Frohman and colleagues provide an insightful and well-focused discussion about future application of pharmacogenetic techniques, proteomics, and microarray analysis that will yield novel profiling information on individual patients that will substantially refine specific therapeutic questions. What is the best treatment for an individual patient? Which patients require intensive therapeutic combination regimens to optimize control of the disease process? What are the appropriate drug dosing targets for an individual patient? Which patients will be predisposed to the development of drug-related adverse events?
In their important study, O’Toole and colleagues studied biomarkers associated with both risk meningoencephalitis and antibody responsiveness using a genomic strategy. They report that expression patterns of genes related to apoptosis and proinflammatory pathways (the tumor necrosis factor pathway in particular) were identified as biomarkers of risk for development of meningoencephalitis. Expression patterns of genes related to protein synthesis, protein trafficking, DNA recombination, DNA repair, and cell cycles were strongly associated with IgG response to immunization. This highly significant study shows for the first time the power and precision of a genomic expression profile strategy to predict an immunotherapeutic response and associated potential adverse effects in patients with Alzheimer disease. Editorial perspective is provided by Roger N. Rosenberg, MD.
Fishel et al report that insulin increased cerebrospinal fluid levels of F2-isoprostane and cytokines and plasma and cerebrospinal fluid β-amyloid 42 levels (Figure). Thus, these data support the position that moderate hyperinsulinemia can elevate inflammatory markers and β-amyloid 42 in the periphery and the brain, thereby potentially increasing the risk of Alzheimer disease.
A, Hyperinsulinemia increased plasma β-amyloid 42 (Aβ42) levels (F1,13 = 4.86, P = .046). Open bar indicates saline condition; filled bar, insulin condition. B, Participants with greater body mass index (BMI) showed greater increases in plasma Aβ42 levels with hyperinsulinemia. C, Insulin-induced elevations of cerebrospinal fluid (CSF) transthyretin (TTR) levels were associated with higher plasma Aβ42 levels. D, Insulin-induced elevations of CSF TTR levels were associated with lower CSF Aβ42 levels. Mean ± SEM CSF TTR levels were 4.75 ± 0.48 mg/L and 4.91 ± 0.52 mg/L during saline and insulin infusions, respectively. Mean ± SEM CSF Aβ42 levels were 1113.45 ± 117.95 pg/mL and 1159.65 ± 115.14 pg/mL during saline and insulin infusions, respectively.
Jagust and colleagues studied whether a larger waist-hip ratio (WHR) is associated with structural brain changes that underlie cognitive decline and dementia. They find that greater WHR and older age are negatively related to hippocampal volume. An increase in WHR was associated with a decrease in hippocampal volume and an increase in white matter hyperintensities. Thus, a larger WHR may be related to neurodegenerative, vascular, or metabolic processes that affect brain structures underlying cognitive decline and dementia.
Kivipelto et al studied the relation of midlife body mass index and the clustering of vascular risk factors to the development of Alzheimer disease. They report that obesity at midlife was associated with an increased risk of dementia and Alzheimer disease, even after adjusting for age, education, sex, and follow-up time. Midlife obesity, high cholesterol levels, and systolic blood pressure were all significant risk factors for dementia. It is their view that by reducing body mass index, it is possible to affect several vascular risk factors, and thus, dietary interventions might modify the risk of dementia.
Schwab et al studied the level of repulsive guidance molecule (RGM) expression in the adult human brain due to focal cerebral ischemia and traumatic brain injury. The RGM is involved in the formation of the brain during development by moderating repulsion of growing axons. The role of the RGM in adult brain pathology needs to be clarified. This is the first report of the RGM in human brain pathology. Following focal cerebral ischemia and traumatic brain injury, RGM-positive cells accumulated in lesional and perilesional areas.
Lee and colleagues show by skin biopsy that vasculitis affects small-diameter sensory nerves in addition to large-diameter nerves.
Brannagan et al find by skin biopsy that patients with celiac disease may have neuropathy involving small fibers. The pattern of symptoms, with frequent facial involvement and a non–length-dependent pattern on skin biopsy findings, suggests a sensory ganglionopathy or an immune-mediated neuropathy.
Di Blasi and colleagues performed molecular analysis of the LAMA2 gene in 15 patients with undetectable or greatly reduced laminin-α2 expression. They also performed 4 prenatal diagnoses and investigated a founder effect. The clinical phenotype was severe in most patients with LAMA2 mutations and associated with undetectable protein expression. The founder mutation (Cys967Stop) probably originated in Albania.
Michiels et al describe the phenotypes and molecular data of a 10-member family with inherited primary erythermalgia, a disorder characterized by recurrent attacks of red, warm, and painful hands and feet. All affected family members were heterozygous for a novel mutation (S241T) of the voltage-gated sodium channel α subunit Nav1.7. These observations support the position that primary erythermalgia is a neuropathic disorder of the small peripheral sensory and sympathetic neurons.
Stoeck et al report elevated levels of the anti-inflammatory cytokines interleukin (IL) 4 and IL-10 in the cerebrospinal fluid of patients with Creutzfeldt-Jakob Disease. These data provide evidence of the possible role of cytokines as immunological modifiers in Creutzfeldt-Jakob disease.
Omuro and colleagues studied 185 patients treated for primary central nervous system lymphoma, including 43 who developed neurotoxicity. The 5-year cumulative incidence of neurotoxicity was 24%. Older age, mental status changes, female sex, and radiotherapy predicted neurotoxicity on a univariate analysis.
Scarmeas et al examined whether the presence of delusions or hallucinations had predictive value for important outcomes in Alzheimer disease. Delusions were noted for 34% of patients at baseline and for 70% at any evaluation. Their presence was associated with increased risk for cognitive and functional decline. Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline, functional decline, institutionalization, and death.
Mutoh and colleagues examined the effects of serum from a patient with subacute sensory axonopathy on the function of the Trk high-affinity nerve growth factor receptor. They found that the patient’s serum inhibited nerve growth factor–induced neurite outgrowth and Trk autophosphorylation in PCtrk cells. Further, the patient’s serum, but not control serum, immunoprecipitated Trk and recognized Trk in brain homogenates as well as in Trk immunoprecipitates. Thus, these data strongly suggest that an anti-Trk autoantibody caused subacute sensory neuropathy in this patient. Editorial comment and perspective is provided by David E. Pleasure, MD.
This Month in The Archives of Neurology. Arch Neurol. 2005;62(10):1502-1504. doi:10.1001/archneur.62.10.1502