HEMOCHROMATOSIS ALLELES INDICATE GENETIC RISK FACTORS FOR STROKE

Some hereditary hemochromatosis patients have a twofold and threefold greater risk for ischemic cerebrovascular disease (ICVD) and ischemic stroke, reported researchers in the March 27 Neurology. However, none of the hemochromatosis genotypes was a predictor of symptomatic carotid atherosclerosis, despite expectations to the contrary.

Previous studies have linked a single nucleotide polymorphism found in the HFE gene with biochemical iron overload and other diseases of the brain, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, said Børge G. Nordestgaard, MD, DMSc, Professor at the University of Copenhagen and Herlev University Hospital in Denmark, and colleagues; they hypothesized that some of those genotypes, homozygous or heterozygous combinations of H63D and C282Y, might also be risk factors for cerebrovascular events. Their investigation consisted of two parts: One included 701 symptomatic carotid atherosclerosis patients, age- and gender-matched with 2,777 controls, and the second was a prospective population study, consisting of 9,178 Danish individuals followed for 24 years, during which 504 participants developed ICVD, of whom 393 had an ischemic stroke.

All study participants were genotyped for H63D and C282Y, and their blood was analyzed for iron overload and oxidized LDL cholesterol. Two thirds of the general population cohort did not exhibit either of the alleles, while 20.5% had the H63D/wild type genotype; 9.2%, C282Y/­wild type; 1.7%, H63D/H63D; 1.4%, C282Y/­H63D; and 0.25%, C282Y/C282Y. Compared with measures in the wild type/wild type subgroup, transferrin saturation was elevated in all except for the H63D/wild type group, while ferritin levels were elevated only in the homozygous C282Y group. Oxidized LDL plasma levels did not differ between genotypes.

“Genotype was not consistently associated with symptomatic carotid atherosclerosis,” stated the authors, after they examined data from the case-control portion of the study. However, cumulative incidences of both ICVD and ischemic stroke as a function of age were higher in participants who were homozygous for H63D than in those with the wild type/wild type genotype (multifactorially adjusted hazard ratios, 2.1 and 2.8, respectively). Based on the 1.7% occurrence of that genotype in the general population, the researchers estimated that the population attributable risk of ICVD was 2%, and the population attributable risk of ischemic stroke was 3%.

While the hereditary hemochromatosis genotype H63D/H63D was strongly associated with ICVD and ischemic stroke, the authors asserted that “the mechanisms behind this observation most likely are not via development of atherosclerosis, as documented in the case-control study, and not via iron overload because neither C282Y homozygosity nor heterozygosity was associated with ICVD or ischemic stroke.” However, they said that the only known biologic effect of H63D is iron accumulation, even though overload is not seen in all carriers, and that “an iron-dependent mechanism … different from classic iron overload as caused by C282Y cannot be ruled out.”

Suggested Reading
Ellervik C, Tybjærg-Hansen A, Appleyard M, et al. Hereditary hemochromatosis genotypes and risk of ischemic stroke. Neurology. 2007;68:1025-1031.

NEUROLOGIC COMPLICATIONS INCREASE WITH CNS-INVOLVED ENTEROVIRUS INFECTION

Long-term neurologic complications, delayed neurodevelopment, and cognitive functioning deficits are increased in relation to the severity of CNS involvement in enterovirus 71 (EV71) infection, especially in those patients who experienced cardiopulmonary failure. Age at onset also affected cognitive functioning, reported Luan-Yin Chang, MD, PhD, and colleagues in the March 22 New England Journal of Medicine.

One hundred forty-two children diagnosed with EV71 infection with CNS involvement between 1998 and 2003 at two Taiwanese hospitals were classified into three groups: those with mild CNS involvement (61 participants, all with aseptic meningitis), those with severe CNS involvement (53 with encephalitis, a poliomyelitis-like syndrome, or encephalomyelitis), and those who experienced cardiopulmonary failure after CNS involvement (28 participants). Median age of the entire cohort at disease onset and at assessment was 1.8 and 5.0 years, respectively; median time to follow-up was 2.9 years after onset.

Physical examinations revealed that all participants with mild CNS involvement recovered completely. Of those with severe CNS involvement, one patient had facial nerve palsy, and 10 had unilateral limb weakness and atrophy. Twenty-one children with cardiopulmonary failure (75%) displayed neurologic sequelae (a significantly higher rate than was observed in children with CNS involvement alone): 18 exhibited weakness and atrophy, 17 exhibited dysphagia necessitating tube feeding, 16 exhibited central hypoventilation necessitating ventilator support, seven exhibited facial nerve palsy, five exhibited seizure and psychomotor retardation from hypoxia, and four exhibited seizure alone. Abnormal MRI results, including high-intensity lesions on the brain stem and spinal cord, were found in 19 of those participants.

Neurodevelopmental delays, as measured by the Denver Developmental Screening Test, and decreased IQ were also significantly associated with greater clinical severity of CNS involvement. Of 63 participants who did not experience cardiopulmonary failure, only one participant (with severe CNS involvement) exhibited neurodevelopmental delays in two of four categories, compared with 21 of 28 participants who did experience cardiopulmonary failure (four had delays in one category, two had delays in two categories, and 15 had delays in all four categories). Borderline intelligence (full-scale IQ of 85 or less) was observed in 50% of the cardiopulmonary failure participants, in 13% of those with mild CNS involvement, and in 11% of those with severe CNS involvement; univariate analysis also found that age younger than 2 at onset yielded a higher risk for borderline IQ.

“EV71 viral antigen has been seen in neurons with immunocytochemical staining,” stated the authors. “Therefore, direct EV71 invasion and subsequent neuron damage could be said to be the main cause of the sequelae.” The observed cognitive effects, the researchers also suggested, may have been caused by both “direct viral CNS effects and the indirect anoxic and ischemic effects on the CNS,” although they acknowledged that the inability to attend school during infection may have had an impact on the children’s testing results. The investigators noted that EV71 infection often happens before children attend school, while many learning and behavioral problems are not noticed until then; therefore, careful follow-up of infected patients is warranted.

Suggested Reading
Chang L-Y, Huang L-M, Gau SS-F, et al. Neurodevelopment and cognition in children after enterovirus 71 infection. N Engl J Med. 2007;356:1226-1234.

PITTSBURGH COMPOUND B DETECTS BETA-AMYLOID IN VIVO

Researchers have demonstrated the ability of Pittsburgh Compound B (PiB) to detect b-amyloid in a living patient, according to a report in the March Archives of Neurology. Brian J. Bacskai, PhD, and colleagues conducted a case study of a 76-year-old man diagnosed with dementia with Lewy bodies who underwent fluorodeoxyglucose 18F and PiB positron emission tomographic brain scans, which showed marked region-specific binding of PiB and abnormal fluorodeoxyglucose uptake. Autopsy results performed three months after the PiB scan confirmed the diagnosis and revealed severe cerebral amyloid angiopathy and moderate numbers of parenchymal b-amyloid plaques.

“Our report substantiates the view that PiB uptake is a sensitive method to detect [b-amyloid] in the brain but points out the fact that clinical conditions other than probable or definite Alzheimer’s disease may harbor PiB-detectable amyloid deposits—thus broadening the range of clinically defined syndromes in which a PiB scan may be positive,” Dr. Bacskai and colleagues noted. The researchers posited that in addition to Alzheimer’s disease, PiB retention could be a feature of amyloid deposition at risk for Alzheimer’s disease in normal older patients, as well as a feature of mild cognitive impairment, cerebral amyloid angiopathy, and dementia with Lewy bodies with amyloid angiopathy.

Although the researchers found a positive correlation between b-amyloid levels and regional PiB binding, it is still not clear whether the negative PiB scans of some patients diagnosed with Alzheimer’s disease are true- or false-negatives. The investigators suggested that PiB retention be regarded “as a method to detect and quantify brain b-amyloidosis,” as opposed to a view that equates amyloid deposition with an initial diagnosis of Alzheimer’s disease.

“To our knowledge, this study is the first pathological examination of a human brain from a patient who had a positive PiB scan during life,” Dr. Bacskai’s team stated. “The most impressive finding was the severe cerebral amyloid angiopathy, which raises the notion that the PiB uptake in this case reflected [b-amyloid] in cerebral vessels more than [b-amyloid] in the brain parenchyma. Whether this observation is the rule or the exception must await additional clinical-pathological correlative studies.”

In an accompanying editorial, David M. Holtzman, MD, stated that Dr. Bacskai and colleagues’ study “provides strong validation that PiB retention is very likely reflective of [b-amyloid] that is deposited as amyloid.” Dr. Holtzman also pointed out that the findings give “strong support that [amyloid deposition in] Alz­heimer’s disease and cerebral amyloid angiopathy can be visualized without requiring brain autopsy or brain biopsy for definite proof.”

Suggested Reading
Bacskai BJ, Frosch MP, Freeman SH, et al. Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. Arch Neurol. 2007;64:431-434.
Holtzman DM. Pittsburgh Compound B retention and verification of amyloid deposition. Arch Neurol. 2007;64:315-316.

TWO NEW BIOMARKERS MAY PREDICT RISK OF ALZHEIMER'S DISEASE

Two reports in the March Archives of Neurology have revealed potential biomarkers for determining which patients are at risk for Alzheimer’s disease. Measures of CSF tau/Ab42 and levels of plasma b-amyloid protein (Ab40 and Ab42) have shown promise in identifying cognitively normal older adults at risk for dementia and mild cognitive impairment (MCI) or Alzheimer’s disease, respectively.

Neill R. Graff-Radford, MBBCh, FRCP, and colleagues examined 563 cognitively normal white participants 55 and older (median age, 78) who, after measurement of baseline plasma Ab levels, had at least one follow-up visit. Fifty-three patients developed MCI or Alzheimer’s disease; among these, patients with plasma Ab42/Ab40 ratios in the lower quartiles had a significantly greater risk of MCI or Alzheimer’s disease. In addition, there was greater cognitive decline among patients with lower Ab42/Ab40 ratios.

The researchers also found a relative risk of 3.1 for MCI or Alzheimer’s disease when comparing patients with Ab42/Ab40 ratios in the lowest and highest quartiles. This finding “suggests that, in this population, the Ab42/Ab40 ratio may be as useful as [apolipoprotein E] and more useful than family history as a premorbid biomarker for identifying those at imminent risk” for MCI and Alzheimer’s disease, Dr. Graff-Radford and colleagues stated.

Furthermore, the five-year cumulative incidence of MCI and Alzheimer’s disease was estimated at 20% for patients older than 80 whose Ab42/Ab40 ratio was below the median, while among patients younger than 80, the five-year cumulative incidence was estimated at 5%. The researchers noted that if these results “are confirmed in additional large longitudinal studies, the plasma Ab42/Ab40 ratio could become an important biomarker for developing and implementing a preventive approach to Alzheimer’s disease therapy in elderly white subjects.”

In a separate study, Anne M. Fagan, PhD, and colleagues studied 139 participants ages 60 to 91 who were either cognitively normal or had very mild or mild Alzheimer’s disease dementia. Patients with very mild or mild Alzheimer’s disease had reduced mean levels of CSF Ab42 and increased levels of CSF tau and phosphorylated tau181. The presence or absence of brain amyloid in participants with and without dementia corresponded with the level of CSF Ab42.

Dr. Fagan and colleagues also found that the same CSF biomarker phenotype was displayed among patients during the mildest symptomatic stage of Alzheimer’s disease and during more advanced stages. The researchers noted that longer longitudinal follow-up of patients without dementia and evaluation of patients younger than 60 will yield more accurate estimates regarding the predictive value of CSF tau/Ab42 and how early in the course of Alzheimer’s disease clinicians could make use of this preclinical biomarker.

“The number of individuals with Alzheimer’s disease dementia will increase dramatically over the next generation if effective therapies are not developed,” Dr. Fagan’s team pointed out. “Having CSF or other markers that predict future cognitive decline in individuals while they are still cognitively normal will help minimize the cohort size and treatment duration required to ascertain therapeutic efficacy in clinical trials, thus moving the field closer toward the ultimate goal of delaying or preventing Alzheimer’s disease.”

Suggested Reading
Graff-Radford NR, Crook JE, Lucas J, et al. Association of low plasma Ab42/Ab40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol. 2007;64:354-362.
Fagan AM, Roe CM, Xiong C, et al. Cerebrospinal fluid tau/b-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64:343-349.

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