As Kalidas and Smith point out, a remarkable revolution is occurring in biomedical science, and this will likely have profound implications in the way we treat neurological diseases in the future. RNA interference (RNAi) is a new technique that can silence any gene that is homologous to double-stranded RNA. In this review, the link between RNAi machinery and the fragile X syndrome is discussed, including future applications of this technology for the therapy of human neurological disease.
Rosso and colleagues describe levels of total tau, phosphorylated tau (Ptau), and amyloid-β1-42 in the cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD). They find that tauopathy associated with 2 tau gene mutations does not appear to be associated with an evident increase in CSF Ptau-181 in patients with FTD in contrast with findings in patients with Alzheimer disease.
Gómez-Tortosa and colleagues have measured cerebrospinal fluid (CSF) levels of tau, β-amyloid, and interleukins 1 and 6 as potential diagnostic markers to distinguish diffuse Lewy body disease (DLBD) from Alzheimer disease (AD). They find that tau levels in CSF contribute to the clinical distinction between AD and DLBD. β-Amyloid levels in CSF were similar in patients with AD and DLBD and tended to be lower than in controls. Further, tau levels reflect disease progression in both dementia disorders.
The serotonin system was studied in patients with Parkinson disease (PD), using positron emission tomography (PET) with the serotonin transporter (SERT) radioligand [11C](+)McN5652. Kerenyi et al show that patients with Parkinson disease have a reduction in the specific distribution volumes of this SERT in the caudate and putamen, along with an expected reduction in striatal dopamine transporters (DATs). Of note, reductions in SERT binding correlated with ratings of disease staging. Thus, SERTs, like DATs, are affected progressively with disease staging in patients with PD.
Maddalena and colleagues describe the combination of cerebrospinal fluid levels of phosphorylated tau protein (phospho-tau) and β-amyloid peptide42 (Aβ42) as markers for Alzheimer disease (AD). They find that the calculated phospho-tau/Aβ42 ratio is significantly increased in AD and provides high diagnostic accuracy in distinguishing AD from controls and other dementias. Editorial comment is provided by Douglas Galasko.
A, Decreased levels of β-amyloid peptide42 (Aβ42), increased levels of phosphorylated tau protein (phospho-tau) (B), and the ratio of phospho-tau to Aβ42 (C) in the cerebrospinal fluid (CSF) in patients with Alzheimer disease (AD), healthy control subjects (HCS), subjects with non-AD dementias (DEM), and subjects with other neurological disorders without dementia (OTH). Error bars indicate SD.
Bisschops and colleagues have studied changes in prevalence and volume of ischemic border zone lesions over time in patients with occlusive disease of the internal carotid artery after 1year of follow-up. They find that in hemispheres ipsilateral to an occluded internal carotid artery, there was an increase in the volume of the internal border zone infarcts. Further, in hemispheres with low carbon dioxide reactivity, there was an increase in the volume of the internal border zone lesion after 1 year. Thus, there is an association between impaired vasomotor reactivity and progression of ischemic lesion volume in the internal border zone.
The contribution of the fornix as a determinant of surgical outcome in patients with preoperatively determined temporal lobe epilepsy was studied by Burneo and colleagues. Seventy-eight patients were included in this study. Eighty percent of patients in the hippocampal atrophy group were seizure free compared with 73% in the fornix and hippocampal atrophy group. Thus, the identification of fornix atrophy, with or without associated hippocampal atrophy, is not an important preoperative determinant of surgical outcome.
The expression pattern of RhoA and RhoB, small GTPase Rho (ras homology protein), was measured in patients with cerebral infarctions. Brabeck and colleagues find that compared with control brains, the highly significant lesional upregulation of both RhoA and RhoB was observed beginning between 2 and 10 days after ischemia and prolonged months after focal infarction. Experimental studies have demonstrated that the inhibition of Rho promotes axon regeneration in vitro and in vivo, and the present findings are in support of research for new pharmacologic interventions to reduce Rho expression in human stroke.
Mutations in the parkin gene, an E3 ubiquitin ligase, cause autosomal recessive early-onset Parkinson disease (PD). Lücking et al have studied parkin gene polymorphisms as risk factors for PD. Homozygous Val 380 was significantly associated with sporadic PD. The functional effects of these coding polymorphisms need to be established more definitively.
The Kii peninsula of Japan has one of the highest incidences of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC). Kokubo and Kuzuhara have studied patients with ALS and PDC from the Kii peninsula. Patients with PDC showed mild to severe atrophy in the frontal and temporal lobes on computed tomography (CT) and magnetic resonance imaging (MRI), and a marked decrease in cerebral blood flow on single-photon emission CT. Patients with ALS, in contrast, showed a decrease in cerebral blood flow in the frontal and temporal lobes without clinical dementia or obvious brain atrophy on CT or MRI. Thus, a reduction in cerebral blood flow in the frontal and temporal lobes in both Kii patients with PDC and ALS, with or without cerebral atrophy, supports the concept that these 2 conditions are different manifestations of a single frontotemporal disorder.
The prevalence of the GAG deletion in the DYT1 gene and the phenotypic variability in the general population was studied by Grundmann and colleagues. They find a wide range of phenotypic variability of the DYT1 mutation. Patients with this deletion were described as having generalized dystonia and also multifocal dystonia. Thus, prediction of the mutation carrier status in dystonic patients, and genetic counseling in affected families with respect to the clinical manifestation, may prove difficult.
Saccade measurements for detection of Alzheimer disease (AD) were studied by Shafiq-Antonacci and colleagues. Patients with AD and controls were studied. In general, patients had significantly longer and more variable saccade latencies than controls. Dementia severity and antisaccade error rate were significantly correlated. These studies may be useful as longitudinal markers for disease progression.
The frequencies in genotype-phenotype correlations of mutations in the α subunit of polymerase γ were studied by Filosto and colleagues as a cause of autosomal recessive progressive external ophthalmoplegia. Four unrelated patients had polymerase γ (POLG) mutations. They found that POLG mutations account for a substantial proportion of patients (13%) and cause both clinically and genetically heterogenous disorders.
This Month in The Archives of Neurology. Arch Neurol. 2003;60(9):1189-1190. doi:10.1001/archneur.60.9.1189