neuropsychiatric complications

Objective: To determine whether plasma homocysteine (Hcy) levels are associated with clinical characteristics, neuropsychological and psychiatric manifestations and cardiovascular comorbidity in patients with Parkinson disease (PD). Background: Elevated Hcy levels are linked to atherosclerosis, vascular disease, depression, and dementia. Patients with PD treated with L-dopa have been shown to have elevated Hcy levels. Design/Methods: Idiopathic PD patients were evaluated using the Unified Parkinsons Disease Rating Scale, Hoehn and Yahr stage, Parkinson Psychosis Rating Scale, Beck Depression Inventory, Frontal Assessment Battery, Mini-Mental Status Examination, and several tests for frontal type cognitive functions. Fasting blood samples were collected for the measurement of Hcy, and carotid B-mode ultrasound was performed to measure intima-media thickness of the common carotid arteries. Results: Seventy-two consecutive PD patients (46 men; average age, 68.7 ± 11.6 years; average disease duration, 7.0 ± 4.7 years) were recruited. All but 10 patients were treated with L-dopa. The average level of Hcy was 16.4 ± 7.8 &mgr;mol/L, and 38.9% of the patients had Hcy level above the reference range (>15.0 &mgr;mol/L). The Hcy levels were associated with PD duration as they were with L-dopa treatment duration but were not associated with the parameters of disease severity or with L-dopa dose. The Hcy levels were associated neither with the common carotid intima-media thickness nor with cardiovascular morbidity. No association was found between Hcy and the neuropsychiatric features of PD such as depression, cognitive performance, or psychosis. Conclusions: Hyperhomocystinemia is common in L-dopa-treatedPD patients but was not associated with neuropsychological complications (depression, dementia, and cognitive decline associated with frontal lobe functioning or psychosis), enhanced disease severity, or vascular comorbidity.

Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms

Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

Immunology, Autoimmunity, and Autoantibodies in Parkinson’s Disease

Recent revelations of immune alterations in Parkinson’s disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson’s disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson’s disease patients (antineuronal cells10.3% vs. 1.3%, p = 0.017; anti-brain lysate 9.1% vs. 1.3%, p = 0.032; anti-dsDNA 10.3% vs. 2.6%, p = 0.049). Clinical manifestations of Parkinson’s disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies.

Association of Preoperative Symptom Profile With Psychiatric Symptoms Following Subthalamic Nucleus Stimulation in Patients With Parkinson's Disease

In order to evaluate the severity of behavioral complications after deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinsons disease and to explore possible predictive factors, the authors evaluated 22 patients for pre- and postoperative symptoms using a neurobehavioral battery. Compared to the time before STN-DBS, several behavioral symptoms had worsened in terms of prevalence and severity and appeared de novo in other patients. Apathy, anxiety, and suicidal ideation increased significantly, while depressive symptoms appeared stable. Compared with patients who improved, patients who had deteriorated behaviorally had similar prevalence and severity of preoperative behavioral symptoms but significantly shorter disease duration.

Enhanced Detection of Diffusion Reductions in Creutzfeldt-Jakob Disease at a Higher B Factor

BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) is sensitive to the cerebral manifestations of human prion diseases. The magnitude of diffusion weighting, termed “b factor,” has only been evaluated at the standard b = 1000 s/mm2. This is the first rigorous evaluation of b = 2000 s/mm2 in Creutzfeldt-Jakob Disease (CJD). MATERIALS AND METHODS: We compared DWI characteristics of 13 patients with CJD and 15 healthy controls at b = 1000 s/mm2 and b = 2000 s/mm2. Apparent diffusion coefficients (ADC) were computed and analyzed for the whole brain by voxel-wise analysis (by SPM5) as well as in anatomically defined volumes of interest (by FSL FIRST). RESULTS: Measured ADC was significantly lower (by approximately 5%–15%) at b = 2000 s/mm2 than at b = 1000 s/mm2 and significantly lower in patients than in controls. The differences between patients and controls were greater and more extensive at b = 2000 s/mm2 than at b = 1000 s/mm2 in the expected regions (thalamus, putamen, and caudate nucleus). CONCLUSIONS: Because higher b factors change the absolute value of observed ADC, as well as lesion detection, care should be taken when combining studies using different b factors. While the clinical application of high b factors is currently limited by a low signal intensity–to-noise ratio, it may offer more information in questionable cases, and our results confirm and extend the central role of diffusion imaging in human prion diseases.

Thalamo-striatal diffusion reductions precede disease onset in prion mutation carriers

Human prion diseases present substantial scientific and public health challenges. They are unique in being sporadic, infectious and inherited, and their pathogen is distinct from all other pathogens in lacking nucleic acids. Despite progress in understanding the molecular structure of prions, their initial cerebral pathophysiology and the loci of cerebral injury are poorly understood. As part of a large prospective study, we analysed early diffusion MRI scans of 14 patients with the E200K genetic form of Creutzfeldt-Jakob Disease, 20 healthy carriers of this mutation that causes the disease and 20 controls without the mutation from the same families. Cerebral diffusion was quantified by the Apparent Diffusion Coefficient, and analysed by voxel-wise statistical parametric mapping technique. Compared to the mutation-negative controls, diffusion was significantly reduced in a thalamic-striatal network, comprising the putamen and mediodorsal, ventrolateral and pulvinar thalamic nuclei, in both the patients and the healthy mutation carriers. With disease onset, these diffusion reductions intensified, but did not spread to other areas. The caudate nucleus was reduced only after symptomatic onset. These findings indicate that cerebral diffusion reductions can be detected early in the course of Creutzfeldt-Jakob Disease, and years before symptomatic onset in mutation carriers, in a distinct subcortical network. We suggest that this network is centrally involved in the pathogenesis of Creutzfeldt-Jakob Disease, and its anatomical connections are sufficient to account for the common symptoms of this disease. Further, we suggest that the abnormalities in healthy mutation-carrying subjects may reflect the accumulation of abnormal prion protein and/or associated vacuolation at this time, temporally close to disease onset.

The Frontal Assessment Battery as a Tool for Evaluation of Frontal Lobe Dysfunction in Patients With Parkinson Disease

Background: Frontal-type cognitive deficits are common in patients with Parkinson disease (PD). The Frontal Assessment Battery (FAB) was developed to assess frontal lobe functions. However, many studies found that it also correlated with a variety of other general neuropsychological tests. Objectives: To evaluate whether the FAB has an added value over the Mini-Mental State Examination (MMSE) and other bedside neuropsychological tests in reflecting cognitive deficits in patients with PD. Methods: Seventy-two consecutive patients with PD underwent cognitive assessment including the FAB, the MMSE, and a variety of other neuropsychological tests. Correlations were examined using the Spearman’s r. Results: Highly significant correlations were found between the total FAB score and tests of attention, executive functions, and memory. To evaluate the contribution of the FAB beyond that of the MMSE, partial correlation was used. Analyses revealed that the FAB still correlated with most of the tests. Dividing the patients according to the median MMSE score revealed that the high correlation between the FAB and the MMSE was preserved in the low MMSE group, while in the high MMSE group the correlation was relatively low. In the high MMSE group, the FAB correlated with 11 tests compared to the MMSE that correlated with one (P < .001), while in the low MMSE group the number of correlations was 13 versus 7, respectively (P = .05). Conclusions: In our sample of patients with PD, the FAB correlated with dysfunction in a variety of cognitive domains including attention, memory, and executive functions. The FAB has an added value over the MMSE, particularly among nondemented patients, an advantage that can be used in clinical practice.