Journal of Alzheimer's Disease - Volume 48, issue 4

Authors: Dubner, Lauren | Wang, Jun | Ho, Lap | Ward, Libby | Pasinetti, Giulio M.

Article Type: Review Article

Abstract: It is currently thought that the lackluster performance of translational paradigms in the prevention of age-related cognitive deteriorative disorders, such as Alzheimer’s disease (AD), may be due to the inadequacy of the prevailing approach of targeting only a single mechanism. Age-related cognitive deterioration and certain neurodegenerative disorders, including AD, are characterized by complex relationships between interrelated biological phenotypes. Thus, alternative strategies that simultaneously target multiple underlying mechanisms may represent a more effective approach to prevention, which is a strategic priority of the National Alzheimer’s Project Act and the National Institute on Aging. In this review article, we discuss recent strategies …designed to clarify the mechanisms by which certain brain-bioavailable, bioactive polyphenols, in particular, flavan-3-ols also known as flavanols, which are highly represented in cocoa extracts, may beneficially influence cognitive deterioration, such as in AD, while promoting healthy brain aging. However, we note that key issues to improve consistency and reproducibility in the development of cocoa extracts as a potential future therapeutic agent requires a better understanding of the cocoa extract sources, their processing, and more standardized testing including brain bioavailability of bioactive metabolites and brain target engagement studies. The ultimate goal of this review is to provide recommendations for future developments of cocoa extracts as a therapeutic agent in AD. Show more

Keywords: Amyloid, chocolate, diet therapy, Lavado, oligomerization, polyphenols, synapses

DOI: 10.3233/JAD-150536

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 879-889, 2015

Authors: Jha, Niraj Kumar | Jha, Saurabh Kumar | Kumar, Dhiraj | Kejriwal, Noopur | Sharma, Renu | Ambasta, Rashmi K. | Kumar, Pravir

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative process primarily characterized by amyloid-β (Aβ) agglomeration, neuroinflammation, and cognitive dysfunction. The prominent cause for dementia is the deposition of Aβ plaques and tau-neurofibrillary tangles that hamper the neuronal organization and function. Aβ pathology further affects numerous signaling cascades that disturb the neuronal homeostasis. For instance, Aβ deposition is responsible for altered expression of insulin encoding genes that lead to insulin resistance, and thereby affecting insulin signaling pathway and glucose metabolism in the brain. As a result, the common pathology of insulin resistance between Type-2 diabetes mellitus and AD has led AD to be …proposed as a form of diabetes and termed ‘Type-3 diabetes’. Since accumulation of Aβ is the prominent cause of neuronal toxicity in AD, its clearance is the prime requisite for therapeutic prospects. This purpose is expertly fulfilled by the potential role of Aβ degrading enzymes such as insulin degrading enzyme (IDE) and Neprilysin (NEP). Therefore, their molecular study is important to uncover the proteolytic and regulatory mechanism of Aβ degradation. Herein, (i) In silico sequential and structural analysis of IDE and NEP has been performed to identify the molecular entities for proteolytic degradation of Aβ in the AD brain, (ii) to analyze their catalytic site to demonstrate the enzymatic action played by IDE and NEP, (iii) to identify their structural homologues that could behave as putative partners of IDE and NEP with similar catalytic action and (iv) to illustrate various IDE- and NEP-mediated therapeutic approaches and factors for clearing Aβ in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , insulin degrading enzyme, Neprilysin, therapeutics

DOI: 10.3233/JAD-150379

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 891-917, 2015

Authors: Giaccone, Giorgio

Article Type: Short Communication

Abstract: The distinction between Alzheimer’s disease (AD) and Primary Age-Related Tauopathy (PART) is a hotly debated issue. As most lines of evidence support the tenet that tau pathology occurs downstream of amyloid-β deposition, it seems reasonable to consider PART as a separate disease process not necessarily related to Aβ and hence AD. Following this view, the early stages of neurofibrillary pathology may not always be the forerunner of diffuse neurofibrillary changes and AD. The ongoing debate further enhances the need for greater caution against any future predictions using tau cerebrospinal fluid and imaging biomarkers.

Keywords: Alzheimer’s disease, Braak staging, neuropathology, Primary Age-Related Tauopathy

DOI: 10.3233/JAD-150435

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 919-921, 2015

Authors: Marshall, Charles R. | Guerreiro, Rita | Thust, Steffi | Fletcher, Phillip | Rohrer, Jonathan D. | Fox, Nick C.

Article Type: Short Communication

Abstract: The authors describe a case of corticobasal syndrome led by progressive apraxia of speech, associated with a novel mutation in exon 10 of the MAPT gene. Genetic bases for progressive apraxia of speech and corticobasal syndrome are only rarely described, and have not been described in conjunction.

Keywords: Corticobasal syndrome, frontotemporal dementia, microtubule-associated protein tau, progressive apraxia of speech

DOI: 10.3233/JAD-150477

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 923-926, 2015

Authors: Moreno, Laura | Rose, Christiane | Mohanraj, Arun | Allinquant, Bernadette | Billard , Jean-Marie | Dutar, Patrick

Article Type: Research Article

Abstract: This study shows a decrease in soluble amyloid-β protein precursor-α (sAβPPα) levels, but no change in sAβPPβ, in the rat hippocampus during healthy aging, associated with the weaker expression of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) in the CA1 area of hippocampal slices. Exogenous application of recombinant sAβPPα increases NMDAR activation in aged animals and could rescue the age-related LTP deficits described. In contrast, it does not affect basal synaptic transmission or glutamate release. These results indicate that improving synaptic sAβPPα availability at synapses helps in reducing the functional NMDAR-related deregulation of hippocampal networks linked to aging.

Keywords: Alzheimer’s disease, amyloid-β protein precursor, α-secretase, glutamate, memory, mouse hippocampus, NMDA receptors, synaptic plasticity

DOI: 10.3233/JAD-150297

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 927-935, 2015

Authors: Struyfs, Hanne | Van Hecke, Wim | Veraart, Jelle | Sijbers, Jan | Slaets, Sylvie | De Belder, Maya | Wuyts, Laura | Peters, Benjamin | Sleegers, Kristel | Robberecht, Caroline | Van Broeckhoven, Christine | De Belder, Frank | Parizel, Paul M. | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: The purpose of this explorative study was to investigate whether diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) parameter changes are reliable measures of white matter integrity changes in Alzheimer’s disease (AD) patients using a whole brain voxel-based analysis (VBA). Therefore, age- and gender-matched patients with mild cognitive impairment (MCI) due to AD (n  = 18), dementia due to AD (n  = 19), and age-matched cognitively healthy controls (n  = 14) were prospectively included. The magnetic resonance imaging protocol included routine structural brain imaging and DKI. Datasets were transformed to a population-specific atlas space. Groups were compared using VBA. Differences in diffusion …and mean kurtosis measures between MCI and AD patients and controls were shown, and were mainly found in the splenium of the corpus callosum and the corona radiata. Hence, DTI and DKI parameter changes are suggestive of white matter changes in AD. Show more

Keywords: Alzheimer’s disease, biomarker, diffusion kurtosis imaging, diffusion tensor imaging, early diagnosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-150253

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 937-948, 2015

Authors: Cermakova, Pavla | Johnell, Kristina | Fastbom, Johan | Garcia-Ptacek, Sara | Lund, Lars H. | Winblad, Bengt | Eriksdotter, Maria | Religa, Dorota

Article Type: Research Article

Abstract: Background: Cardiovascular diseases are leading causes of death and patients with dementia are often affected by them. Objective: Investigate associations of cardiovascular diseases with different dementia disorders and determine their impact on mortality. Methods: This study included 29,630 patients from the Swedish Dementia Registry (mean age 79 years, 59% women) diagnosed with Alzheimer’s disease (AD), mixed dementia, vascular dementia, dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), frontotemporal dementia (FTD), or unspecified dementia. Records of cardiovascular diseases come from the Swedish National Patient Register. Multinomial logistic regression and cox proportional hazard models were applied. …Results: Compared to AD, we found a higher burden of all cardiovascular diseases in mixed and vascular dementia. Cerebrovascular diseases were more associated with DLB than with AD. Diabetes mellitus was less associated with PDD and DLB than with AD. Ischemic heart disease was less associated with PDD and FTD than AD. All cardiovascular diseases predicted death in patients with AD, mixed, and vascular dementia. Only ischemic heart disease significantly predicted death in DLB patients (HR = 1.72; 95% CI = 1.16–2.55). In PDD patients, heart failure and diabetes mellitus were associated with a higher risk of death (HR = 3.06; 95% CI = 1.74–5.41 and HR = 3.44; 95% CI = 1.31–9.03). In FTD patients, ischemic heart disease and atrial fibrillation or flutter significantly predicted death (HR = 2.11; 95% CI = 1.08–4.14 and HR = 3.15; 95% CI = 1.60–6.22, respectively). Conclusion: Our study highlights differences in the occurrence and prognostic significance of cardiovascular diseases in several dementia disorders. This has implications for the care and treatment of the different dementia disorders. Show more

Keywords: Alzheimer’s disease, cardiovascular diseases, dementia, mortality

DOI: 10.3233/JAD-150499

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 949-958, 2015

Authors: Laiterä, Tiina | Kurki, Mitja I. | Pursiheimo, Juha-Pekka | Zetterberg, Henrik | Helisalmi, Seppo | Rauramaa, Tuomas | Alafuzoff, Irina | Remes, Anne M. | Soininen, Hilkka | Haapasalo, Annakaisa | Jääskeläinen, Juha E. | Hiltunen, Mikko | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer’s disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ -secretase activity. Objectives: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. Methods: The genome-wide expression profile of ∼35,000 probes …was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα , sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. Results: After correcting the results for multiple testing, significant differences in the expression of TTR and A βPP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A βPP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of α -secretase (ADAM10 ) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAβPPα and sAβPPβ, but TTR levels did not predict the brain pathology or the shunt response. Conclusions: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, gene expression profiling, idiopathic normal pressure hydrocephalus, transthyretin

DOI: 10.3233/JAD-150268

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 959-968, 2015

Authors: Conejero-Goldberg, Concepcion | Hyde, Thomas M. | Chen, Shufen | Herman, Mary M. | Kleinman, Joel E. | Davies, Peter | Goldberg, Terry E.

Article Type: Research Article

Abstract: Transcriptional profiling of postmortem Alzheimer’s disease (AD) brain tissue has yielded important insights into disease. We recently described a novel approach to understand transcriptional changes in AD designed to identify both neuro-susceptibility and intrinsic neuroprotective factors in young non-AD E4 carriers. Here we extend our work to APOE4 related AD itself. In temporal cortex (BA 21), a region known to be vulnerable to AD pathology, we identified over 1400 transcripts that differed between APOE4 controls and APOE4 carriers diagnosed with AD. Results from somatosensory cortex (BA 1/2/3), a region relatively preserved in AD differed strikingly from temporal cortex in that …differences were far fewer (37 vs. 1492). We also conducted another set of contrasts involving APOE3 AD cases and APOE4 AD cases to better understand what transcriptional differences were dependent on genotype, but independent of disease status and found 6 transcripts to differ. We also conducted detailed pathway analyses in BA 1/2/3 and found significant transcriptional upregulations in pro-survival gene networks (e.g., TNF and NFkB). In summary, our results indicate that many of the molecular changes identified in the brains of patients with AD reflect the non-specific consequences of neurodegeneration, rather than causative processes. Additionally, the molecular signatures specific to somatosensory cortex may make it uniquely resistant to AD pathology and thereby could provide important leads for treatment. Show more

Keywords: Alzheimer’s disease, APOE, gene expression, human brain, microarray

DOI: 10.3233/JAD-150345

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 969-978, 2015

Authors: Sparre-Sørensen, Maja | Kristensen, Gustav

Article Type: Research Article

Abstract: Background: Several studies published over the last few years have shown that malnutrition is a risk factor for developing and worsening Alzheimer’s disease (AD) and that a balanced diet can delay the onset of the disease. During the period from January 1999 to January 2007, a statistically significant increase in the number of deaths related to malnutrition was found among the elderly in Denmark. Many more may have been suffering from malnutrition, but not to such a degree that it led to their deaths. Objective: The aim of this study is to examine whether or not the …effect of the malnutrition period can be seen in the number of AD-related deaths. Methods: All Danes listed in the National Death Register from 1994 to 2012 where included in this study. Regression analyses based on the Expansion Method were used. Results: We found a sudden statistically significant rise in the number of deaths from AD associated with the period when the general nutritional state among the elderly in Denmark worsened (from 1999 to 2007). Conclusion: The study concludes that the malnutrition period resulted in an excess death rate from Alzheimer’s disease. All in all, a total of 345 extra lives were lost, and many might have developed AD earlier than they otherwise would, due to malnutrition. Show more

Keywords: Alzheimer’s disease, death rate, Expansion Method, malnutrition

DOI: 10.3233/JAD-150472

Citation: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 979-985, 2015