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Estrogen improves motor disability in parkinsonian postmenopausal women with motor fluctuations

Objective: To test the efficacy, tolerance, and safety of low-dose oral estrogen in postmenopausal women with PD associated with motor fluctuations. Background: Motor fluctuations in PD may be predictable or unpredictable, and eventually affect most patients after long-term levodopa therapy. Although estrogen can modulate nigrostriatal dopamine levels, its effects on PD are unclear. Methods: Patients were randomized to receive conjugated estrogen (oral Premarin 0.625 mg daily; n = 20) or placebo (n = 20) in a double-blind, parallel-group, prospective study over 8 weeks. Existing antiparkinsonian drug regimes were kept unchanged. Changes in “on” and “off” periods using patient diaries, Unified Parkinson’s Disease Rating Scale (UPDRS) score, timed tapping score, and Hamilton Depression Scale score were determined by one rater. Subgroup analyses were also performed on patients with only predictable motor fluctuations. Results: Both treatment groups were similar in age, duration of disease and menopause, antiparkinsonian medication, and compliance with test medication and diary assessments. “On” and “off” times, and motor score (UPDRS subscale III) improved with estrogen, using the Mann–Whitney U test (p < 0.05 after Bonferroni adjustment). Mean “on” time improved by 7% (9 hours/week of awake time) in estrogen-treated patients versus a deterioration of 0.5% (1.4 hours) in placebo-treated patients (95% confidence interval, [CI] of mean difference, 5.73 to 14.9). Mean “off” time improved by 4% (4.4 hours/week of awake time) in estrogen-treated patients versus no change in placebo-treated patients (95% CI, 1.54 to 7.16). Mean subscale III score improved by 3.5 points in estrogen-treated patients versus 0.4 in placebo-treated patients (95% CI, 1.02 to 5.18). No other significant changes were observed (p > 0.05). Subgroup analyses in patients with only predictable motor fluctuations showed similar results, except improvement in mean subscale III score was marginally not significant (p = 0.07; 95% CI, 1.06 to 6.24). Five patients on estrogen had facial flushing, three had lower abdominal discomfort, and two had mild withdrawal vaginal bleeding. The adverse events were mild and resolved without sequelae. Conclusion: Low-dose estrogen is a safe and effective adjunct therapy to existing antiparkinsonian treatment in reducing motor disability in postmenopausal women with PD associated with motor fluctuations.

Human catechol-O-methyltransferase down-regulation by estradiol

Catechol-O-methyltransferase (COMT) is a crucial enzyme in dopamine and levodopa metabolism. Previously we reported that physiological concentrations of 17beta-estradiol (E2) down-regulated steady-state 1.3-kb COMT mRNA levels in MCF-7 cells. In this study, we investigated whether similar reductions occurred in a glial cell line (U138MG) and whether COMT protein and activity levels paralleled the reduction in COMT mRNA levels in MCF-7 cells. In addition, we explored the mechanism of E2 action. E2 had no effect on COMT mRNA levels in U138MG cells, but significantly reduced COMT protein and activity in MCF-7 cells (activity by 53% at 10(-7) M of E2, by 45% at 10(-8) M, and by 28% at 10(-9) M relative to non-E2-treated cells). A specific estrogen receptor antagonist (ICI 182780) blocked these estrogenic effects. Estrogen receptor in nuclear extracts of MCF-7 cells, which were pretreated with E2 (10(-9) M) for 48 h, bound to the whole proximal and distal promoter regions, as determined by electrophoretic mobility shift analysis (EMSA). We propose that E2 decreased COMT activity through down-regulation of its gene and protein expression mediated via ER interaction with response elements in the promoter region of the gene. Our findings may explain the lower of COMT activity in women compared to that in men, and, in part, the beneficial effects of E2 therapy in post-menopausal Parkinsons disease patients.

Emotion recognition in patients with idiopathic Parkinson's disease

Emotion recognition (ER) was examined in 64 patients with idiopathic Parkinsons disease (PD; 56 bilateral and 8 right‐sided) and 64 matched healthy volunteers. Participants were administered an ER battery, consisting of the following subscores: overall ER (OER), overall facial ER, facial emotion identification (FEI) and discrimination, overall prosodic ER, and prosodic emotion identification (PEI) and discrimination. Measures of visuospatial functions, auditory attention, and depression were also administered. After controlling for visuospatial functions, auditory attention and depression, results indicated that patients with bilateral PD had poorer performance on all ER subscores, regardless of the modality and type of experimental task involved, relative to healthy volunteers. However, patients with right‐sided PD had difficulty on FEI and PEI only. Whereas none of the clinical variables examined in this study predicted any of the ER subscores, visual organization and auditory attention positively predicted OER in patients with PD. In addition, visual organization also positively predicted FEI in these patients. Implications are discussed in terms of the neural substrates underlying ER.

Predicting Mendelian Disease-Causing Non-Synonymous Single Nucleotide Variants in Exome Sequencing Studies

Exome sequencing is becoming a standard tool for mapping Mendelian disease-causing (or pathogenic) non-synonymous single nucleotide variants (nsSNVs). Minor allele frequency (MAF) filtering approach and functional prediction methods are commonly used to identify candidate pathogenic mutations in these studies. Combining multiple functional prediction methods may increase accuracy in prediction. Here, we propose to use a logit model to combine multiple prediction methods and compute an unbiased probability of a rare variant being pathogenic. Also, for the first time we assess the predictive power of seven prediction methods (including SIFT, PolyPhen2, CONDEL, and logit) in predicting pathogenic nsSNVs from other rare variants, which reflects the situation after MAF filtering is done in exome-sequencing studies. We found that a logit model combining all or some original prediction methods outperforms other methods examined, but is unable to discriminate between autosomal dominant and autosomal recessive disease mutations. Finally, based on the predictions of the logit model, we estimate that an individual has around 5% of rare nsSNVs that are pathogenic and carries ∼22 pathogenic derived alleles at least, which if made homozygous by consanguineous marriages may lead to recessive diseases.

COX-2-deficient mice are less prone to MPTP-neurotoxicity than wild-type mice.

The primary lesion in Parkinsons disease is the death of dopaminergic neurons in the substantia nigra. The role of cyclooxygenase (COX)-2 in the etiology of Parkinsons disease was explored using COX-2 gene knockout mice. Mortality after injection of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP, a chemical known to cause parkinsonism in humans) in heterozygous COX-2-deficient mice was lower than that in wild-type mice. The number of tyrosine hydroxylase immunoreactive neurons in the substantia nigra pars compacta of MPTP-treated wild-type mice declined to a greater extent than in heterozygous mice. Inhibition of COX-2 protein expression decreased the lesion caused by MPTP and protected the dopaminergic neurons in substantia nigra pars compacta. This result suggested that inhibition of COX-2 has potential therapeutic implications.

Cerebral infarcts complicating tuberculous meningitis.

Cerebral infarction (CI) is a serious complication of tuberculous meningitis (TBM). It can be asymptomatic or symptomatic, causing stroke. We studied 40 TBM patients. All had initial CT brain scan, CT/MRI brain scan 3 months later and urgent CT brain scan for deterioration. CI was classified into lacunar infarction (LI) or large artery infarction (LAI). Twelve (30%) had CI, in 9 (23%) it was symptomatic and in 3 (8%) silent. Seven (58%) had LAI ± LI. Eight (67%) had multiple CI. Two died from brainstem CI and 6 were dependent at 1 year. Patients with LAI might develop posterior circulation CI more frequently than those with LI only. CI is a common complication of TBM locally, with LAI and multiple CI being common. Two thirds of TBM patients complicated by CI had poor prognosis despite adjunctive dexamethasone treatment.

Peripheral Neuropathy in Systemic Lupus Erythematosus

The prevalence of clinically apparent peripheral neuropathy in systemic lupus erythematosus is reported to be between 2% to 18%. The purpose of this prospective case-control study was to determine the prevalence of peripheral neuropathy (PN) using electrodiagnostic criteria. Subgroup analysis was performed to determine whether PN correlated with disease activity, renal involvement, or serum immune markers. Fifty-four systemic lupus erythematosus patients and 30 controls were recruited in the study. The right median, ulnar, peroneal, tibial, and sural sensory and motor nerve conduction studies were obtained. PN in our study was defined as any abnormal values in motor and sensory distal latency, sensory action potential, motor action potential, or conduction velocity affecting 2 or more nerves. Of the 54 patients studied, PN was present in 15 patients (27.8%) of which 4 were symptomatic. There was a significant correlation between PN and anti-SM antibody, and there was a trend showing decreased motor and sensory action potential amplitudes in our systemic lupus erythematosus group compared to the controls. This observation was also seen in an active disease group when compared to those with inactive disease. The amplitude of the action potential was more often affected than the distal latency, and sensory nerves were more susceptible than motor nerves. The sural sensory action potential amplitude appears to be the most sensitive indicator of PN which may be used as an index to monitor disease activity.

Epileptic Seizures Attributed to Cerebral Hyperperfusion after Percutaneous Transluminal Angioplasty and Stenting of the Internal Carotid Artery

Cerebral hyperperfusion syndrome as a complication of carotid endarterectomy (CEA) has been widely reported in the surgical literature. It may occur within hours to 3 weeks after CEA and is characterized by symptoms ranging from headaches, fits, confusion, focal neurological signs to intracerebral hemorrhage. Although percutaneous transluminal angioplasty (PTA) and stenting are increasingly performed as an alternative to CEA in the treatment of carotid artery stenosis, few cases of cerebral hyperperfusion injury following carotid stenting have been reported. We describe 2 cases of cerebral hyperperfusion syndrome following PTA and stenting for high-grade internal carotid artery (ICA) stenosis. Both cases involved a lesion of 95% in severity. The first case was a 73-year-old man who developed generalized convulsion 7 h following stenting to the left ICA. The second case was an 80-year-old woman who developed recurrent right periorbital headache and confusion 16 h after stenting to the right ICA, followed by left upper limb seizure 14 days later. Both patients fully recovered without any intracerebral hemorrhage or infarction. To our knowledge, this is the first report of cerebral hyperperfusion injury after carotid stenting without associated intracranial hemorrhage and with full recovery. In the patient with neurological symptoms following carotid stenting, it is important to consider cerebral hyperperfusion syndrome as a differential diagnosis to embolic or hemorrhagic stroke since early recognition and meticulous control of blood pressure may prevent progression to cerebral hemorrhage and death.

The default mode network is disrupted in parkinson's disease with visual hallucinations

Background: Visual hallucinations (VH) are one of the most striking nonmotor symptoms in Parkinsons disease (PD), and predict dementia and mortality. Aberrant default mode network (DMN) is associated with other psychoses. Here, we tested the hypothesis that DMN dysfunction contributes to VH in PD. Methods: Resting state functional data was acquired from individuals with PD with VH (PDVH) and without VH (PDnonVH), matched for levodopa drug equivalent dose, and a healthy control group (HC). Independent component analysis was used to investigate group differences in functional connectivity within the DMN. In addition, we investigated whether the functional changes associated with hallucinations were accompanied by differences in cortical thickness. Results: There were no group differences in cortical thickness but functional coactivation within components of the DMN was significantly lower in both PDVH and PDnonVH groups compared to HC. Functional coactivation within the DMN was found to be greater in PDVH group relative to PDnonVH group. Conclusion: Our study demonstrates, for the first time that, within a functionally abnormal DMN in PD, relatively higher “connectivity” is associated with VH. We postulate that aberrant connectivity in a large scale network affects sensory information processing and perception, and contributes to “positive” symptom generation in PD. Hum Brain Mapp 35:5658–5666, 2014.

Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease

This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinsons disease (PD). Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation, but as an integral part of this process, superoxides and other reactive oxygen species are also produced. Excessive free radical production contributes to oxidative stress. Cells have evolved to handle such stress via various endogenous anti-oxidant proteins. One such family of proteins is the mitochondrial uncoupling proteins (UCPs), which are anion carriers located in the mitochondrial inner membrane. There are five known homologues (UCP1 to 5), of which UCP4 and 5 are predominantly expressed in neural cells. In a series of previous publications, we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium (MPP+; toxic metabolite of MPTP) and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential, and reducing oxidative stress. We also showed how their expression can be influenced by nuclear factor kappa-B (NF-κB) signaling pathway specifically in UCP4. Furthermore, we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin (hormone produced by adipocytes) acting via UCP2 against MPP+-induced toxicity. There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD. Their expression, which can be induced, may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.