Cerebrospinal fluid markers that predict SIV CNS disease

Predictive cerebrospinal fluid markers would provide valuable tools for tracking the development and progression of HIV CNS disease. In this study, expression of IL-6, MCP-1, and viral RNA in cerebrospinal fluid collected from SIV-inoculated macaques during acute, asymptomatic, and terminal stages of infection was quantitated to determine whether one or several of these parameters paralleled the severity of SIV encephalitis. Animals that developed moderate to severe SIV encephalitis had significantly elevated levels of CSF IL-6, MCP-1, and SIV RNA during asymptomatic infection and persisting through terminal disease as compared to animals developing mild or no CNS disease.     

The mGluR theory of fragile X mental retardation

Many of the diverse functional consequences of activating group 1 metabotropic glutamate receptors require translation of pre-existing mRNA near synapses. One of these consequences is long-term depression (LTD) of transmission at hippocampal synapses. Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus. This finding is consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs. Here we present a theory that can account for diverse neurological and psychiatric aspects of fragile X syndrome, based on the assumption that many of the protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome. The theory suggests new directions for basic research as well as novel therapeutic approaches for the treatment of humans with fragile X, the most frequent inherited cause of mental retardation and an identified cause of autism.     

Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease

Environmental toxins have been implicated in the etiology of Parkinson's disease. Recent findings of defects in the ubiquitin-proteasome system in hereditary and sporadic forms of the illness suggest that environmental proteasome inhibitors are candidate PD-inducing toxins. Here, we systemically injected six doses of naturally occurring (epoxomicin) or synthetic (Z-lle-Glu(OtBu)-Ala-Leu-al [PSI]) proteasome inhibitors into adult rats over a period of 2 weeks. After a latency of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture, which improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra pars compacta. In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, alpha-synuclein/ubiquitin-containing, inclusions resembling Lewy bodies were present in some of the remaining neurons. This animal model induced by proteasome inhibitors closely recapitulates key features of PD and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness.     

Incidence and prevalence of dementia in elderly adults with mental retardation without down syndrome

Rates of dementia in adults with mental retardation without Down syndrome were equivalent to or lower than would be expected compared to general population rates, whereas prevalence rates of other chronic health concerns varied as a function of condition. Given that individual differences in vulnerability to Alzheimer's disease have been hypothesized to be due to variation in cognitive reserve, adults with mental retardation, who have long-standing intellectual and cognitive impairments, should be at increased risk. This suggests that factors determining intelligence may have little or no direct relationship to risk for dementia and that dementia risk for individuals with mental retardation will be comparable to that of adults without mental retardation unless predisposing risk factors for dementia are also present.     

Symptom and demographic profiles in first-episode schizophrenia

First-episode schizophrenia (FE-SZP) presents a diagnostic challenge because of symptomatic overlap between the various causes of psychosis. An early and accurate diagnosis is important for the implementation of appropriate treatment, for determining prognosis and for identifying research participants. In an effort to facilitate early diagnosis, we followed a group of first-episode psychosis patients with a presumptive diagnosis of schizophrenia who were subsequently diagnosed at 6-month follow-up with either schizophrenia (n=104) or other psychiatric diagnoses (n=19). The two groups-first-episode schizophrenia and first-episode non-schizophrenia-were compared on measures of demographics, symptoms, quality of life, premorbid adjustment and lateral dominance. Odds ratios were calculated for each variable and all significant variables were entered into a multivariate prediction model. The model showed that higher levels of anhedonia and hallucinations increased the odds of a final diagnosis of schizophrenia. This predictive model was validated in a smaller group of patients.     

Conversion to dementia among two groups with cognitive impairment. A preliminary report

OBJECTIVE: To determine the conversion rates to dementia in patients diagnosed with mild cognitive impairment (MCI) thought to be caused by incipient Alzheimer's disease (MCI-AD) or with MCI with features of vascular disease (MCI-Vas). METHODS: On the basis of patient history, neurocognitive, neurological and MRI evaluation, 99 patients were diagnosed with MCI-AD and 35 with MCI-Vas. Conversion to dementia over an average of a 2.4 +/- 1.8-year period was determined. RESULTS: Over the follow-up period, 44% converted to dementia, 51.5% remained classified as MCI, and 4.5% were reclassified as cognitively normal. The conversion rate to dementia was significantly faster at 3 years for the MCI-AD (50.5%) than for the MCI-Vas group (25.7%). The neuropsychological test found to best differentiate converters from non-converters was the Fuld-OME, a measure of learning and recall. Age, education, gender or APOE epsilon4 allele frequency did not differentiate converters from non-converters. CONCLUSIONS: MCI-AD and MCI-Vas are clinically meaningful subtypes of MCI that may convert to dementia at different rates. Prospective studies on larger subsets of MCI patients are required to confirm these findings.     

Lewy-body formation is an aggresome-related process: a hypothesis

Parkinson's disease (PD) is an age-related neurodegenerative disorder that is associated with the formation of intracytoplasmic protein aggregates (Lewy-body inclusions) in neurons of the substantia nigra pars compacta and other brain areas. These inclusions were discovered over 90 years ago, but the mechanism underlying their formation and their relevance to the neurodegenerative process are unknown. Recent studies have begun to shed light on the biogenesis of Lewy bodies and suggest that they are related to aggresomes. Aggresomes are cytoprotective proteinaceous inclusions formed at the centrosome that segregate and facilitate the degradation of excess amounts of unwanted and possibly cytotoxic proteins. The concept of Lewy bodies as aggresome-related inclusions fits well with ongoing discoveries suggesting that altered protein handling might contribute to the neurodegenerative process in familial and sporadic forms of PD.     

Spared somatomotor and cognitive functions in a patient with a large porencephalic cyst revealed by fMRI

To date functional magnetic resonance imaging (fMRI) has not been extensively used in presurgical evaluation of patients with intractable epilepsy. Patient S.P. presented with left frontal originating seizures, secondary to a large porencephalic cyst that encompassed much of his occipital and temporal cortex and a substantial portion of ipsilateral parietal cortex. Nevertheless, S.P. did not demonstrate any gross impairments of praxis or speech. Scalp electroencephalogram (EEG) telemetry revealed reduced background activity in the left hemisphere, an absence of identifiable normal sleep states, and confirmed the left frontal origin of his seizures with a prolonged postictal state, suggesting that the remaining cortex in S.P.'s left hemisphere did not function normally despite his apparently normal appearance. Dichotic listening results also suggested that S.P. had an atypical language representation suggestive of either bilateral or right hemisphere speech representation. Surgical intervention to remove the remaining left hemisphere cortex was a serious consideration for treatment of S.P.'s seizures. We used fMRI to evaluate whether or not the remaining cortex in S.P.'s left hemisphere supported any cognitive or motor functions. Even though the volume of cerebral cortex was severely reduced and displaced in the left hemisphere, fMRI revealed significant activation in this remaining tissue in response to motor, somatosensory, and word generation tasks. In other words, we were able to demonstrate using fMRI that the remaining tissue in S.P.'s left hemisphere continued to support some motor and cognitive functions. The possible implications of these findings in terms of functional reorganisation are discussed briefly.