Journal of Alzheimer's Disease - Volume 43, issue 2

Authors: Kumar, Pravir | Jha, Niraj Kumar | Jha, Saurabh Kumar | Ramani, Karunya | Ambasta, Rashmi K.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is characterized by dementia, cognitive disabilities, and tauopathy. Tau is a microtubule associated protein that helps maintain the neuronal network. While phosphorylation of tau protein causes disruption of the microtubular network, dephosphorylation allows reconstitution of the microtubule network. Several kinases, e.g., MARK, MAPK, and protein kinase C, are known to hyperphosphorylate tau, leading to disruption of the microtubular network and formation of neurofibrillary tangles (NFTs), which are further glycosylated, glycated, and have lipid peroxide adducts that impair the neuronal transport system and affect memory formation and retention. Moreover, intracerebral administration of amyloid-β oligomers causes hyperphosphorylation of tau, …but whether it is involved in the formation of NFTs is still unclear. Further, amyloid burden activates AMP-activated protein kinase that increases phosphorylation of tau at position Ser262/Ser356 and Ser396. Several phosphatases are present at low levels in AD brains indicating that their down regulation results in abnormal hyperphosphorylation of tau. However, evidence strengthens a possible link between tau phosphorylation and molecular chaperone mediated tau metabolism for the clearance of toxic tau accumulation and has a crucial role in tauopathy. Furthermore, accumulation of phosphorylated tau protein and the possibility of removing the toxic phosphorylated tau protein from the milieu indicates that the chaperone interacts with phosphorylated tau and promotes its degradation. For instance, Hsp90 and cdc37 regulate tau stability and phosphorylation dynamics whereas Hsp27 is able to modulate neuronal plasticity, while 14-3-3 is involved in the interaction of tau with small HSPs. Hsp70 ATPase acts as a modulator in AD therapeutics while Hsc70 rapidly engages tau after microtubular destabilization. Herein, we highlight the various causes of tauopathy and HSP-E3 ligase mediated therapeutics in AD. Show more

Keywords: Heat shock proteins, tau phosphorylation, tauopathy, ubiquitin E3 ligase

DOI: 10.3233/JAD-140933

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 341-361, 2015

Authors: Zea-Sevilla, Mª Ascensión | Bermejo-Velasco, Pedro | Serrano-Heranz, Regino | Calero, Miguel

Article Type: Short Communication

Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease associated with mutations in the NOTCH3 gene on chromosome 19, and represents the most common hereditary stroke disorder. We describe a pedigree, which suffered the classical clinical CADASIL pattern of migraine headaches, recurrent subcortical infarcts, and subcortical dementia, associated with a previously undescribed missense mutation (c.[244T>C], p.[C82R]) in NOTCH3. This new mutation extends the list of known pathogenic mutations responsible for CADASIL, which are associated with an odd number of cysteine residues within any of the epidermal growth factor-like repeats of Notch3 receptor protein.

Keywords: CADASIL, C82R, dementia, headache, migraine, NOTCH3 mutation, Notch3 receptor protein, stroke

DOI: 10.3233/JAD-141218

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 363-367, 2015

Authors: Schreiner, Bernadette | Hedskog, Louise | Wiehager, Birgitta | Ankarcrona, Maria

Article Type: Short Communication

Abstract: Extracellular aggregates of amyloid-β peptides (Aβ) are a hallmark in Alzheimer's disease (AD) brains. Recent findings suggest that Aβ is generated intracellularly and potential production sites include endosomes and trans-Golgi network. We determined the production of Aβ in subcellular fractions isolated from mouse brain. We found that a considerable amount of Aβ is produced at mitochondria-endoplasmic reticulum (ER) contact sites including outer mitochondrial membrane and mitochondria-associated ER membranes. Enhanced Aβ production at this site may disturb ER, mitochondrial and mitochondria-ER contact site function. This may be one key step in the cascade of events eventually leading to neurodegeneration in AD.

Keywords: Alzheimer's disease, endoplasmic reticulum (ER), intracellular amyloid-β peptides, mitochondria-ER contact sites, mitochondria, mitochondria-associated ER membranes (MAM)

DOI: 10.3233/JAD-132543

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 369-374, 2015

Authors: Maderna, Emanuela | Cattaneo, Cristina | Cacciatore, Francesca | Catania, Marcella | Di Fede, Giuseppe | Tagliavini, Fabrizio | Giaccone, Giorgio

Article Type: Short Communication

Abstract: The neuropathological hallmark of Alzheimer's disease (AD) is the co-occurrence of extracellular amyloid-β (Aβ) deposition and intraneuronal neurofibrillary changes composed of abnormal tau. Over the last decades, the concept emerged that neurofibrillary changes progress in a hierarchical manner from mesial temporal structures through the associative neocortex to primary sensory and motor fields, paralleling cognitive deterioration closer than Aβ. The observation that two patients (one cognitively normal, one with dementia) exhibited neurofibrillary changes closely overlapping as regards their entity and topographic distribution but differed for characteristics of Aβ deposition suggests that the latter may directly contribute in determining cognitive impairment in …AD. Show more

Keywords: Alzheimer's disease, amyloid-β, dispersion index, immunohistochemistry, neurofibrillary pathology

DOI: 10.3233/JAD-140540

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 375-379, 2015

Authors: Shakespeare, Timothy J. | Yong, Keir X.X. | Foxe, David | Hodges, John | Crutch, Sebastian J.

Article Type: Short Communication

Abstract: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visual dysfunction and parietal, occipital, and occipitotemporal atrophy. The aim of this study was to compare the impact of PCA and typical Alzheimer's disease (tAD) on everyday functional abilities and neuropsychiatric status. The Cambridge Behavioural Inventory-Revised was given to carers of 32 PCA and 71 tAD patients. PCA patients showed significantly greater impairment in everyday skills and self-care while the tAD group showed greater impairment in aspects of memory and orientation, and motivation. We suggest that PCA poses specific challenges for those caring for people affected by the condition.

Keywords: Caregivers, early onset Alzheimer's disease, psychology, questionnaires, self-care, self-report

DOI: 10.3233/JAD-141071

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 381-384, 2015

Authors: Cerami, Chiara | Crespi, Chiara | Della Rosa, Pasquale Anthony | Dodich, Alessandra | Marcone, Alessandra | Magnani, Giuseppe | Coppi, Elisabetta | Falini, Andrea | Cappa, Stefano F. | Perani, Daniela

Article Type: Research Article

Abstract: Posterior cortical atrophy (PCA) is characterized by basic visual and high order visual-spatial dysfunctions. In this study, we investigated long-distance deafferentation processes within the frontal-parietal-occipital network in ten PCA patients using a MRI-PET combined approach. Objective voxel-based [18 F]FDG-PET imaging measured metabolic changes in single patients. Comprehensive investigation of diffusion tensor imaging (DTI) metrics and grey-matter density with voxel-based morphometry were obtained in a subgroup of 6 patients. Fractional anisotropy in the superior longitudinal fasciculus correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. [18 F]FDG-PET analysis showed in each PCA case the typical …bilateral hypometabolic pattern, involving posterior temporal, parietal, and occipital cortex, with additional hypometabolic foci in the frontal eye fields. Voxel-based morphometry showed right-sided atrophy in the parieto-occipital cortex, as well as a limited temporal involvement. DTI revealed extensive degeneration of the major anterior-posterior connecting fiber bundles and of commissural frontal lobe tracts. Microstructural measures in the superior longitudinal fasciculus were correlated with the PET metabolic changes within the inferior parietal and frontal eye field regions. Our results confirmed the predominant occipital-temporal and occipital-parietal degeneration in PCA patients. [18 F]FDG-PET and DTI-MRI combined approaches revealed neurodegeneration effects well beyond the classical posterior cortical involvement, most likely as a consequence of deafferentation processes within the occipital-parietal-frontal network that could be at the basis of visuo-perceptual, visuo-spatial integration and attention deficits in PCA. Show more

Keywords: Dementia, diffusion tensor imaging, [18F]FDG-PET imaging, frontal eye field, posterior cortical atrophy, voxel-based morphometry

DOI: 10.3233/JAD-141275

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 385-395, 2015

Authors: Perrar, Klaus Maria | Schmidt, Holger | Eisenmann, Yvonne | Cremer, Bernadette | Voltz, Raymond

Article Type: Research Article

Abstract: Background: Epidemiological data shows an increasing number of people affected by dementia. It is mentioned that people with severe dementia have special care needs which are intensified at the end-of-life. Objective: This paper offers a systematic analysis of the current status of research on the needs of people with severe dementia in the last phase of their lives. Methods: A systematic review of the MEDLINE, CINAHL, Cochrane Library, PsycINFO, and AMED databases performed up to April 2014 was further expanded by contacting experts, conducting internet searches, and screening relevant reference lists. Studies were screened according to …defined criteria and appraised for methodological quality. Findings were then synthesized using a narrative thematic approach to identify and categorize relevant needs into thematic categories and subcategories. Results: A total of ten studies published from 1993–2013 were identified, encompassing qualitative (n = 7), quantitative (n = 2), and a mixed-methods study (n = 1). Data synthesis yielded seven themes, with physical, social, and psychological needs the categories most frequently mentioned. Other categories were spiritual, supportive, and environmental needs and needs related to individuality. Needs were often named, but what they entailed operationally was not highlighted in detail. Conclusion: This systematic review shows the paucity of empirical findings on the needs of people with severe dementia. The structured presentation of thematic categories points to a clearer delineation of these needs. Thus, this overview emphasizes the topics for future research and can likewise serve as an orientation for care provision. Show more

Keywords: Dementia, health services needs and demand, palliative care, review, terminal care

DOI: 10.3233/JAD-140435

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 397-413, 2015

Authors: Ramirez, Joel | Berezuk, Courtney | McNeely, Alicia A. | Scott, Christopher J.M. | Gao, Fuqiang | Black, Sandra E.

Article Type: Research Article

Abstract: Background: Visible Virchow-Robin spaces (VRS) are commonly used markers for small vessel disease in aging and dementia. Objective: However, as previous reports were based on subjective visual ratings, the goal of this project was to validate and apply an MRI-based quantitative measure of VRS as a potential neuroimaging biomarker. Methods: A modified version of Lesion Explorer was applied to MRIs from Alzheimer's disease patients (AD: n = 203) and normal elderly controls (NC: n = 94). Inter-rater reliability, technique validity, group/gender differences, and correlations with other small vessel disease markers were examined (lacunes and white matter …hyperintensities, WMH). Results: Inter-rater reliability and spatial congruence was excellent (ICC = 0.99, SI = 0.96), and VRS volumes were highly correlated with established rating scales (CS: ρ = 0.84, p < 0.001; BG: ρ = 0.75, p < 0.001). Compared to NC, AD had significantly greater volumes of WMH (p < 0.01), lacunes (p < 0.001), and VRS in the white matter (p < 0.01), but not in the basal ganglia (n.s.). Compared to women, demented and non-demented men had greater VRS in the white matter (p < 0.001), but not in the basal ganglia (n.s.). Additionally, VRS were correlated with lacunes and WMH, but only in AD (r = 0.3, p < 0.01). Conclusion: Compared to women, men may be more susceptible to greater volumes of VRS, particularly in the white matter. Results support the hypothesis that VRS in the white matter may be more related to AD-related vascular pathology compared to VRS found in the basal ganglia. Future work using this novel VRS segmentation tool will examine its potential utility as an imaging biomarker of vascular rather than parenchymal amyloid. Show more

Keywords: Alzheimer's disease, lacunes, perivascular spaces, small vessel disease, Virchow-Robin, white matter hyperintensities

DOI: 10.3233/JAD-132528

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 415-424, 2015

Authors: Subaiea, Gehad M. | Ahmed, Aseef H. | Adwan, Lina I. | Zawia, Nasser H.

Article Type: Research Article

Abstract: We have previously reported that tolfenamic acid treatment decreases the amyloidogenic proteins in C57BL/6 and in old hemizygous R1.40 transgenic mice via the degradation of the transcription factor specificity 1 protein (Sp1). The lowering of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in hemizygous R1.40 transgenic mice was accompanied by reversal of the identified spatial reference and working memory deficits observed in the mouse model. In this study, we examined the ability of tolfenamic acid to reduce the amyloid plaque burden, as well as to ameliorate spatial learning and memory deficits in homozygous R1.40 mice. Results from immunohistochemical analysis indicated …that tolfenamic acid treatment resulted in a profound decrease in cerebral Aβ plaque burden that was accompanied by improvements in spatial working memory assessed by spontaneous alternation ratio in the Y-maze. These results provide further evidence that tolfenamic acid could be utilized as a repurposed drug to modify Alzheimer's disease pathogenesis. Show more

Keywords: AD transgenic mouse model, Alzheimer's disease, amyloid-β plaque burden, immunohistochemistry, learning and memory, Morris water maze, tolfenamic acid, Y-maze

DOI: 10.3233/JAD-132726

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 425-433, 2015

Authors: Simieli, Lucas | Barbieri, Fabio Augusto | Orcioli-Silva, Diego | Lirani-Silva, Ellen | Stella, Florindo | Gobbi, Lilian Teresa Bucken

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to analyze the effects of dual tasking on obstacle crossing during walking by individuals with Alzheimer's disease (AD) and by healthy older people. Methods: Thirty four elderly individuals (16 healthy subjects and 18 individuals with AD) were recruited to participate in this study. Three AD individuals and one control participant were excluded due to exclusion criteria. The participants were instructed to walk barefoot at their own speed along an 8 m long pathway. Each participant performed five trials for each condition (unobstructed walking, unobstructed walking with dual tasking, and obstacle crossing …during walking with dual tasking). The trials were completely randomized for each participant. The mid-pathway stride was measured in the unobstructed walking trials and the stride that occurred during the obstacle avoidance was measured in the trials that involved obstacle crossing. Results/Conclusion: The behavior of the healthy elderly subjects and individuals with AD was similar for obstacle crossing during walking with dual tasking. Both groups used the “posture first” strategy to prioritize stability and showed decreased attention to executive tasking while walking. Additionally, AD had a strong influence on the modifications that are made by the elderly while walking under different walking conditions. Show more

Keywords: Alzheimer's disease, dual task, obstacle avoidance, posture first, variability

DOI: 10.3233/JAD-140807

Citation: Journal of Alzheimer's Disease, vol. 43, no. 2, pp. 435-441, 2015