Journal of Alzheimer's Disease - Volume 25, issue 3

Authors: Barnett, Aaron | Brewer, Gregory J.

Article Type: Review Article

Abstract: Some hypothesize that aging in humans is a cumulative process of macromolecular and mitochondrial damage starting years, even decades before any symptoms arise. Aging may begin when the rate of damage exceeds the rate of continual repair and turnover. Quality control for damaged mitochondria entails cellular digestion by mitophagy, a specialized kind of autophagy. Insufficient protective autophagy could cause damaged cellular components to accumulate over many years until they affect normal function in the cell. Alternatively, aging could be the result of overactive, pathologic autophagy. Current knowledge supports both hypotheses with conflicting data, depending on which stage of autophagy is …examined. To distinguish these opposite hypotheses, two criteria need to be observed. First, is there a buildup of undigested waste that can be removed by stimulation of autophagy? Or second, if autophagy is overactive, does inhibition of autophagy rescue cell, organ and organism demise. Both of these are best determined by rate measures rather than measures at a single time point. Here, we review the generalized process of autophagy, with a focus on the limited information available for neuron mitophagy, aging, and Alzheimer's disease (AD). In two mouse models, treatment with rapamycin abolishes the AD pathology and reverses memory deficits. As a working model, we hypothesize that insufficient protective autophagy accelerates both aging and AD pathology, possibly caused by defects in autophagosome fusion with lysosomes. Show more

Keywords: Autophagosome, autophagy, beclin, lysosome mitochondrial turnover, mTOR

DOI: 10.3233/JAD-2011-101989

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 385-394, 2011

Authors: Sutherland, Greg T. | Siebert, Gerhard A. | Kril, Jillian J. | Mellick, George D.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative disorders. Why some individuals develop one disease rather than the other is not clear. Association studies with a case-control design are the time-honored approach to identifying risk factors. Extensive association studies have been carried out in both diseases creating a large knowledge database, however, reproducible risk factors remain rare. This general lack of knowledge of pathogenesis prevents us from reducing the worldwide burden of these diseases. Case-control studies are reductionist paradigms that assume, for maximum power, that the two populations being compared are exclusive and homogenous. The …common occurrence of incidental AD and PD-type pathology combined with ‘intermediate phenotypes’ such as dementia with Lewy bodies suggest that aging itself, AD, and PD are part of a complex continuum characterized by variable amounts of amyloid-β, tau, and α-synuclein pathology. This heterogeneity may be a contributor to the lack of reproducibility in association studies to date. Here, we speculate on alternative experimental approaches to the case-control paradigm and consider how the association-study literature for AD and PD might be re-interpreted in terms of a disease spectrum. Show more

Keywords: Alzheimer's disease, association studies, dementia, neuropathology, Parkinson's disease

DOI: 10.3233/JAD-2011-110026

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 395-415, 2011

Authors: Larner, Andrew J. | Marson, Anthony G.

Article Type: Editorial

Abstract: Much remains uncertain about epileptic seizures in the context of Alzheimer's disease: pathogenesis, frequency, semiology, natural history, treatment. The authors suggest a pragmatic approach to developing the evidence base in order to inform decisions on seizure treatment, based on prior pragmatic studies in epilepsy.

DOI: 10.3233/JAD-2011-102148

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 417-419, 2011

Authors: Schürmann, Britta | Wiese, Birgitt | Bickel, Horst | Weyerer, Siegfried | Riedel-Heller, Steffi G. | Pentzek, Michael | Bachmann, Cadja | Williams, Julie | van den Bussche, Hendrik | Maier, Wolfgang | Jessen, Frank

Article Type: Short Communication

Abstract: A variant within the clusterin gene has been recently associated with increased risk for Alzheimer's disease (AD) in genome wide association studies. Here we tested the association of the respective single nucleotide polymorphisms (rs11136000) with plasma concentration of clusterin in 67 AD subjects and 191 cognitively unimpaired elderly individuals. We observed an association of the rs11136000 AD-risk variant with low clusterin plasma levels in an allele-dose dependent manner in the healthy individuals (p = 0.011). This effect was numerically also present in the AD patients. We conclude that the rs11136000 AD-risk variant is associated with low clusterin plasma levels.

Keywords: Alzheimer's disease, clusterin, genome wide association study, risk gene

DOI: 10.3233/JAD-2011-110251

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 421-424, 2011

Authors: Gallo, Maura | Marcello, Norina | Curcio, Sabrina A.M. | Colao, Rosanna | Geracitano, Silvana | Bernardi, Livia | Anfossi, Maria | Puccio, Gianfranco | Frangipane, Francesca | Clodomiro, Alessandra | Mirabelli, Maria | Vasso, Franca | Smirne, Nicoletta | Muraca, Gabriella | Di Lorenzo, Raffaele | Maletta, Raffaele | Ghidoni, Enrico | Bugiani, Orso | Tagliavini, Fabrizio | Giaccone, Giorgio | Bruni, Amalia C.

Article Type: Research Article

Abstract: We report a novel presenilin1 (PSEN1) gene mutation (I143 V) in a four-generation family with Alzheimer's disease. Clinical, molecular, and neuropathological examinations were performed on index patient; thirteen affected subjects were also identified. The index patient presented at 55 with personality changes, apathy, reduction of verbal fluency, and temporal and spatial disorientation. At 68, she showed visual hallucinations; blurred language, and rigidity. She became bedridden and died at 75. A novel mutation at codon 143 was found in PSEN1 gene, changing isoleucine to valine. The brain showed severe atrophy of the frontal and temporal lobes. Parenchymal amyloid-β (Aβ) deposits were …abundant, diffuse to grey structures and contained Aβ42 , but very few Aβ40 . Amyloid angiopathy was absent. Neurofibrillary changes were severe. Our study confirms that PSEN1 mutations can be associated with unusual phenotypes. The peculiarity of the age at onset (not very early), the long course, and the frontal involvement, together with the rather complete absence of Aβ40 and of amyloid angiopathy, widen the spectrum of PSEN1-linked phenotypes. Show more

Keywords: Alzheimer's disease, neurodegeneration, neuropathology, PSEN1 mutation

DOI: 10.3233/JAD-2011-110185

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 425-431, 2011

Authors: Avdesh, Avdesh | Wong, Patrick | Martins, Ralph N. | Martin-Iverson, Mathew T.

Article Type: Research Article

Abstract: The E4 allele of the apolipoprotein E (ApoE) gene has been identified as a major risk factor for the development of late onset Alzheimer's disease (AD). However, the mechanisms by which this gene affects AD are not fully understood. Studies of ApoE knock-out (ApoE KO) mice have revealed an exacerbation of two major pathologies that are diagnostic of AD: neurofibrillary tangles and senile plaques. However, evidence as to whether these mice have cognitive deficits is not yet conclusive. This ambiguity may arise partly from confounds associated with reliance on limited memory models, primarily, the Morris water maze task. An 8-arm …radial maze task was therefore used to measure spatial memory in the ApoE KO mice, compared to controls over time. Furthermore, the effectiveness of a combination antioxidant therapy (CAT), designed to slow down the progression of AD based on concepts of oxidative stress and inflammatory processes underlying the pathology, was tested on memory ability. A significant strain difference was observed with the ApoE KO mice performing better than controls in terms of reference memory and corrects entries. No significant strain difference was observed for performance in terms of working memory errors. No significant effect of the CAT supplementation was observed. Show more

Keywords: 8-arm radial maze, Alzheimer's disease, ApoE knock-out mice, memory

DOI: 10.3233/JAD-2011-101944

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 433-444, 2011

Authors: Abner, Erin L. | Kryscio, Richard J. | Schmitt, Frederick A. | SantaCruz, Karen S. | Jicha, Gregory A. | Lin, Yushun | Neltner, Janna M. | Smith, Charles D. | Van Eldik, Linda J. | Nelson, Peter T.

Article Type: Research Article

Abstract: Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical ‘dementia’ status) was correlated …with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. Show more

Keywords: GRN, miRNA, microRNA, neurofibrillary tangles, neuropathology

DOI: 10.3233/JAD-2011-101980

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 445-453, 2011

Authors: Elliott-Hunt, Caroline R. | Holmes, Fiona E. | Hartley, Dean M. | Perez, Sylvia | Mufson, Elliott J. | Wynick, David

Article Type: Research Article

Abstract: Expression of the neuropeptide galanin is known to be upregulated in the brain of patients with Alzheimer's disease (AD). We and others have shown that galanin plays a neuroprotective role in a number of excitotoxic injury paradigms, mediated by activation of the second galanin receptor subtype (GAL2 ). In the present study, we investigated whether galanin/GAL2 plays a similar protective role against amyloid-β(Aβ) toxicity. Here we report that galanin or the GAL2/3 -specific peptide agonist Gal2-11, both equally protect primary dispersed mouse wildtype (WT) neonatal hippocampal neurons from 250 nM Aβ1–42 toxicity in a dose dependent manner. The amount …of Aβ1–42 induced cell death was significantly greater in mice with loss-of-function mutations in galanin (Gal-KO) or GAL2 (GAL2 -MUT) compared to strain-matched WT controls. Conversely, cell death was significantly reduced in galanin over-expressing (Gal-OE) transgenic mice compared to strain-matched WT controls. Exogenous galanin or Gal2-11 rescued the deficits in the Gal-KO but not the GAL2-MUT cultures, confirming that the protective effects of endogenous or exogenous galanin are mediated by activation of GAL2 . Despite the high levels of endogenous galanin in the Gal-OE cultures, the addition of exogenous 100 nM or 50 nM galanin or 100 nM Gal2-11 further significantly reduced cell death, implying that GAL2 -mediated neuroprotection is not at maximum in the Gal-OE mice. These data further support the hypothesis that galanin over-expression in AD is a neuroprotective response and imply that the development of a drug-like GAL2 agonist might reduce the progression of symptoms in patients with AD. Show more

Keywords: Alzheimer's disease, amyloid toxicity, galanin, GAL2, neuroprotection, transgenic models

DOI: 10.3233/JAD-2011-110011

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 455-462, 2011

Authors: Schulz, Jörg B. | Rainer, Michael | Klünemann, Hans-Hermann | Kurz, Alexander | Wolf, Stefanie | Sternberg, Kati | Tennigkeit, Frank

Article Type: Research Article

Abstract: The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. The primary efficacy endpoint was the change from baseline in the Consortium to Establish a Registry for Alzheimer's Disease -Neuropsychological Battery (CERAD-NP) total score. Secondary efficacy endpoints included change …from baseline in Functional Communication Language Inventory (FLCI) and ADCS-ADL19 total score, and the response from baseline in Clinical Global Impression of Change (CGI-C). The CERAD-NP total score improved significantly after 12 weeks of once-daily memantine treatment compared with baseline (5.9 ± 8.8; p < 0.0001). The FLCI total score improved significantly after 12 weeks compared with baseline (4.4 ± 6.8; p < 0.0001). These significant improvements were already observed after 4 and 8 weeks of once-daily memantine treatment and persisted after a 4-week wash-out period. ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile. Show more

Keywords: Alzheimer's disease, clinical trial, cognition, functional communication, memantine, once-daily, open-label

DOI: 10.3233/JAD-2011-101929

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 463-475, 2011

Authors: Jacobs, Heidi I.L. | Van Boxtel, Martin P.J. | van der Elst, Wim | Burgmans, Saartje | Smeets, Floortje | Gronenschild, Ed H.B.M. | Verhey, Frans R.J. | Uylings, Harry B.M. | Jolles, Jelle

Article Type: Research Article

Abstract: Medial temporal lobe (MTL) atrophy is considered to be one of the most important predictors of Alzheimer's disease (AD). This study investigates whether atrophy in parietal and prefrontal areas increases the predictive value of MTL atrophy in three groups of different cognitive status. Seventy-five older adults were classified as cognitively stable (n = 38) or cognitively declining (n = 37) after three years follow-up. At follow-up, the grey matter of the MTL, inferior prefrontal cortex (IPC), and inferior parietal lobule (IPL) was delineated on MRI scans. Six years later, a dementia assessment resulted in distinguishing and separating a third group …(n = 9) who can be considered as preclinical AD cases at scan time. Ordinal logistic regressions analysis showed that the left and right MTL, as well as the right IPC and IPL accurately predicted group membership. Receiver Operating Curves showed that the MTL was best in distinguishing cognitively stable from cognitively declining individuals. The accuracy of the differentiation between preclinical AD and cognitively stable participants improved when MTL and IPL volumes were combined, while differentiating preclinical AD and cognitively declined participants was accomplished most accurately by the combined volume of all three areas. We conclude that depending on the current cognitive status of an individual, adding IPL or IPC atrophy improved the accuracy of predicting conversion to AD by up to 22%. Diagnosis of preclinical AD may lead to more false positive outcomes if only the MTL atrophy is considered. Show more

Keywords: Alzheimer's disease, magnetic resonance imaging, medial temporal lobe, parietal lobe, sensitivity and specificity

DOI: 10.3233/JAD-2011-102043

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 477-490, 2011