Journal of Alzheimer's Disease - Volume 54, issue 4

Authors: Levy, Boaz | Tsoy, Elena | Gable, Samuel

Article Type: Review Article

Abstract: A comprehensive approach to the prevention of Alzheimer’s disease (AD) warrants a synergy across multiple domains and procedures. Whereas the study of biological markers has mobilized major activity in the field, the development of cognitive markers is largely ignored, despite the unique advantages they may offer. Cognitive markers essentially assess the core clinical feature that biological markers intend to predict. In this respect, cognitive markers expand the foundation of preclinical diagnostics and disease staging in a manner that integrates both physiological and psychological factors. In addition, the cost-effective implementation of cognitive markers makes them remarkably conducive to community-wide screenings, and …thereby a vital component of any global blueprint for prevention. Specifically, in the primary care setting, cognitive markers may provide effective gate keeping for more invasive, labor intensive, and expensive procedures. From this perspective, cognitive markers may provide the first step for identifying preclinical treatment recipients in general public. Moreover, the detection of preclinical decline via cognitive markers can increase awareness of AD risk and the motivation for making protective lifestyle changes. The behavioral approach might be expedient for prevention in light of the compelling evidence of lifestyle amelioration of AD risk. In an integrative view, incorporating cognitive markers to primary care may facilitate a synergetic development in preventive interventions that carries epidemiological significance. This paper addresses the theoretical, methodological, and pragmatic aspects of this prospect. Show more

Keywords: Alzheimer’s disease, early diagnosis, prevention, screening

DOI: 10.3233/JAD-160309

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1259-1272, 2016

Authors: Itzhaki, Ruth F.

Article Type: Review Article

Abstract: The last 8 or so years have seen a large increase in the number of studies supporting the concept of a major role for herpes simplex virus type 1 (HSV1) in Alzheimer’s disease (AD). The main advances have been made through studies in humans and in mice, investigating the likelihood of reactivation of the latent virus in brain. Others have aimed to explain the mechanisms in cells whereby the increase in amyloid-beta (Aβ) production on HSV1 infection of cells and mouse brains occurs, and the reason that infected cells make this increase. The possibility that other herpesviruses are involved in …the development of AD has been explored, and human herpesvirus type 6, Epstein-Barr virus, and cytomegalovirus, in particular, have been implicated. Epidemiological studies have further supported the role specifically of HSV1 and its reactivation in the disease. Antiviral studies have continued, comparing those acting by different mechanisms, such as restricting viral replication, or blocking viral entry into cells, to treat HSV1-infected cell cultures, and then examining the extent to which the virus-induced increases in Aβ and AD-like tau are reduced. All the studies support the usage of antiviral treatment to slow or halt the progression of AD. Show more

Keywords: Alzheimer’s disease, amyloid-beta, antivirals, brain, epidemiology, herpes simplex virus type 1, virus reactivation

DOI: 10.3233/JAD-160607

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1273-1281, 2016

Authors: McCully , Kilmer S.

Article Type: Review Article

Abstract: Hyperhomocysteinemia is a risk factor for development of dementia and Alzheimer’s disease (AD), and low blood levels of folate and cobalamin are associated with hyperhomocysteinemia and AD. In elderly subjects with cognitive decline, supplementation with folate, cobalamin, and pyridoxal demonstrated reduction of cerebral atrophy in gray matter regions vulnerable to the AD process. Multiple pathogenic microbes are implicated as pathogenic factors in AD and atherosclerosis, and the deposition of amyloid-β (Aβ), phosphorylation of tau protein, neuronal injury, and apoptosis in AD are secondary to microbial infection. Glucose utilization and blood flow are reduced in AD, and these changes are accompanied …by downregulation of glucose transport, Na, K-ATPase, oxidative phosphorylation, and energy consumption. Thioretinaco ozonide, the complex formed from thioretinamide, cobalamin, ozone, and oxygen is proposed to constitute the active site of oxidative phosphorylation, catalyzing synthesis of adenosine triphosphate (ATP) from nicotinamide adenine dinucleotide (NAD+ ) and phosphate. Pathogenic microbes cause synthesis of polyamines in host cells by increasing the transfer of aminopropyl groups from adenosyl methionine to putrescine, resulting in depletion of intracellular adenosyl methionine concentrations in host cells. Depletion of adenosyl methionine causes dysregulation of methionine metabolism, hyperhomocysteinemia, reduced biosynthesis of thioretinamide and thioretinaco ozonide, decreased oxidative phosphorylation, decreased production of nitric oxide and peroxynitrite, and impaired host response to infectious microbes, contributing to the pathogenesis of dementia and atherosclerosis. Show more

Keywords: Adenosyl methionine, aging, atherosclerosis, cystathionine synthase, dementia, homocysteine, nitric oxide, oxidative phosphorylation, peroxynitrite, polyamines, thioretinaco ozonide

DOI: 10.3233/JAD-160549

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1283-1290, 2016

Authors: Renard, Dimitri | Gabelle, Audrey | Hirtz, Christophe | Demattei, Christophe | Thouvenot, Eric | Lehmann, Sylvain

Article Type: Short Communication

Abstract: We evaluated cerebrospinal fluid amyloid-β 1-40 (Aβ40 ), amyloid-β 1–42 (Aβ42 ), total and phosphorylated-tau (t-tau and p-tau) in patients with symptomatic isolated cortical supratentorial superficial siderosis (SS), by prospectively recruiting ten patients with SS in the absence of pre-existing cognitive dysfunction, and comparing biomarkers with lobar hematoma cerebral amyloid angiopathy patients (LH-CAA, n  = 13), Alzheimer’s disease patients (AD, n  = 42), and controls (n  = 16). Compared to controls, SS patients showed statistically significant higher t-tau (p  = 0.019) and lower Aβ42 (p  = 0.0084). Compared to other groups, SS showed statistically significant lower t-tau, p-tau, and Aβ40 compared to AD …(p  = 0.0063, p  = 0.0004, and p  = 0022, respectively), and higher p-tau compared to LH-CAA (p  = 0.012). Show more

Keywords: Amyloid-β, cerebral amyloid angiopathy, cerebrospinal fluid, tau, superficial siderosis

DOI: 10.3233/JAD-160400

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1291-1295, 2016

Authors: Weston, Philip S.J. | Paterson, Ross W. | Dickson, John | Barnes, Anna | Bomanji, Jamshed B. | Kayani, Irfan | Lunn, Michael P. | Mummery, Catherine J. | Warren, Jason D. | Rossor, Martin N. | Fox, Nick C. | Zetterberg, Henrik | Schott, Jonathan M.

Article Type: Short Communication

Abstract: Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer’s disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist’s working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic …uncertainty remains. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, clinical decision-making, diagnosis, PET

DOI: 10.3233/JAD-160302

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1297-1302, 2016

Authors: Iso-Markku, Paula | Waller, Katja | Vuoksimaa, Eero | Heikkilä, Kauko | Rinne, Juha | Kaprio, Jaakko | Kujala, Urho M.

Article Type: Research Article

Abstract: Background: Physical activity has been associated with a reduced risk of cognitive decline but the nature of this association remains obscure. Objective: To study associations between midlife physical activity and cognition in old age for a prospective cohort of Finnish twins. Methods: Physical activity in the Finnish Twin Cohort was assessed using questionnaire responses collected in 1975 and 1981. After a mean follow-up of 25.1 years, the subjects’ (n  = 3050; mean age 74.2; range 66–97) cognition was evaluated with a validated telephone interview. Both participation in vigorous physical activity, and the volume of physical activity, …divided into quintiles, were used as predictors of cognitive impairment. Metrics collected by TELE were used to categorize participants as: cognitively impaired, suffering mild cognitive impairment, or cognitively healthy. Results: Participation in vigorous physical activity compared to non-participation for both 1975 and 1981 was associated with a lower risk of cognitive impairment in individual-based analyses (fully adjusted OR 0.50, 95% CI 0.35–0.73). Pairwise analyses yielded similar but statistically non-significant associations. In terms of the volume of physical activity, the most active quintile of individuals (OR 0.69, 95% CI 0.46–1.04) had a reduced risk of cognitive decline compared with the most sedentary quintile in the fully adjusted model although no clear dose-response was found. Conclusion: Vigorous midlife physical activity was associated with less cognitive impairment but without a clear dose-response association between the volume of physical activity and cognition. Show more

Keywords: Cohort studies, cognition, dementia, exercise, genetics

DOI: 10.3233/JAD-160377

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1303-1317, 2016

Authors: Ritter, Kerstin | Lange, Catharina | Weygandt, Martin | Mäurer, Anja | Roberts, Anna | Estrella, Melanie | Suppa, Per | Spies, Lothar | Prasad, Vikas | Steffen, Ingo | Apostolova, Ivayla | Bittner, Daniel | Gövercin, Mehmet | Brenner, Winfried | Mende, Christine | Peters, Oliver | Seybold, Joachim | Fiebach, Jochen B. | Steinhagen-Thiessen, Elisabeth | Hampel, Harald | Haynes, John-Dylan | Buchert, Ralph

Article Type: Research Article

Abstract: Background: The cause of cognitive impairment in acutely hospitalized geriatric patients is often unclear. The diagnostic process is challenging but important in order to treat potentially life-threatening etiologies or identify underlying neurodegenerative disease. Objective: To evaluate the add-on diagnostic value of structural and metabolic neuroimaging in newly manifested cognitive impairment in elderly geriatric inpatients. Methods: Eighty-one inpatients (55 females, 81.6±5.5 y) without history of cognitive complaints prior to hospitalization were recruited in 10 acute geriatrics clinics. Primary inclusion criterion was a clinical hypothesis of Alzheimer’s disease (AD), cerebrovascular disease (CVD), or mixed AD+CVD etiology (MD), …which remained uncertain after standard diagnostic workup. Additional procedures performed after enrollment included detailed neuropsychological testing and structural MRI and FDG-PET of the brain. An interdisciplinary expert team established the most probable etiologic diagnosis (non-neurodegenerative, AD, CVD, or MD) integrating all available data. Automatic multimodal classification based on Random Undersampling Boosting was used for rater-independent assessment of the complementary contribution of the additional diagnostic procedures to the etiologic diagnosis. Results: Automatic 4-class classification based on all diagnostic routine standard procedures combined reproduced the etiologic expert diagnosis in 31% of the patients (p  = 0.100, chance level 25%). Highest accuracy by a single modality was achieved by MRI or FDG-PET (both 45%, p ≤0.001). Integration of all modalities resulted in 76% accuracy (p ≤0.001). Conclusion: These results indicate substantial improvement of diagnostic accuracy in uncertain de novo cognitive impairment in acutely hospitalized geriatric patients with the integration of structural MRI and brain FDG-PET into the diagnostic process. Show more

Keywords: Cognitive impairment, geriatric inpatients, magnetic resonance imaging, multimodal classification, positron emission tomography

DOI: 10.3233/JAD-160380

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1319-1331, 2016

Authors: Mirza, Ambreen | King, Andrew | Troakes, Claire | Exley, Christopher

Article Type: Research Article

Abstract: Aluminum in human brain tissue is implicated in the etiologies of neurodegenerative diseases including Alzheimer’s disease. While methods for the accurate and precise measurement of aluminum in human brain tissue are widely acknowledged, the same cannot be said for the visualization of aluminum. Herein we have used transversely-heated graphite furnace atomic absorption spectrometry to measure aluminum in the brain of a donor with Alzheimer’s disease, and we have developed and validated fluorescence microscopy and the fluor lumogallion to show the presence of aluminum in the same tissue. Aluminum is observed as characteristic orange fluorescence that is neither reproduced by other …metals nor explained by autofluorescence. This new and relatively simple method to visualize aluminum in human brain tissue should enable more rigorous testing of the aluminum hypothesis of Alzheimer’s disease (and other neurological conditions) in the future. Show more

Keywords: Aluminum, Alzheimer’s disease, brain tissue, fluorescence microscopy, lumogallion, transversely heated graphite furnace atomic absorption spectrometry

DOI: 10.3233/JAD-160648

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1333-1338, 2016

Authors: Farr, Susan A. | Sandoval, Karin E. | Niehoff, Michael L. | Witt, Ken A. | Kumar, Vijaya B. | Morley, John E.

Article Type: Research Article

Abstract: Glycogen synthase kinase (GSK)-3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer’s disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ), and neurodegeneration. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3β (G AO) when injected centrally can decrease GSK-3β levels, improve learning and memory, and decrease oxidative stress. In addition, we showed that G AO can cross the blood-brain barrier. Herein the impact of peripherally administered G AO in both the non-transgenic SAMP8 and transgenic Tg2576 (APPswe) models of AD were examined respective to …learning and memory. Brain tissues were then evaluated for expression changes in the phosphorylated-Tyr 216 residue, which leads to GSK-3β activation, and the phosphorylated-Ser9 residue, which reduces GSK-3β activity. SAMP8 G AO-treated mice showed improved acquisition and retention using aversive T-maze, and improved declarative memory as measured by the novel object recognition (NOR) test. Expression of the phosphorylated-Tyr 216 was decreased and the phosphorylated-Ser9 was increased in G AO-treated SAMP8 mice. Tg2576 G AO-treated mice improved acquisition and retention in both the T-maze and NOR tests, with an increased phosphorylated-Ser9 GSK-3β expression. Results demonstrate that peripheral administration of G AO improves learning and memory, corresponding with alterations in GSK-3β phosphorylation state. This study supports peripherally administered G AO as a viable means to mediate GSK-3β activity within the brain and a possible treatment for AD. Show more

Keywords: Antisense, GSK-3β, learning, memory, SAMP8, tau

DOI: 10.3233/JAD-160416

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1339-1348, 2016

Authors: Yoshino, Yuta | Mori, Takaaki | Yoshida, Taku | Yamazaki, Kiyohiro | Ozaki, Yuki | Sao, Tomoko | Funahashi, Yu | Iga, Jun-ichi | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Despite the continuing debate about the amyloid hypothesis in Alzheimer’s disease (AD), the precise pathogenesis is still unclear. Mixed pathology is common and multiple different protein aggregates are seen in human postmortem brains. Aggregates consisting of the alpha-synuclein protein encoded by the Synuclein Alpha gene (SCNA) are common in both dementia with Lewy bodies and AD. We examined SNCA mRNA expression and methylation rates of the CpG island at intron 1 of SNCA in peripheral leukocytes in 50 AD and age- and sex-matched control subjects to verify whether alpha-synuclein pathology affects the AD pathogenesis. SNCA mRNA expression …in AD subjects was significantly higher than that in control subjects (1.62±0.73 versus 0.98±0.50, p  < 0.001). We found significant differences between AD and control subjects at seven CpG sites (average rate; 8.8±2.7 versus 9.5±2.5, respectively: p  = 0.027). The methylation rates tended to be lower in AD subjects at all CpG sites. We conclude that mRNA expression and methylation of SNCA intron 1 are altered in AD, which may be caused by Lewy body pathology in AD. Show more

Keywords: Alpha-synuclein, Alzheimer’s disease, Lewy bodies, methylation, SNCA

DOI: 10.3233/JAD-160430

Citation: Journal of Alzheimer's Disease, vol. 54, no. 4, pp. 1349-1357, 2016