Neuropsychological, MRI and EEG findings after very mild traumatic brain injury

Neuropsychological performance, magnetic resonance imaging (MRI) and electroencephalography (EEG) were investigated in 12 consecutive patients with very mild traumatic brain injury (MTBI) (Glasgow coma score 15) within 24 hours and 6 weeks after injury. The data were compared to 14 control subjects. There was a significant impairment in neuropsychological performance (verbal memory, arithmetic abilities and psychomotor reaction time) at onset and after 6 weeks, whereas verbal fluency and non-verbal memory test revealed no significant differences matching the control values. In MRI scans, three patients showed traumatic lesions (slight epidural haematoma, haemorrhagic contusions and white matter lesions indicating diffuse axonal injury). In the EEG recordings, no generalized slowing or focal changes were found. Structural and functional impairment can be identified using neuroimaging and neuropsychological examination, even in very MTBI patients.     

Drug-induced thrombocytopenia is associated with increased binding of IgG to platelets both in vivo and in vitro

Thrombocytopenia is a common serious adverse effect of drug treatment. A variety of in vitro diagnostic techniques to confirm the diagnosis are available, but the majority lack sufficient sensitivity to detect all cases of drug-induced thrombocytopenia. We studied 19 patients with suspected drug-induced thrombocytopenia and demonstrated that platelet- associated IgG (PAIgG) was elevated in all at the time of thrombocytopenia, and PAIgG returned to normal levels as the thrombocytopenia resolved. In the majority of patients, the platelet count rapidly returned to normal after the drug was discontinued; however, in six patients, the thrombocytopenia persisted well beyond the period of time that the offending drug would be expected to be cleared from the blood. In 13 patients, serum obtained after recovery was used to identify the drug responsible for the thrombocytopenia in an in vitro assay. In all cases, the addition of the drug historically associated with the thrombocytopenic episode was associated with an increased binding of IgG to control platelets. For uncertain reasons, the concentration of drug required to increase the in vitro binding of IgG to test platelets was often more than the concentration usually achieved in vivo. Wider application of these techniques may provide better understanding of the clinical characteristics and mechanisms responsible for drug-induce thrombocytopenia.     

Basal forebrain atrophy is a distinctive pattern in dementia with Lewy bodies

We determined brain atrophy patterns in dementia with Lewy bodies and Alzheimer's disease using voxel-based morphometry, an indirect volumetry. Ten patients with dementia with Lewy bodies, 10 patients with Alzheimer's disease and 10 controls were included. All groups were matched for age; sex and global differences in voxel intensities were included as confounding covariates. We observed basal forebrain atrophy discriminating dementia with Lewy bodies from Alzheimer's disease. Compared to controls, atrophy of lateral prefrontal cortex and left premotor cortex was seen in dementia with Lewy bodies whereas atrophy of the medial temporal cortex, posterior parietal cortex, thalamus and temporo-occipital areas was observed in Alzheimer's disease. Atrophy of insular cortex was found in both patient groups.     

Riluzole in Huntington's disease (HD): an open label study with one year follow up

In an open label study, we administered riluzole (50 mg twice a day) to nine patients with genetically confirmed Huntington's disease (HD) (clinical stages 1–3; mean age 46.4 (SD 9.3) years; mean disease duration 8 (SD 3.3) years). The study was designed to evaluate (1) safety and tolerability of riluzole and (2) effects of riluzole on motor impairment, functional disability, cognitive impairment, and behavioral abnormalities using the Unified HD Rating Scale. Patients were evaluated at baseline and after three and twelve months of riluzole therapy. Laboratory tests (hematology and liver enzymes) were repeated monthly. All adverse experiences, reported spontaneously or observed directly by the investigator, were recorded. Riluzole was well tolerated. No increase of serum liver enzymes was seen throughout the study in all but one patient showing a mild elevation. At three months, mean total motor scale (TMS), mean TMS chorea subscore, and mean total functional capacity scale were significantly improved compared with baseline. At twelve months, however, this beneficial effect on motor status and overall function was not sustained. In contrast, severity and frequency of behavioral dysfunction as well as psychomotor speed assessed by the symbol digit modalities test were improved compared with baseline. Our data suggest that there are transient antichoreatic effects and more sustained effects of riluzole on psychomotor speed and behavior in patients with HD. A double-blind, placebo-controlled trial appears highly warranted to establish definitely the symptomatic versus neuroprotective actions of riluzole in HD. Received: 2 February 2001, Received in revised form: 2 April 2001, Accepted: 9 April 2001     

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABA(B) receptors in cortical neurons

Endocytosis is considered as an important mechanism for regulating cell surface numbers and thereby signaling strength of G protein-coupled receptors. Currently, little is known about the endocytotic pathways of GABA_B receptors in neurons. Here we report that GABA_B receptors are constitutively internalized presumably via clathrin-dependent endocytosis in cultured cortical neurons. Colocalization of GABA_B receptors with endosomal marker proteins indicated sorting of GABA_B receptors from early endosomes to recycling endosomes and to lysosomes. Cell surface biotinylation experiments revealed fast constitutive recycling of GABA_B receptors as the predominant pathway that was accelerated by the GABA_B receptor agonist baclofen. Finally, degradation of GABA_B receptors in lysosomes was demonstrated by their intracellular accumulation upon inhibition of lysosomal proteases and by blocking recycling which resulted in the redirection of receptors to lysosomes for degradation. These data imply rapid constitutive – agonist-accelerated – recycling of GABA_B receptors presumably via clathrin-coated pits and their final targeting to lysosomes for degradation.     

Megalencephalic leukoencephalopathy with cysts without MLC1 defect

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disease characterized by early infantile macrocephaly and delayed motor and cognitive deterioration. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen cerebral white matter and subcortical cysts. On follow‐up, atrophy ensues. Approximately 80% of MLC patients have mutations in MLC1. We report 16 MLC patients without MLC1 mutations. Eight retained the classical clinical and MRI phenotype. The other 8 showed major MRI improvement. They lacked motor decline. Five had normal intelligence; 3 displayed cognitive deficiency. In conclusion, 2 phenotypes can be distinguished among the non‐MLC1 mutated MLC patients: a classical and a benign phenotype. ANN NEUROL 2010;67:834–837     

Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial

Down syndrome (DS) is the most common genetic cause of intellectual disability. The N-methyl-D-aspartate (NMDA) receptor uncompetitive antagonist, memantine hydrochloride (memantine), has been shown to improve learning/memory and rescue one form of hippocampus synaptic plasticity dysfunction in the best-studied mouse model of DS available, the Ts65Dn mouse. Given the status of memantine as a treatment for Alzheimer''s disease (AD) approved by the Food and Drug Administration, the preclinical evidence of potential efficacy in Ts65Dn mice, and the favorable safety profile of memantine, we designed a study to investigate whether the findings in the mouse model could be translated to individuals with DS. In this pilot, proof-of-principle study we hypothesized that memantine therapy would improve test scores of young adults with DS on measures of episodic and spatial memory, which are generally considered to be hippocampus dependent. Accordingly, in this randomized, double-blind, placebo-controlled trial, we compared the effect of 16-week treatment with either memantine or placebo on cognitive and adaptive functions of 40 young adults with DS using a carefully selected set of neuropsychological outcome measures. Safety and tolerability were also monitored. Although no significant differences were observed between the memantine and placebo groups on the two primary outcome measures, we found a significant improvement in the memantine group in one of the secondary measures associated with the primary hypothesis. Only infrequent and mild adverse events were noted.