Journal of Alzheimer's Disease - Volume 47, issue 2

Authors: Kincses, Zsigmond Tamas | Király, András | Veréb, Dániel | Vécsei, László

Article Type: Review Article

Abstract: The importance of imaging biomarkers has been acknowledged in the diagnosis and in the follow-up of Alzheimer’s disease (AD), one of the major causes of dementia. Next to the molecular biomarkers and PET imaging investigations, structural MRI approaches provide important information about the disease progression and about the pathomechanism. Furthermore,a growing body of literature retranslates these imaging biomarkers to various rodent models of the disease. The goal of this review is to provide an overview of the macro- and microstructural imaging biomarkers of AD, concentrating on atrophy measures and diffusion MRI alterations. A survey is also given of the imaging …approaches used in rodent models of dementias that can promote drug development. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, magnetic resonance imaging, rodent model

DOI: 10.3233/JAD-143195

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 277-290, 2015

Authors: Lista, Simone | O’Bryant, Sid E. | Blennow, Kaj | Dubois, Bruno | Hugon, Jacques | Zetterberg, Henrik | Hampel, Harald

Article Type: Research Article

Abstract: Most forms of Alzheimer’s disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of …which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the “exploratory biomarker discovery arena”, proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD. Show more

Keywords: Alzheimer’s disease, blood-based biomarkers, cerebrospinal fluid biomarkers, familial Alzheimer’s disease, metabolomics/lipidomics, neuroimaging markers, proteomics, sporadic Alzheimer’s disease, systems biology, temporal ordering of biomarkers

DOI: 10.3233/JAD-143006

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 291-317, 2015

Authors: Di Donato, Ilaria | Stabile, Carmen | Bianchi, Silvia | Taglia, Ilaria | Mignarri, Andrea | Salvatore, Simona | Giorgio, Elisa | Brusco, Alfredo | Simone, Isabella | Dotti, Maria Teresa | Federico, Antonio

Article Type: Short Communication

Abstract: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant cerebral white matter degeneration leading to progressive cognitive and motor dysfunction. The peripheral nervous system is generally spared. Recently, mutations in the colony-stimulating factor-1 receptor (CSF1R ) gene have been shown to be associated with HDLS. Here we report a new case of HDLS, carrying a mutation in CSF1R and manifesting rapidly progressive dementia and peripheral neuropathy.

Keywords: CSF1R, HDLS, leukoencephalopathy, presenile dementia

DOI: 10.3233/JAD-150097

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 319-322, 2015

Authors: Román, Gustavo C.

Article Type: Short Communication

Abstract: Recent epigenome-wide association studies have confirmed the importance of epigenetic effects mediated by DNA methylation in late-onset Alzheimer’s disease (LOAD). Metabolic folate pathways and methyl donor reactions facilitated by B-group vitamins may be critical in the pathogenesis of LOAD. Methylenetetrahydrofolate reductase (MTHFR ) gene mutations were studied in consecutive Alzheimer’s Disease & Memory Clinic patients up to December 2014. DNA analyses of MTHFR –C667T and – A1298C homozygous and heterozygous polymorphisms in 93 consecutive elderly patients revealed high prevalence of MTHFR mutations (92.5%). Findings require confirmation in a larger series, but MTHFR mutations may become a LOAD marker, …opening novel possibilities for prevention and treatment. Show more

Keywords: Alzheimer’s disease, DNA methylation, epigenetics, MTHFR gene, vitamins B-group

DOI: 10.3233/JAD-150304

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 323-327, 2015

Authors: Taglialatela, Giulio | Rastellini, Cristiana | Cicalese, Luca

Article Type: Short Communication

Abstract: Experimental evidence suggests that the protein phosphatase calcineurin mediates the action of amyloid-β (Aβ) oligomers, the most toxic amyloid species thought to drive initial cognitive decline in Alzheimer’s disease (AD). However, there is currently no evidence that inhibition of calcineurin could prevent the onset of AD in humans. Here, we report for the first time that individuals chronically treated with calcineurin inhibitors to prevent solid organ transplant rejection have a significantly lower incidence of AD/dementia as compared to the general population. This result prompts further clinical development of calcineurin inhibition as a viable treatment for AD.

Keywords: Alzheimer’s disease, calcineurin, dementia, FK506, solid organ transplant

DOI: 10.3233/JAD-150065

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 329-333, 2015

Authors: Deiber, Marie-Pierre | Meziane, Hadj Boumediene | Hasler, Roland | Rodriguez, Cristelle | Toma, Simona | Ackermann, Marine | Herrmann, François | Giannakopoulos, Panteleimon

Article Type: Research Article

Abstract: Future treatments of Alzheimer’s disease need the identification of cases at high risk at the preclinical stage of the disease before the development of irreversible structural damage. We investigated here whether subtle cognitive deterioration in a population of healthy elderly individuals could be predicted by EEG signals at baseline under cognitive activation. Continuous EEG was recorded in 97 elderly control subjects and 45 age-matched mild cognitive impairment (MCI) cases during a simple attentional and a 2-back working memory task. Upon 18-month neuropsychological follow-up, the final sample included 55 stable (sCON) and 42 deteriorated (dCON) controls. We examined the P1, N1, …P3, and PNwm event-related components as well as the oscillatory activities in the theta (4–7 Hz), alpha (8–13 Hz), and beta (14–25 Hz) frequency ranges (ERD/ERS: event-related desynchronization/synchronization, and ITC: inter-trial coherence). Behavioral performance, P1, and N1 components were comparable in all groups. The P3, PNwm, and all oscillatory activity indices were altered in MCI cases compared to controls. Only three EEG indices distinguished the two control groups: alpha and beta ERD (dCON >  sCON) and beta ITC (dCON <  sCON). These findings show that subtle cognitive deterioration has no impact on EEG indices associated with perception, discrimination, and working memory processes but mostly affects attention, resulting in an enhanced recruitment of attentional resources. In addition, cognitive decline alters neural firing synchronization at high frequencies (14–25 Hz) at early stages, and possibly affects lower frequencies (4–13 Hz) only at more severe stages. Show more

Keywords: Alzheimer’s disease, attention, brain waves, cognitive decline, EEG, EEG phase synchronization, working memory

DOI: 10.3233/JAD-150111

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 335-349, 2015

Authors: Steel, Ariah J. | Eslick, Guy D.

Article Type: Research Article

Abstract: The role of infectious agents in the development of AD has long been debated, in particular, the herpesviridae family. We therefore conducted a meta-analysis to quantitatively assess all published data to establish whether there is an association. We identified studies that looked for the presence of viral DNA in the brain and/or antibody seropositivity in people with AD from four electronic databases. 35 studies met our inclusion criteria (AD cases = 1294; controls = 3059). There was an increased risk for AD when herpesviridae is present in the brain compared to controls [OR 1.38; 95% CI 1.14–1.66]. Sub-analysis showed that APOE ɛ …4 and HSV1 together increased the risk of AD development [OR 2.71; 95% CI 1.08–6.80]. HSV1 together with the presence of the APOE ɛ 4 allele increases the risk of developing AD. Show more

Keywords: Alzheimer’s disease, dementia, herpes virus 1, HSV1, infection, neurodegeneration

DOI: 10.3233/JAD-140822

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 351-364, 2015

Authors: Hartl, Daniela | Gu, Wei | Mayhaus, Manuel | Pichler, Sabrina | Schöpe, Jakob | Wagenpfeil, Stefan | Riemenschneider, Matthias

Article Type: Research Article

Abstract: Accumulation and aggregation of amyloid-β (Aβ) are considered etiologic processes in Alzheimer’s disease (AD). However, the roles of other AβPP cleavage products in disease pathology remain elusive. Here, we measured levels of the major secreted AβPP processing products sAβPPα , sAβPPβ, and Aβ species in postmortem collected ventricular CSF of 196 AD patients and 74 controls. In AD we identified Aβ42 to decrease continuously with progressing Braak stages, whereas Aβ40 was upregulated in early stages of the disease (Braak stage 4) and down-regulated with progressing pathology. Interestingly, both sAβPPα and sAβPPβ were upregulated in AD as compared …to controls (sAβPPα , p  = 0.02; sAβPPβ, p  = 0.01). Moreover, we observed a strong positive correlation of both alternative AβPP processing products, sAβPPα and sAβPPβ (r 2 = 0.781; p  <  0.0001). Together, our results argue for generally enhanced AβPP processing in AD patients and emphasize the necessity of analyzing the roles of all AβPP processing products in AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, soluble AβPP, ventricular cerebrospinal fluid

DOI: 10.3233/JAD-150191

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 365-372, 2015

Authors: Pimentel, Luisa S. | Allard, Simon | Do Carmo, Sonia | Weinreb, Orly | Danik, Marc | Hanzel, Cecilia E. | Youdim, Moussa B. | Cuello, A. Claudio

Article Type: Research Article

Abstract: Current therapies for Alzheimer’s disease (AD) offer partial symptomatic relief and do not modify disease progression. There is substantial evidence indicating a disease onset years before clinical diagnosis, at which point no effective therapy has been found. In this study, we investigated the efficacy of a new multi-target drug, M30, at relatively early stages of the AD-like amyloid pathology in a robust rat transgenic model. McGill-R-Thy1-APP transgenic rats develop the full AD-like amyloid pathology in a progressive fashion, and have a minimal genetic burden. McGill rats were given 5 mg/kg M30 or vehicle per os , every 2 days for 4 …months, starting at a stage where the transgenic animals suffer detectable cognitive impairments. At the completion of the treatment, cognitive functions were assessed with Novel Object Location and Novel Object Recognition tests. The brains were then analyzed to assess amyloid-β (Aβ) burden and the levels of key inflammatory markers. Long-term treatment with M30 was associated with both the prevention and the reversal of transgene-related cognitive decline. The effects on cognition were accompanied by a shift of the Aβ-immunoreactive material toward an amyloid plaque aggregated molecular form, diminished molecular signs of CNS inflammation and a change in microglia morphology toward a surveying phenotype. This study is the first to demonstrate the therapeutic potential of M30 in a rat model of the AD amyloid pathology. It provides a rationale for further investigations with M30 and with potential multi-target approaches to delay, prevent or reverse the progression the AD pathology at early disease-stages. Show more

Keywords: Alzheimer’s disease, CNS inflammation, cognitive impairments, neurodegeneration, neuroprotection, transgenic rat

DOI: 10.3233/JAD-143126

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 373-383, 2015

Authors: Rangasamy, Suresh B. | Corbett, Grant T. | Roy, Avik | Modi, Khushbu K. | Bennett, David A. | Mufson, Elliott J. | Ghosh, Sankar | Pahan, Kalipada

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia. Despite intense investigations, no effective therapy is available to halt its progression. We found that NF-κ B was activated within the hippocampus and cortex of AD subjects and that activated forms of NF-κ B negatively correlated with cognitive function monitored by Mini-Mental State Examination and global cognitive z score. Accordingly, NF-κ B activation was also observed in the hippocampus of a transgenic (5XFAD) mouse model of AD. It has been shown that peptides corresponding to the NF-κ B essential modifier (NEMO)-binding domain (NBD) of Iκ B kinase α (IKKα …) or Iκ B kinase β (IKKβ) specifically inhibit the induction of NF-κ B activation without inhibiting the basal NF-κ B activity. Interestingly, after intranasal administration, wild-type NBD peptide entered into the hippocampus, reduced hippocampal activation of NF-κ B, suppressed hippocampal microglial activation, lowered the burden of Aβ in the hippocampus, attenuated apoptosis of hippocampal neurons, protected plasticity-related molecules, and improved memory and learning in 5XFAD mice. Mutated NBD peptide had no such protective effect, indicating the specificity of our finding. These results suggest that selective targeting of NF-κ B activation by intranasal administration of NBD peptide may be of therapeutic benefit for AD patients. Show more

Keywords: Alzheimer’s disease, memory, NBD peptide, neuroinflammation, NF-κB, plasticity

DOI: 10.3233/JAD-150040

Citation: Journal of Alzheimer's Disease, vol. 47, no. 2, pp. 385-402, 2015