Journal of Alzheimer's Disease - Volume 34, issue 2

Authors: Pavlik, Valory | Massman, Paul | Barber, Robert | Doody, Rachelle | for the Texas Alzheimer's Research and Care Consortium (TARCC)

Article Type: Research Article

Abstract: Insulin resistance increases the risk of cognitive impairment and dementia, but higher insulin levels may be cognitively protective after a diagnosis of Alzheimer's disease (AD). The role of peripheral insulin as a predictor of cognitive decline both before and after an AD diagnosis needs further elucidation. We studied 197 AD cases and 198 normal controls enrolled in the Texas Alzheimer's Research and Care Consortium. Standardized protocols were used to collect age, gender, education, body mass index (BMI), serum insulin (not restricted to fasting), hemoglobin A1c (HbA1c), lipids, smoking and cardiovascular disease history, and neuropsychological tests including Mini-Mental State Examination, American …National Adult Reading Test (AMNART) errors, Controlled Word Association Test (COWAT), Boston Naming Test, Wechsler Memory Scale-Revised (WMSR) Digit Span, Trails A and B, WMSR Logical Memory (LM) I and II, and Visual Reproduction (VR) I and II. We used linear regression to test the contribution of log-transformed serum insulin to each score, adjusting for age, gender, education, and BMI. In the AD cases, higher serum insulin was associated with worse performance on the COWAT (p < 0.001) and Trails B (p = 0.04). In controls, higher serum insulin was associated with worse performance on the AMNART (p = 0.001), COWAT (p = 0.007), Digit Span (p = 0.004), LM I (p = 0.004), LM II (p = 0.009), and marginally with VR II (p = 0.076). Adjustment for HbA1c, APOE4, and cardiovascular disease, or restricting the sample to mild AD, did not alter these associations. In non-demented older individuals, higher peripheral insulin appears to be associated with worse cognitive performance in multiple domains, but is not a consistent predictor in AD cases. These findings indicate the need for additional research on the role of insulin in the transition between normal and impaired cognitive function. Show more

Keywords: Alzheimer's disease, case-control study, cognitive function, hyperinsulinemia

DOI: 10.3233/JAD-121999

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 449-456, 2013

Authors: Chien, David T. | Bahri, Shadfar | Szardenings, A. Katrin | Walsh, Joseph C. | Mu, Fanrong | Su, Min-Ying | Shankle, William R. | Elizarov, Arkadij | Kolb, Hartmuth C.

Article Type: Research Article

Abstract: Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer's disease. We have developed a novel PHF-tau targeting positron emission tomography imaging agent, [F-18]-T807, which may be useful for imaging Alzheimer's disease and other tauopathies. Here in, we describe the first human brain images with [F-18]-T807.

Keywords: Alzheimer's disease, amyloid-β, brain imaging, mild cognitive impairment, molecular imaging, neurofibrillary tangles, paired helical filaments, tau, tau aggregates, tauopathy

DOI: 10.3233/JAD-122059

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 457-468, 2013

Authors: Désiré, Laurent | Blondiaux, Elodie | Carrière, Jennifer | Haddad, Raphael | Sol, Olivier | Fehlbaum-Beurdeley, Pascale | Einstein, Rich | Zhou, Weiyin | Pando, Matthew P.

Article Type: Research Article

Abstract: Monitoring the genomic expression of patients in clinical trials for Alzheimer's disease (AD) can assist trial design and treatment response analysis. Here, we report on the identification in AD patients of blood-based transcriptomic signatures associated with treatment response of EHT 0202, a new compound with potential disease-modifying and symptomatic properties, in a 3-month, placebo-controlled, Phase IIA study aimed at determining the clinical safety, tolerability, and exploratory efficacy of EHT 0202 (40 and 80 mg bid) as adjunctive therapy to one cholinesterase inhibitor in mild to moderate AD patients. Genome-wide transcriptomic profiling was performed on blood samples taken prior to treatment …and at study completion in a subpopulation of 60 AD patients selected as either the 10 worst disease decliners or the 10 best improvers of each treatment group, using ADAS-Cog scores as measure of disease severity. In the patients responding to EHT 0202, a pre-treatment (baseline) transcriptomic signature showed activation of pathways related to AD, CNS disorders, diabetes, inflammation, and autoimmunity, while a post-treatment signature indicated reduced activation of these pathways with induced metabolic and transcription stimulation. This pilot study demonstrates the utility of blood transcriptomic signatures used as biomarkers for predicting patient response or monitoring efficacy, for an administered therapeutic drug in a complex disease such as AD. For EHT 0202 or other AD drugs, such biomarkers may help to improve strategies to better identify appropriate patient populations for treatment, understand the drug mechanism of efficacy, and/or clarify the inherent subjectivity in most clinical endpoints used in this disease. Show more

Keywords: Alzheimer's disease, biomarker, blood, drug response, gene expression, microarray, molecular signature, transcriptome

DOI: 10.3233/JAD-121501

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 469-483, 2013

Authors: Le Ber, Isabelle | Camuzat, Agnès | Guillot-Noel, Lena | Hannequin, Didier | Lacomblez, Lucette | Golfier, Véronique | Puel, Michèle | Martinaud, Olivier | Deramecourt, Vincent | Rivaud-Pechoux, Sophie | Millecamps, Stéphanie | Vercelletto, Martine | Couratier, Philippe | Sellal, François | Pasquier, Florence | Salachas, François | Thomas-Antérion, Catherine | Didic, Mira | Pariente, Jérémie | Seilhean, Danielle | Ruberg, Merle | Wargon, Isabelle | Blanc, Frédéric | Camu, William | Michel, Bernard-François | Berger, Eric | Sauvée, Mathilde | Thauvin-Robinet, Christel | Mondon, Karl | Tournier-Lasserve, Elisabeth | Goizet, Cyril | Fleury, Marie | Viennet, Gabriel | Verpillat, Patrice | Meininger, Vincent | Duyckaerts, Charles | Dubois, Bruno | Brice, Alexis | the French research network on FTLD/FTLD-ALS

Article Type: Research Article

Abstract: Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies …in the literature (23–50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9–56.1) than in MAPT patients (46.8, 95%CI: 43.0–50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6–61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed. Show more

Keywords: Amyotrophic lateral sclerosis, C9ORF72, frontotemporal dementia, frontotemporal lobar degeneration, protein TDP43

DOI: 10.3233/JAD-121456

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 485-499, 2013

Authors: Geda, Yonas E. | Ragossnig, Marion | Roberts, Lewis A. | Roberts, Rosebud O. | Pankratz, V. Shane | Christianson, Teresa J.H. | Mielke, Michelle M. | Levine, James A. | Boeve, Bradley F. | Sochor, Ondřej | Tangalos, Eric G. | Knopman, David S. | Petersen, Ronald C.

Article Type: Research Article

Abstract: In a population-based case-control study, we examined whether moderate and high caloric intakes are differentially associated with the odds of having mild cognitive impairment (MCI). The sample was derived from the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Non-demented study participants aged 70–92 years (1,072 cognitively normal persons and 161 subjects with MCI) reported their caloric consumption within 1 year of the date of interview by completing a Food Frequency Questionnaire. An expert consensus panel classified each subject as either cognitively normal or having MCI based on published criteria. We conducted multivariable logistic regression analyses to compute odds …ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age, gender, education, depression, medical comorbidity, and body mass index. We also conducted stratified analyses by apolipoprotein E ε4 genotype status. Analyses were conducted in tertiles of caloric intake: 600 to <1,526 kcals per day (reference group); 1,526 to 2,143 kcals per day (moderate caloric intake group); and >2,143 kcals per day (high caloric intake group). In the primary analysis, there was no significant difference between the moderate caloric intake group and the reference group (OR 0.87, 95% CI 0.53–1.42, p = 0.57). However, high caloric intake was associated with a nearly two-fold increased odds of having MCI (OR 1.96, 95% CI 1.26–3.06, p = 0.003) as compared to the reference group. Therefore, high caloric intake was associated with MCI but not moderate caloric intake. This association is not necessarily a cause-effect relationship. Show more

Keywords: Aging, APOE ε4 genotype, caloric intake, mild cognitive impairment, population-based

DOI: 10.3233/JAD-121270

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 501-507, 2013

Authors: Espinosa, Janaína | Rocha, Andreia | Nunes, Fernanda | Costa, Marcelo S. | Schein, Vanessa | Kazlauckas, Vanessa | Kalinine, Eduardo | Souza, Diogo O. | Cunha, Rodrigo A. | Porciúncula, Lisiane O.

Article Type: Research Article

Abstract: Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-β-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after …four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action. Show more

Keywords: Adenosine receptors, Alzheimer's disease, caffeine, memory, streptozotocin

DOI: 10.3233/JAD-111982

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 509-518, 2013

Authors: Ancelin, Marie-Laure | Ripoche, Emmanuelle | Dupuy, Anne-Marie | Barberger-Gateau, Pascale | Auriacombe, Sophie | Rouaud, Olivier | Berr, Claudine | Carrière, Isabelle | Ritchie, Karen

Article Type: Research Article

Abstract: Cholesterol is a risk factor for developing vascular pathologies, which is in turn an important risk factor for dementia. Previous studies linking lipids and dementia have yielded inconsistent results, which may be attributable to sex differences in the etiology of both vascular disease and dementia. The aim of this study was to evaluate the associations between lipids and incident dementia in 7053 community-dwelling elderly. Dementia was diagnosed at baseline, and 2, 4, and 7-year follow-up. Multivariate Cox models stratified by sex and history of vascular pathologies at baseline were adjusted for sociodemographic, mental and physical health variables, and genetic vulnerability. …In men without vascular pathologies, an increased incidence of all-cause dementia but not Alzheimer's disease (AD) was associated with high triglyceride (TG) (HR = 1.55, 95% CI = 1.04–2.32, p = 0.03) and low HDL-cholesterol levels (HR = 1.49, 95% CI = 0.99–2.23, p = 0.05). In women without vascular pathologies, low TG levels were associated with a decreased risk of AD (HR = 0.65, 95% CI = 0.43–0.97, p = 0.03). A decreased risk was also found with high TG levels which may depend on genetic vulnerability to dyslipidemia related to APOA5. For both sexes, no significant associations were found between total- or LDL-cholesterol and dementia or AD. Low HDL-cholesterol and high TG levels may be risk factors of dementia in elderly men whereas low TG is associated with decreased incident AD in women. This data suggests a complex sex-specific etiology of vascular dementia and AD. Show more

Keywords: Alzheimer's disease, apolipoprotein, atherosclerosis, dementia, elderly, lipids, prospective cohort

DOI: 10.3233/JAD-121228

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 519-528, 2013

Authors: Dugger, Brittany N. | Hidalgo, Jose A. | Chiarolanza, Glenn | Mariner, Monica | Henry-Watson, Jonette | Sue, Lucia I. | Beach, Thomas G.

Article Type: Research Article

Abstract: Abnormal phosphorylation of the microtubule-associated protein tau develops in selected brain regions in normal aging and becomes widespread throughout the brain in Alzheimer's disease (AD). Braak and others have described the distribution of neurofibrillary tangles and deposition of abnormally phosphorylated tau (p-tau) and correlated this with the progressive cognitive dysfunction in AD. However, to date there have been no comprehensive studies examining abnormally phosphorylated tau deposition in the spinal cord as part of normal aging or AD. We investigated, using immunohistochemical methods, the presence of p-tau in the spinal cord of 46 cases with a clinicopathological diagnosis of AD as …well as 37 non-demented aged (ND) individuals lacking any defined central nervous system-related clinicopathological diagnosis. We found the cervical cord segments to be the most frequently affected subdivision (96% AD versus 43% ND), followed by thoracic (69% AD versus 37% ND), lumbar (65% AD versus 27% ND), and sacral (53% AD versus 13% ND). The spinal cord was often affected at early-stage brain disease, with p-tau spinal cord immunoreactivity in 40% of subjects at Braak neurofibrillary stage I; however, there were no cases having spinal cord p-tau that did not have p-tau within the brain. As p-tau immunoreactivity is present within the spinal cords of ND as well as AD subjects, it is likely that the phosphorylation of spinal cord tau occurs in the preclinical stage of AD, prior to dementia. The presence of significant spinal cord p-tau-immunoreactive pathology has important implications for both the pathogenesis and clinical manifestations of AD. Show more

Keywords: Aging, autopsy, neurofibrillary tangle, pathology, peripheral nervous system, senile dementia, systemic disorder

DOI: 10.3233/JAD-121864

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 529-536, 2013

Authors: Schmid, Nicole S. | Taylor, Kirsten I. | Foldi, Nancy S. | Berres, Manfred | Monsch, Andreas U.

Article Type: Research Article

Abstract: We investigated the earliest neuropsychological changes in Alzheimer's disease (AD) by comparing the baseline performance of 29 individuals who subsequently developed AD within an average of 7.91 ± 2.70 years with 29 pairwise-matched individuals who remained cognitively healthy (NC). We hypothesized that subtle, qualitative changes in cognition precede clinical AD by several years, and therefore examined subjective as well as standard quantitative measures of cognition, in addition to subjective estimates of mood and medical status. Participants were selected from the 825 members of the longitudinal BASEL study (BAsel Study on the ELderly), all of whom had been ApoE-genotyped and received …comprehensive bi-annual neuropsychological assessments. Within 13 years, 29 were diagnosed with probable AD. Each individual who progressed to AD (AD-P) was pairwise matched to a NC participant based on age, education, demographic status, observation period, and, importantly, ApoE genotype. A regression analysis using the lasso technique identified which of 115 neuropsychological variables best discriminated baseline NC from baseline AD-P performance. This analysis yielded eleven neuropsychological variables that optimally discriminated the two groups (correct classification rate: 60.4%): 1) Intrusions and 2) response bias in verbal learning and memory tasks; 3) delayed figure recall; 4–6) three Wechsler Adult Intelligence Scale (WAIS) Block Design subtest variables; 7–8) number of errors and repetitions on letter fluency; and 9–11) self-report of memory problems, a feeling of sadness, and cardiac problems. These results suggest that the preclinical neuropsychological cascade to AD includes subtle but identifiable qualitative impairments in verbal and visual memory, visuospatial processing, error control, and subjective neuropsychological complaints. Show more

Keywords: Aging, Alzheimer disease, depressive symptoms, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-121234

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 537-546, 2013

Authors: Royall, Donald R. | Palmer, Raymond F. | Vidoni, Eric D. | Honea, Robyn A.

Article Type: Research Article

Abstract: Depressive symptoms are associated with an increased risk of Alzheimer's disease (AD) but the mechanism(s) involved has not been well established. In a convenience sample of participants in the University of Kansas' Brain Aging Project, we use structural equation modeling (SEM) to explicitly distinguish depressive symptom-related variance in cognitive task performance (i.e., DEPCOG) from that which is unrelated to a depressive symptoms. DEPCOG is strongly associated with the cognitive correlates of functional status (δ), which we previously associated with elements of the Default Mode Network (DMN). Both δ and DEPCOG map to a posterior cingulate seeded network that has recently …been associated with amyloid-β deposition and includes elements of the DMN. Both contribute significantly to clinical dementia status and dementia severity, as measured by the Clinical Dementia Rating Scale Sum of Boxes. These findings suggest that the cognitive correlates of depressive symptoms, even in the absence of a major depressive episode, may contribute to dementia in their own right, and could be responsible for some cases of incident clinical “AD”. This conclusion suggests new opportunities for the latter's diagnosis, prevention, and treatment. Show more

Keywords: Aging, cognition, dementia, depression, g, functional status

DOI: 10.3233/JAD-121639

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 547-560, 2013

Article Type: Other

DOI: 10.3233/JAD-121640

Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 561-562, 2013