Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Long-term Thalamic Deep Brain Stimulation for Essential Tremor: Clinical Outcome and Stimulation Parameters.

BACKGROUND: The reasons underlying the loss of efficacy of deep brain stimulation (DBS) of the thalamic nucleus ventralis intermedius (VIM-DBS) over time in patients with essential tremor are not well understood. METHODS: Long-term clinical outcome and stimulation parameters were evaluated in 14 patients with essential tremor who underwent VIM-DBS. The mean ± standard deviation postoperative follow-up was 7.7 ± 3.8 years. At each visit (every 3-6 months), tremor was assessed using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) and stimulation parameters were recorded (contacts, voltage, frequency, pulse width, and total electrical energy delivered by the internal generator [TEED 1sec]). RESULTS: The mean reduction in FTM-TRS score was 73.4% at 6 months after VIM-DBS surgery (P < 0.001) and 50.1% at the last visit (P < 0.001). The gradual worsening of FTM-TRS scores over time fit a linear regression model (coefficient of determination [R2] = 0.887; P < 0.001). Stimulation adjustments to optimize tremor control required a statistically significant increase in voltage (P = 0.01), pulse width (P = 0.01), frequency (P = 0.02), and TEED 1sec (P = 0.008). TEED 1sec fit a third-order polynomial curve model throughout the follow-up period (R2 = 0.966; P < 0.001). The initial exponential increase (first 4 years of VIM-DBS) was followed by a plateau and a further increase from the seventh year onward. CONCLUSIONS: The current findings suggest that the waning effect of VIM-DBS over time in patients with essential tremor may be the consequence of a combination of factors. Superimposed on the progression of the disease, tolerance can occur during the early years of stimulation.

Neurophysiological study in cerebrotendinous xanthomatosis.

INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive disease due to mutations of the 27α-hydroxylase. It is characterized by cataracts, xanthomas, and neurological manifestations. Polyneuropathy has been reported, although it is unclear whether it is axonal or demyelinating. METHODS: We report clinical and neurophysiological results of 13 patients with CTX diagnosed in Spain. RESULTS: In 8 patients (62%), peripheral neuropathy was demonstrated (4 demyelinating, 3 axonal, and 1 mixed; 3 predominantly motor and 5 sensorimotor). All patients had clinical signs/symptoms of peripheral neuropathy. Upper limb somatosensory evoked potentials (SSEPs) were affected in 38% of patients, and lower limb SSEPs in 67%. Fifty percent of patients had delayed brainstem auditory evoked potentials, and 43% had affected visual evoked potentials. DISCUSSION: In this series, polyneuropathy was predominantly sensorimotor and demyelinating. Neurophysiological studies correlated only partially with clinical follow-up. Therefore, we recommend neurophysiological follow-up studies only if clinical symptoms are present.

Levodopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are common and difficult to treat. This review focuses on three issues related to LID: clinical features, classification and rating, pathophysiology and pathogenesis, and management. The three primary clinical syndromes are OFF-period dystonia, peak-dose dyskinesia, and diphasic dyskinesia. Several other forms also occur, making the evaluation and choice of treatment complicated. A core component of the pathophysiology of LID is overactivity of the direct striatal output pathway. This pathway provides a direct GABAergic connection by which the striatum inhibits the output regions of the basal ganglia, i.e., the internal globus pallidus and the substantia nigra pars reticulata. Altering dopaminergic dosing and timing can abate dyskinesias, but usually impact the control of parkinsonism. Putative therapies to reduce the problem of dyskinesias could focus on the glutamatergic, GABAergic, alpha2 adrenergic, serotonergic (5HT1A, 5HT2A), opioid, histamine H3, adenosine A2A receptors, the monoamine transport or cannabinoid CB1 receptors systems. The only currently available drug with an evidence-based recommendation on efficacy for dyskinesia is amantadine. Therapy goals include the prevention of dyskinesia and treatment of dyskinesias that are troublesome clinically. New rating measures to assess severity and disability related to dyskinesia are in the process of development and clinimetric testing.