Alzheimer Disease: Rosenberg RN

Rosenberg RN. · No affiliation provided · Arch Neurol. · Pubmed #16831959 No free full text.

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Rosenberg RN. · No affiliation provided · Arch Neurol. · Pubmed #16344337 links to  free full text

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Rosenberg RN. · No affiliation provided · Arch Neurol. · Pubmed #16216931 links to  free full text

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Rosenberg RN. · No affiliation provided · Arch Neurol. · Pubmed #14676040 links to  free full text

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Rosenberg RN. · No affiliation provided · Arch Neurol. · Pubmed #12223021 links to  free full text

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Waring SC, Rosenberg RN. · Department of Epidemiology, The University of Texas School of Public Health, 1200 Herman Pressler, RAS-E629, Houston, TX 77030, USA. · Arch Neurol. · Pubmed #18332245 links to  free full text

Abstract: The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.

Rosenberg RN. · Department of Neurology and the Alzheimer's Disease Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9036, USA. · Arch Gen Psychiatry. · Pubmed #16275806 links to  free full text

Abstract: CONTEXT: Alzheimer disease (AD) is a major public health issue with a prediction of 12 million Americans being affected by 2025 from the present 4 million. Molecular and genetic findings have provided significant insights into the roles that amyloid, tau, and apolipoprotein E isoforms have in the causation of AD. A central issue in AD pathogenesis is the amyloid cascade hypothesis. It states that abnormal amyloid processing and accumulation is the primary causative factor of AD and other associated neuropathologic abnormalities are of secondary consequence. It is presented to provide the rationale for novel drug and vaccination therapeutic strategies. Future research directed at prediction and prevention of AD through a genomic and proteomic analysis with identification of multiple polymorphic genes that interact, resulting in increased risk for late-onset AD, are the realistic and ultimate goals. A new approach for drug development is required, one that will emphasize a genomic and proteomic analysis to identify at-risk gene sets whose genetic expression is sufficient to cause late onset, sporadic AD. Prediction and prevention of disease prior to clinical signs and symptoms are the goals. OBJECTIVE: A review and analysis from electronic literature databases and subsequent reference searches of the molecular genetic data. including pertinent genetic mutations and abnormal biochemical findings causal of AD, are cited. The amyloid cascade hypothesis, the contributions of apolipoprotein E, and hyperphosphorylated tau are discussed as to their roles in pathogenesis. Molecular targets for potential drug and vaccination therapies are cited from a critical assessment of the molecular and biomedical data. These data form the basis for rational, target-specific drug and vaccination therapies currently employed and planned for the near future. Phase 2 and 3 clinical trial results of drug and vaccination therapies are cited. CONCLUSIONS: A new approach is needed as current pharmacologic therapy directed at symptomatic relief has proved to be marginally effective. The genomic and proteomic basis of AD will be defined in the near future, and corresponding molecular therapeutic targets will be identified. Genomic neurology has arrived and its application to resolving AD is our best hope.

Baskin F, Rosenberg RN, Fang X, Hynan LS, Moore CB, Weiner M, Vega GL. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, TX 75390-9036, USA. · Neurology. · Pubmed #12821755 No free full text.

Abstract: Platelets, like neurons, contain 120- to 130- and 110-kd amyloid precursor proteins (APPs). Their ratio is reduced in AD, further reductions correlating with reduced Mini-Mental Status Examination scores [r(11) = 0.69, p < 0.05]. As statins alter APP processing, platelet APPs were analyzed in patients with AD given anticholesterol drugs for 6 weeks. APP ratios increased [t(37) = -3.888, p = 0.0004], proportionally with reduced cholesterol [r(36) = -0.45, p = 0.005]. Longer trials may reveal slowed cognitive loss, validating this index.

Weiner MF, de la Plata CM, Fields BA, Womack KB, Rosenberg RN, Gong YH, Qu BX, Diaz-Arrastia R, Hynan LS. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9129, USA. · Curr Alzheimer Res. · Pubmed #19199875 No free full text.

Abstract: We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61-89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5-13 years in the AD group and 12-16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 micromol/L vs. 9.8 micromol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eepsilon4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).

Weiner MF, Rosenberg RN, Womack KB, Svetlik DA, Fuller C, Fields J, Hynan LS. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18580594 No free full text.

Abstract: Factors predisposing to and associated with atherosclerosis may impact the onset and progression of Alzheimer disease (AD). The high prevalence of atherosclerosis and associated risk factors in American Indians makes them ideal subjects to test this association. We compared frequency of history of hypertension, myocardial infarction, stroke, diabetes, and high cholesterol in 34 American Indians with AD with 34 age-matched American Indian controls, and 34 age-matched whites with probable AD. We also measured waist size, height, and weight, and acquired blood for determination of plasma homocysteine and apolipoprotein E genotype. The 3 groups did not differ significantly in age or sex. History of hypertension and diabetes was significantly more common among American Indian AD patients than Indian controls or whites with AD. The 3 groups did not differ in history of stroke or myocardial infarction. Body mass index was significantly greater in both Indian groups than the white AD group. Plasma homocysteine levels were greater, but not significantly so, in the Indian AD than the Indian control group. Thus, there is preliminary evidence of a modest association between history of hypertension and diabetes and AD in a small sample of American Indians. This suggests that changes in lifestyle factors could influence the expression of AD in American Indians.

Qu BX, Xiang Q, Li L, Johnston SA, Hynan LS, Rosenberg RN. · Alzheimer's Disease Center, Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9036, USA. · J Neurol Sci. · Pubmed #17574274 links to  free full text

Abstract: Abeta42 peptide aggregation and deposition is an important component of the neuropathology of Alzheimer's disease (AD). Gene-gun mediated gene vaccination targeting Abeta42 is a potential method to prevent and treat AD. APPswe/PS1DeltaE9 transgenic (Tg) mice were immunized with an Abeta42 gene construct delivered by the gene gun. The vaccinated mice developed Th2 antibodies (IgG1) against Abeta42. The Abeta42 levels in brain were decreased by 41% and increased in plasma 43% in the vaccinated compared with control mice as assessed by ELISA analysis. Abeta42 plaque deposits in cerebral cortex and hippocampus were reduced by 51% and 52%, respectively, as shown by quantitative immunolabeling. Glial cell activation was also significantly attenuated in vaccinated compared with control mice. One rhesus monkey was vaccinated and developed anti-Abeta42 antibody. These new findings advance significantly our knowledge that gene-gun mediated Abeta42 gene immunization effectively induces a Th2 immune response and reduces the Abeta42 levels in brain in APPswe/PS1DeltaE9 mice. Abeta42 gene vaccination may be safe and efficient immunotherapy for AD.

Rosenberg RN. · Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. · JAMA. · Pubmed #16862641 No free full text.

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Qu B, Boyer PJ, Johnston SA, Hynan LS, Rosenberg RN. · Alzheimer's Diseases Center, Department of Neurology, University of Texas Southwestern Medical Center, 5323, Harry Hines, Dallas, 75390-9036, USA. · J Neurol Sci. · Pubmed #16556449 links to  free full text

Abstract: OBJECTIVE: To demonstrate that in APPswe/PS1DeltaE9 transgenic mice, gene gun mediated Abeta42 gene vaccination elicits a high titer of anti-Abeta42 antibodies causal of a significant reduction of Abeta42 deposition in brain. METHODS: Gene gun immunization is conducted with transgenic mice using the Abeta42 gene in a bacterial plasmid with the pSP72-E3L-Abeta42 construct. Enzyme-linked immunoabsorbent assays (ELISA) and Western blots are used to monitor anti-Abeta42 antibody levels in serum and Abeta42 levels in brain tissues. Enzyme-linked immunospot (ELISPOT) assays are used for detection of peripheral blood T cells to release gamma-interferon. Immunofluorescence detection of Abeta42 plaques and quantification of amyloid burden of brain tissue were measured and sections were analyzed with Image J (NIH) software. RESULTS: Gene gun vaccination with the Abeta42 gene resulted in high titers of anti-Abeta42 antibody production of the Th2-type. Levels of Abeta42 in treated transgenic mouse brain were reduced by 60-77.5%. The Mann-Whitney U-test P=0.0286. INTERPRETATION: We have developed a gene gun mediated Abeta42 gene vaccination method that is efficient to break host Abeta42 tolerance without using adjuvant and induces a Th2 immune response. Abeta42 gene vaccination significantly reduces the Abeta42 burden of the brain in treated APPswe/PS1DeltaE9 transgenic mice with no overlap between treated and control mice.

Yetkin FZ, Rosenberg RN, Weiner MF, Purdy PD, Cullum CM. · Department of Radiology and Alzheimer's Disease Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8896, USA. · Eur Radiol. · Pubmed #16402259 No free full text.

Abstract: The goals of this study were to evaluate brain activation in patients with probable Alzheimer's disease (AD), mild cognitive impairment (MCI), and controls while performing a working memory (WM) task. Eleven AD patients, ten MCI subjects, and nine controls underwent functional magnetic resonance imaging (fMRI) while performing a visual WM task. Statistical parametric maps of brain activation were obtained in each group, and group activation difference maps were generated. Ability to perform the task did not differ among the groups. Activation was observed in the parahippocampal region, superior-middle-inferior frontal gyri, parietal region, anterior-posterior cingulate, fusiform gyrus, and basal ganglia. MCI and AD groups showed more activation than the controls in the right superior frontal gyrus, bilateral middle temporal, middle frontal, anterior cingulate, and fusiform gyri. Activation in the right parahippocampal gyrus, left inferior frontal gyrus, bilateral cingulate and lingual gyri, right lentiform nucleus, right fusiform gyrus, and left supramarginal gyrus in the AD group was less than in the MCI group. The WM task evoked activation in widely distributed regions, consistent with previous fMRI studies. AD and MCI patients showed an increased extent of activation and recruitment of additional areas.

Tang K, Hynan LS, Baskin F, Rosenberg RN. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, United States. · J Neurol Sci. · Pubmed #16256140 links to  free full text

Abstract: The amyloid precursor protein (APP) in brain is processed either by an amyloidogenic pathway by beta-secretase and gamma-secretase to yield Abeta (beta-amyloid 4 kDa) peptide or by alpha-secretase within the beta-amyloid domain to yield non-amyloidogenic products. We have studied blood platelet levels of a 22-kDa fragment containing the Abeta (beta-amyloid 4 kDa) peptide, beta-secretase (BACE1), alpha-secretase (ADAM10), and APP isoform ratios of the 120-130 kDa to 110 kDa peptides from 31 Alzheimer's disease (AD) patients and 10 age-matched healthy control subjects. We found increased levels of Abeta4, increased activation of beta-secretase (BACE1), decreased activation of alpha-secretase (ADAM10) and decreased APP ratios in AD patients compared to normal control subjects. These observations indicate that the blood platelet APP is processed by the same amyloidogenic and non-amyloidogenic pathways as utilized in brain and that APP processing in AD patients is altered compared to control subjects and may be a useful bio-marker for the diagnosis of AD, the progression of disease and for monitoring drug responses in clinical trials.

Whyte SR, Cullum CM, Hynan LS, Lacritz LH, Rosenberg RN, Weiner MF. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8846, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15942324 No free full text.

Abstract: The performance of 40 elderly Native Americans and 40 demographically similar Caucasians clinically diagnosed with Alzheimer disease were compared on the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB). The purpose was to determine whether performance on the CERAD-NB, a cognitive screening battery used to evaluate dementia in the elderly, is affected by cultural differences between these two groups, after controlling for age, education, and gender. All subjects were administered the CERAD-NB as part of a standard diagnostic evaluation. Statistical analyses revealed no significant differences between the two groups on any measures from the CERAD-NB. Thus, the CERAD-NB appears to be an efficient cognitive screening assessment in English-speaking Native Americans with known or suspected dementing illness and it appears that special norms may not be necessary in this population. However, additional studies of larger samples are needed for confirmation and to explore factors such as education, acculturation, and degree of Native American heritage, which may influence cognitive test performance.

Qu B, Rosenberg RN, Li L, Boyer PJ, Johnston SA. · Center for Biomedical Inventions, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5232 Harry Hines Boulevard, Dallas, TX 75390-9036, USA. · Arch Neurol. · Pubmed #15596606 links to  free full text

Abstract: BACKGROUND: The amyloid-beta (Abeta) peptide has a central role in the neurodegeneration of Alzheimer disease (AD). Immunization of AD transgenic mice with Abeta(1-42) (Abeta(42)) peptide reduces both the spatial memory impairments and AD-like neuropathologic changes in these mice. Therapeutic immunization with Abeta in patients with AD was shown to be effective in reducing Abeta deposition, but studies were discontinued owing to the development of an autoimmune, cell-mediated meningoencephalitis. We hypothesized that gene vaccination could be used to generate an immune response to Abeta(42) that produced antibody response but avoided an adverse cell-mediated immune effect. OBJECTIVE: To develop an effective genetic immunization approach for treatment and prevention of AD without causing an autoimmune, cell-mediated meningoencephalitis. METHODS: Mice were vaccinated with a plasmid that encodes Abeta(42), administered by gene gun. The immune response of the mice to Abeta(42) was monitored by measurement of (1) antibody levels by enzyme-linked immunosorbent assay (ELISA) and Western blot and (2) Abeta(42)-specific T-cell response as measured by interferon-gamma enzyme-linked immunospot (ELISPOT) assay. RESULTS: Gene-gun delivery of the mouse Abeta(42) dimer gene induced significant humoral immune responses in BALB/c wild-type mice after 3 vaccinations in 10-day intervals. All 3 mice in the treated group showed significant humoral immune responses. The ELISPOT assay for interferon-gamma release with mouse Abeta(42) peptide and Abeta(9-18) showed no evident cytotoxic T-lymphocyte response. We further tested the responses of wild-type BALB/c mice to the monomer Abeta(42) gene vaccine. Western blot evaluation showed both human and mouse Abeta monomer gene vaccine elicited detectable humoral immune responses. We also introduced the human Abeta(42) monomer gene vaccine into AD double transgenic mice APPswe/PSEN1(A246E). Mice were vaccinated with plasmids that encode Abeta(1-42) and Abeta(1-16), or with plasmid without the Abeta gene. Treated mice showed significant humoral immune responses as demonstrated by ELISA and by Western blot. These mice also showed no significant cellular immune response as tested by ELISPOT. One of the treated mice was killed at 7 months of age for histological observations, and scattered amyloid plaques were noted in all layers of the cerebral cortex and in the hippocampus in both Abeta(42)- and control-vaccinated mice. No definite difference was discerned between the experimental and control animals. CONCLUSIONS: Gene-gun-administered genetic immunization with the Abeta(42) gene in wild-type BALB/c and AD transgenic mice can effectively elicit humoral immune responses without a significant T-cell-mediated immune response to the Abeta peptide. This immunotherapeutic approach could provide an alternative active immunization method for therapy and prevention of AD.

Cooper DB, Lacritz LH, Weiner MF, Rosenberg RN, Cullum CM. · Institute for Rehabilitation & Research, Baylor College of Medicine, Houston, TX, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15494616 No free full text.

Abstract: Verbal fluency tests are commonly used in neurocognitive and mental status examinations in patients with suspected dementia. Inflation of test scores as a result of practice effects may yield false-negative results in test-retest and multidisciplinary settings, particularly among patients with mild cognitive deficits. To address this issue, animal naming was administered twice within a 1-week period to a group of individuals referred for suspected dementia who were ultimately diagnosed with mild cognitive impairment (MCI; amnestic form), probable Alzheimer disease (AD), or no dementia. A 2 x 3 repeated-measures analysis of variance revealed a statistically significant interaction between administration time and group. Post hoc analyses indicated that nondemented controls were the only group to demonstrate a significant practice effect, producing an average of approximately three more animal names at time two. Like patients with a diagnosis of AD, subjects with amnestic MCI failed to benefit from repeated exposure to the animal naming test, and only controls showed an average improvement upon retest. This underscores the cognitive similarity between individuals diagnosed with amnestic MCI and AD and suggests that improvement upon retest may be a diagnostically useful finding.

Weiner MF, Rosenberg RN, Svetlik D, Hynan LS, Womack KB, White C, Good S, Fuller C, Wharton D, Richter R. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA. · Int Psychogeriatr. · Pubmed #15000416 No free full text.

Abstract: OBJECTIVE: This study compared medical history and findings on initial clinical examination in Native Americans diagnosed with possible or probable Alzheimer's disease (AD) at Native American satellite clinics of the University of Texas (UT) Southwestern Medical Center's Alzheimer's Disease Center with those of Whites diagnosed with probable AD at the UT Southwestern Medical Center's Alzheimer's Disease Clinic. METHODS: The information reviewed was contained in the database of the UT Southwestern Alzheimer's Disease Center. RESULTS: In relation to Whites, Native Americans had slightly but significantly greater age at onset of symptoms (71.7 vs. 69.6 years, t = -2.08, p = .04) and equivalent cognitive scores at evaluation (Mini-Mental State Exam score = 17.4 vs. 18.5, t = 0.98, p = .33), despite significantly lower educational level (11.4 vs. 13.4 years, t = 5.63, p < .001). Native Americans were more frequently depressed on examination (22.8% vs. 9.5%, chi2 = 12, p = .001) and reported diabetes, hypertension, and heart disease significantly more often than did Whites (p < .01 for all), but their survival time after AD diagnosis was similar to that of Whites despite these comorbidities. CONCLUSIONS: With the exception of a greater prevalence of depression and cardiovascular risk factors in Native Americans than in Whites, Native Americans had a course of illness similar to that of Whites.

Weiner MF, Hynan LS, Parikh B, Zaki N, White CL, Bigio EH, Lipton AM, Martin-Cook K, Svetlik DA, Cullum CM, Vobach S, Rosenberg RN. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75390-9070, USA. · J Geriatr Psychiatry Neurol. · Pubmed #14653435 No free full text.

Abstract: To determine if Alzheimer's disease (AD), its Lewy body (LB) variant (LBV), and diffuse LB disease (DLBD) are distinguishable at initial clinical evaluation, data from autopsy-confirmed AD, LBV, and DLBD were examined. No significant differences were found in age at onset, age at death, total duration of illness, duration of illness before initial visit, duration of illness from initial visit to death, or severity of illness at initial evaluation. Hallucinations and delusions were significantly more frequent for LBV and DLBD, respectively, than for AD, and falls were more frequent for DLBD than for AD. Extrapyramidal symptoms (EPS) were less frequent in neuroleptic-free AD subjects than in LB subjects; the percentage of AD patients with EPS after neuroleptic exposure was less than that among LB patients. Seizures were significantly more common for DLBD than for AD or LBV. LB dementias differed from AD at initial evaluation, with more frequent hallucinations and delusions, EPSs, and seizures, and longitudinally in neuroleptic sensitivity, but the data did not distinguish LBV from DLBD.

Cooper DB, Epker M, Lacritz L, Weine M, Rosenberg RN, Honig L, Cullum CM. · Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 75390-8898, USA. · Clin Neuropsychol. · Pubmed #11778573 No free full text.

Abstract: Evaluation of patients with suspected Alzheimer's disease (AD) often involves clinicians of multiple disciplines working in collaboration to maximize diagnostic accuracy. Accordingly, repeated administrations of some common tests of mental status may occur within a relatively brief time period. The effect of such retesting on subsequent results is largely unknown for many cognitive tasks, despite the possibility that repeated administrations may artificially inflate scores. To assess the potential impact of practice effects on a commonly administered verbal fluency task, animal naming was administered twice within a 1-week period to 111 patients with probable AD and 12 persons without dementia. Non-demended subjects were the only group to demonstrate a small (3 point), but statistically significant practice effect. Regardless of level of cognitive impairment, patients with AD did not show significant practice effects over repeated administrations of animal naming after a relatively brief test-retest interval, suggesting the robust nature of this task in AD.

Lacritz LH, Cullum CM, Weiner MF, Rosenberg RN. · The University of Texas Southwestern Medical Center at Dallas, 75390-8898, USA. · Appl Neuropsychol. · Pubmed #11686654 No free full text.

Abstract: We examined the validity of the revised Hopkins Verbal Learning Test (HVLT-R) by comparing performances on the HVLT-R and the California Verbal Learning Test (CVLT) in participants with Alzheimer's disease (AD). Total learning, delayed recall, intrusion errors, and recognition performance were significantly related across tests, but the number of perseverative responses showed no linear association. Despite similar results across measures, some of the variables were only modestly correlated, which may reflect differences in test procedures and the limited range of scores for some variables. Furthermore, the HVLT-R may not be challenging enough to elicit some of the types of recall errors commonly seen in AD to the same extent as the CVLT Nonetheless, the HVLT-R shows promise for providing a multidimensional assessment of verbal learning and memory and may be ideal in cases where brief assessment ofmemory and/or serial evaluations are needed.

Kaltreider LB, Cicerello AR, Lacritz LH, Honig LS, Rosenberg RN, Cullum MC. · The University of Texas Southwestern Medical Center at Dallas, TX 75390-8898, USA. · Clin Neuropsychol. · Pubmed #11262701 No free full text.

Abstract: This investigation examined the relationship of the word list from the CERAD neuropsychological battery to the California Verbal Learning Test (CVLT) in a sample of 138 subjects with Probable Alzheimer's disease (AD). Results revealed modest but statistically significant associations between the two measures on many key variables. Total words learned showed the strongest association, with lower correlations for delayed recall, intrusion errors, and recognition variables. As expected, the CERAD and CVLT assess similar aspects of verbal learning in patients with AD. However, the modest level of many of the correlations suggests that caution should be exercised in applying the same interpretive strategies derived on more comprehensive measures to shorter ones.

Baskin F, Rosenberg RN, Iyer L, Schellenberg GD, Hynan L, Nee LE. · Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., 75390-9036, Dallas, TX, USA. · J Neurol Sci. · Pubmed #11166800 No free full text.

Abstract: The Alzheimer's disease (AD) related amyloid precursor protein (APP) is stored, cleaved and released similarly from neurons and from platelets. We have reported that the proportion of 120-130 to 110 kDa carboxyl-cleaved APP present in the platelets of AD patients is significantly lower than that of platelets of age-matched controls. This reduced APP isoform ratio, not seen in several other disease groups, is further reduced as the severity of AD increases. Since the neuropathology of AD is believed to begin many years before the onset of cognitive loss, we have also compared platelet APP ratios of four pre-symptomatic young adults carrying a presenilin-1 mutation to seven siblings homozygous for the normal PS-1 gene in an effort to determine whether reduced APP ratios are present before apparent cognitive loss in familial AD. Decreased platelet APP ratios were not seen in any of these subjects at this time. We will continue to monitor these subjects as they near the mean age of AD onset in these families. As the magnitude of the APP ratio reduction is proportional to the severity of cognitive loss in sporadic AD, these cognitively normal incipient AD subjects would not be expected to present significant reductions in this AD severity index at this time. Alternatively, the absence of platelet APP ratio reductions may result from a failure of platelets from familial PS-1 AD subjects to manifest altered APPs, as has been reported for PS-2 AD subjects, unlike those of sporadic AD patients. Continued monitoring of cognitive status in our sub-set of controls with AD-like low APP ratios may yet validate the ability of this assay to detect incipient sporadic AD.

Baskin F, Rosenberg RN, Iyer L, Hynan L, Cullum CM. · Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9036, USA. · Neurology. · Pubmed #10822427 No free full text.

Abstract: BACKGROUND: Platelets and neurons both contain large quantities of two carboxyl-truncated 120 to 130 and 110 kDa Alzheimer amyloid precursor proteins (APPs). Platelets taken from patients with AD have been reported to contain a reduced ratio of these APPs. OBJECTIVE: To further study the AD specificity of reduced platelet APP ratios and to determine whether, after 3 years, cognitive losses in AD are accompanied by similarly reduced platelet APP ratios. METHODS: To test the AD specificity of reduced platelet APP ratios, we quantitated these APPs in eight patients with PD and six patients with hemorrhagic stroke (HS). To determine whether further cognitive losses correlate with platelet APP ratio reductions in patients with AD, the authors re-examined platelet APPs and Mini-Mental State Examination (MMSE) scores of 10 patients with AD and 11 controls, who were tested 3 years ago. APP ratios were determined by the average of six assays using Western blotting with m22C11 monoclonal antibody, enhanced chemoluminescence, and digital scanning of autoradiographs. RESULTS: APP ratios were normal in the patients with PD and HS, further supporting the AD specificity of this assay. After 3 years, the MMSE scores and APP ratios of our control subjects changed by <4%. However, the average MMSE scores of our patients with AD declined from 16.4 to 8.3, and their average 120 to 130/110 kDa APP ratios declined from 5.8 to 3.6. The difference between AD and control APP ratios, with no overlap, is significant and the correlation between the 3-year decline in AD MMSE scores and reduced APP ratios (r = 0.69) was significant. CONCLUSIONS: Although the number of subjects analyzed was limited, reduced platelet APP ratios appear to be a specific biological marker of AD and a biological index of the severity of cognitive loss in AD.