Norman Relkin

Intraneuronal Aβ42 accumulation in human brain

Alzheimers disease (AD) is characterized by the deposition of senile plaques (SPs) and neurofibrillary tangles (NFTs) in vulnerable brain regions. SPs are composed of aggregated β-amyloid (Aβ) 40/42(43) peptides. Evidence implicates a central role for Aβ in the pathophysiology of AD. Mutations in βAPP and presenilin 1 (PS1) lead to elevated secretion of Aβ, especially the more amyloidogenic Aβ42. Immunohistochemical studies have also emphasized the importance of Aβ42 in initiating plaque pathology. Cell biological studies have demonstrated that Aβ is generated intracellularly. Recently, endogenous Aβ42 staining was demonstrated within cultured neurons by confocal immunofluorescence microscopy and within neurons of PS1 mutant transgenic mice. A central question about the role of Aβ in disease concerns whether extracellular Aβ deposition or intracellular Aβ accumulation initiates the disease process. Here we report that human neurons in AD-vulnerable brain regions specifically accumulate γ-cleaved Aβ42 and suggest that this intraneuronal Aβ42 immunoreactivity appears to precede both NFT and Aβ plaque deposition. This study suggests that intracellular Aβ42 accumulation is an early event in neuronal dysfunction and that preventing intraneuronal Aβ42 aggregation may be an important therapeutic direction for the treatment of AD.

Distinct cortical areas associated with native and second languages

The ability to acquire and use several languages selectively is a unique and essential human capacity. Here we investigate the fundamental question of how multiple languages are represented in a human brain. We applied functional magnetic resonance imaging (fMRI) to determine the spatial relationship between native and second languages in the human cortex, and show that within the frontal-lobe language-sensitive regions (Brocas area), second languages acquired in adulthood (‘late’ bilingual subjects) are spatially separated from native languages. However, when acquired during the early language acquisition stage of development (‘early’ bilingual subjects), native and second languages tend to be represented in common frontal cortical areas. In both late and early bilingual subjects, the temporal-lobe language-sensitive regions (Wernickes area) also show effectively little or no separation of activity based on the age of language acquisition. This discovery of language-specific regions in Brocas area advances our understanding of the cortical representation that underlies multiple language functions.

Diagnosing idiopathic normal-pressure hydrocephalus

OBJECTIVE:The precise incidence and prevalence of idiopathic normal-pressure hydrocephalus (INPH) is not known, and evidence-based clinical diagnostic criteria have not been developed previously. This report contains evidence-based guidelines for clinical diagnosis of INPH that are intended to facilitate future epidemiological studies of INPH, promote earlier and more accurate diagnosis, and ultimately improve treatment outcome. METHODS:The criteria for the diagnosis of INPH are based on evidence from the medical literature, supplemented as necessary by expert opinion. From 1966 to 2003, 653 publications on “normal-pressure hydrocephalus” were cited in MEDLINE, including 29 articles that met the more stringent criteria of including “idiopathic normal-pressure hydrocephalus” in their title. Additional studies were considered that explicitly identified INPH cases and/or specified the criteria for a diagnosis of INPH. Studies were graded according to the class of evidence and results summarized in evidentiary tables. For issues of clinical relevance that lacked substantive evidence from the medical literature, the opinions of consulting experts were considered and contributed to “Options.” RESULTS:Evidence-based guidelines for the clinical diagnosis of INPH have been developed. A detailed understanding of the range of clinical manifestations of this disorder and adherence to practice guidelines should improve the timely and accurate recognition of this disorder. CONCLUSION:It is recommended that INPH be classified into probable, possible, and unlikely categories. We hope that these criteria will be widely applied in clinical practice and will promote greater consistency in patient selection in future clinical investigations involving INPH.

Disclosure of APOE Genotype for Risk of Alzheimer's Disease

BACKGROUND The apolipoprotein E (APOE) genotype provides information on the risk of Alzheimers disease, but the genotyping of patients and their family members has been discouraged. We examined the effect of genotype disclosure in a prospective, randomized, controlled trial. METHODS We randomly assigned 162 asymptomatic adults who had a parent with Alzheimers disease to receive the results of their own APOE genotyping (disclosure group) or not to receive such results (nondisclosure group). We measured symptoms of anxiety, depression, and test-related distress 6 weeks, 6 months, and 1 year after disclosure or nondisclosure. RESULTS There were no significant differences between the two groups in changes in time-averaged measures of anxiety (4.5 in the disclosure group and 4.4 in the nondisclosure group, P=0.84), depression (8.8 and 8.7, respectively; P=0.98), or test-related distress (6.9 and 7.5, respectively; P=0.61). Secondary comparisons between the nondisclosure group and a disclosure subgroup of subjects carrying the APOE epsilon4 allele (which is associated with increased risk) also revealed no significant differences. However, the epsilon4-negative subgroup had a significantly lower level of test-related distress than did the epsilon4-positive subgroup (P=0.01). Subjects with clinically meaningful changes in psychological outcomes were distributed evenly among the nondisclosure group and the epsilon4-positive and epsilon4-negative subgroups. Baseline scores for anxiety and depression were strongly associated with post-disclosure scores of these measures (P<0.001 for both comparisons). CONCLUSIONS The disclosure of APOE genotyping results to adult children of patients with Alzheimers disease did not result in significant short-term psychological risks. Test-related distress was reduced among those who learned that they were APOE epsilon4-negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure. (ClinicalTrials.gov number, NCT00571025.)

18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease.

Intravenous immunoglobulin (IVIg) has been proposed as a potential agent for Alzheimers disease (AD) immunotherapy because it contains antibodies against beta-amyloid (Abeta). We carried out an open label dose-ranging study in 8 mild AD patients in which IVIg was added to approved AD therapies for 6 months, discontinued, and then resumed for another 9 months. Infusions were generally well-tolerated. Anti-Abeta antibodies in the serum from AD patients increased in proportion to IVIg dose and had a shorter half-life than anti-hepatitis antibodies and total IgG. Plasma Abeta levels increased transiently after each infusion. Cerebrospinal fluid Abeta decreased significantly at 6 months, returned to baseline after washout and decreased again after IVIg was re-administered for an additional 9 months. Mini-mental state scores increased an average of 2.5 points after 6 months, returned to baseline during washout and remained stable during subsequent IVIg treatment. Our findings confirm and extend those obtained by Dodel et al. [Dodel, R.C., Du, Y., Depboylu, C., Hampel, H., Frolich, L., Haag, A., Hemmeter, U., Paulsen, S., Teipel, S.J., Brettschneider, S., Spottke, A., Nolker, C., Moller, H.J., Wei, X., Farlow, M., Sommer, N., Oertel, W.H., 2004. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimers disease. J. Neurol. Neurosurg. Psychiatry 75, 1472-1474] from a 6-month trial of IVIg in 5 AD patients and justify further studies of IVIg for treatment of AD.

An Integrated Functional Magnetic Resonance Imaging Procedure for Preoperative Mapping of Cortical Areas Associated with Tactile, Motor, Language, and Visual Functions

OBJECTIVETo evaluate an integrated battery of preoperative functional magnetic resonance imaging (fMRI) tasks developed to identify cortical areas associated with tactile, motor, language, and visual functions. METHODSSensitivity of each task was determined by the probability that a targeted region was activated for both healthy volunteers (n = 63) and surgical patients with lesions in these critical areas (n = 125). Accuracy of each task was determined by the correspondence between the fMRI maps and intraoperative electrophysiological measurements, including somatosensory evoked potentials (n = 16), direct cortical stimulation (n = 9), and language mapping (n = 5), and by preoperative Wada tests (n = 13) and visual field examinations (n = 6). RESULTSFor healthy volunteers, the overall sensitivity was 100% for identification of the central sulcus, visual cortex, and putative Wernicke’s area, and 93% for the putative Broca’s area (dominant hemisphere). For patients with tumors affecting these regions of interest, task sensitivity was 97% for identification of the central sulcus, 100% for the visual cortex, 91% for the putative Wernicke’s area, and 77% for the putative Broca’s area. These sensitivities were enhanced by the use of multiple tasks to target related functions. Concordance of the fMRI maps and intraoperative electrophysiological measurements was observed whenever both techniques yielded maps and Wada and visual field examinations were consistent with fMRI results. CONCLUSIONThis integrated fMRI task battery offers standardized and noninvasive preoperative maps of multiple critical functions to facilitate assessment of surgical risk, planning of surgical routes, and direction of conventional, intraoperative electrophysiological procedures. Thus, a greater range of structural and functional relationships is brought to bear in the service of optimal outcomes for neurosurgery.

The Value of Supplemental Prognostic Tests for the Preoperative Assessment of Idiopathic Normal-pressure Hydrocephalus

OBJECTIVE:The diagnosis and management of idiopathic normal-pressure hydrocephalus (INPH) remains unclear. Moreover, the value of supplementary tests to predict which patients would benefit from placement of a shunt has not been established. This report develops evidence-based guidelines for the use of supplementary tests as an aid in prognosis. METHODS:MEDLINE searches from 1966 to the present were undertaken by use of the query NPH, normal-pressure hydrocephalus, lumbar drain, CSF [cerebrospinal fluid] tap test, and external CSF drainage in humans. This resulted in 242 articles. To provide a scientific, evidence-based review, we have chosen to restrict our analysis to clinically relevant studies usually consisting of large numbers of shunted NPH patients. Studies that did not specify INPH or secondary NPH were considered in a separate evidentiary table. RESULTS:Evidence-based guidelines for use in supplementary tests have been developed. A positive response to a 40- to 50-ml tap test has a higher degree of certainty for a favorable response to shunt placement than can be obtained by clinical examination. However, the tap test cannot be used as an exclusionary test because of its low sensitivity (26–61%). Determination of the CSF outflow resistance via an infusion test carries a higher sensitivity (57–100%) compared with the tap test and a similar positive predictive value of 75 to 92%. Prolonged external lumbar drainage in excess of 300 ml is associated with high sensitivity (50–100%) and high positive predictive value (80–100%). CONCLUSION:To date, a single standard for the prognostic evaluation of INPH patients is lacking. However, supplemental tests can increase predictive accuracy for prognosis to greater than 90%. Additional multicenter prospective randomized clinical trials are needed.

Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals.

Active immunization with the human amyloid peptide (Abeta42) or passive immunization with anti-Abeta42 antibodies protects mice that express a mutant human amyloid precursor protein (APP) transgene from cerebral amyloid deposits. If anti-Abeta42 antibodies protect APP-transgenic mice, a model of Alzheimers disease (AD), a high titer of anti-Abeta42 antibodies may protect humans from AD. The titer of anti-Abeta42 antibodies in serum from individuals with and without late onset AD was measured using an ELISA. The titer of Ig (IgM, IgG and IgA) and IgG anti-Abeta42 peptide antibodies was significantly higher in serum from elderly controls than AD patients. Furthermore, IgG but not Ig anti-Abeta42 antibodies distinguished sera from AD patients and elderly controls that did not have the apolipoprotein E4 allele. The low titer of anti-Abeta42 antibodies in AD patients does not reflect the well-established, age-associated defect in the antibody response to most protein antigens, as there was no positive correlation between the serum titer of anti-Abeta42 antibodies and anti-influenza hemagglutinin antibodies induced by influenza vaccine in elderly humans. The lower titer of serum anti-Abeta42 peptide antibodies in AD patients may reflect the reported specific impairment of helper T cell activity for B cells that produce anti-amyloid-beta42 peptide antibodies in APP-transgenic mice.

Cerebrospinal fluid proteomic biomarkers for Alzheimer's disease

To find a panel of proteins in antemortem cerebrospinal fluid (CSF) that could be used to differentiate between samples from Alzheimers disease (AD) patients and samples from healthy and neurological control subjects.

Lower Cognitive Performance of Older Football Players Possessing Apolipoprotein E ε4

OBJECTIVETo determine whether the cognitive status of professional football players varies as a function of age and apolipoprotein E (APOE) genotype. METHODSFifty-three active players underwent APOE and neuropsychological assessments. Players were grouped according to age (proxy indicator of high/low exposure to contact) and the presence/absence of at least one copy of the &egr;4 allele. Outcome measures were overall cognitive performance and scores in cognitive domains. RESULTSAs a group, older players possessing APOE &egr;4 exhibited significantly lower cognitive test scores than did all other players studied, including non-&egr;4-possessing players and younger &egr;4-carriers. Measures of general cognitive functioning, information-processing speed and accuracy, and attention were related to poorer performance among the &egr;4-carrying players. In an analysis of variance model, the interaction between APOE genotype and age was significant (P = 0.004). As determined using linear regression, age accounted for 34% of the variance in the memory index among APOE &egr;4-possessing players but did not contribute significantly to variance among the non-&egr;4-possessing players. Older APOE &egr;4-carriers were significantly overrepresented among players whose scores indicated possible cognitive impairment, with the criterion of performing two or more standard deviations below the general normal values in a summary index of general cognitive functioning. CONCLUSIONOlder professional football players who possessed the APOE &egr;4 allele scored lower on cognitive tests than did players without this allele or less experienced players of any genotype. The cognitive status of professional athletes with repeated exposure to head trauma may therefore be influenced by age, inherited factors such as APOE genotype, and cumulative exposure to contact.