Journal of Alzheimer's Disease - Volume 50, issue 2

Authors: Gardener, Samantha L. | Rainey-Smith, Stephanie R. | Martins, Ralph N.

Article Type: Review Article

Abstract: Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer’s disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based …anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity. Show more

Keywords: Alzheimer’s disease, cardiovascular disease, curcumin, diabetes, diet, docosahexaenoic acid, eicosapentaenoic acid, flavonoids, inflammation, obesity

DOI: 10.3233/JAD-150765

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 301-334, 2016

Authors: Chakrabarti, Mrinmay | McDonald, Alexander J. | Will Reed, J. | Moss, Melissa A. | Das, Bhaskar C. | Ray, Swapan K.

Article Type: Review Article

Abstract: Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer’s disease (AD). Recent studies demonstrated …severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuroprotection, regenerative medicine, retinoids

DOI: 10.3233/JAD-150450

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 335-352, 2016

Authors: Oldoni, Emanuela | Fumagalli, Giorgio G. | Serpente, Maria | Fenoglio, Chiara | Scarioni, Marta | Arighi, Andrea | Bruno, Giuseppe | Talarico, Giuseppina | Confaloni, Annamaria | Piscopo, Paola | Nacmias, Benedetta | Sorbi, Sandro | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Binetti, Giuliano | Ghidoni, Roberta | Benussi, Luisa | Grande, Giulia | Arosio, Beatrice | Bursey, Devan | Kauwe, John S. | Cioffi, Sara MG | Arcaro, Marina | Mari, Daniela | Mariani, Claudio | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: The missense P39L variant in the prion protein gene (PRNP ) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may …be an extremely rare cause of FTD (0.13%). Show more

Keywords: Frontotemporal dementia, mutation, P39L, prion, PRNP

DOI: 10.3233/JAD-150863

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 353-357, 2016

Authors: Hardy, Chris J.D. | Buckley, Aisling H. | Downey, Laura E. | Lehmann, Manja | Zimmerer, Vitor C. | Varley, Rosemary A. | Crutch, Sebastian J. | Rohrer, Jonathan D. | Warrington, Elizabeth K. | Warren, Jason D.

Article Type: Research Article

Abstract: Background: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. Objective: We aimed to quantify the extent of language deficits in this patient group. Methods: We assessed a cohort of patients with bvFTD (n  = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n  = 14), nonfluent variant primary progressive aphasia (nfvPPA; n  = 18), and healthy age-matched individuals (n  = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images. …Results: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. Conclusions: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker. Show more

Keywords: Behavioral variant frontotemporal dementia, frontotemporal dementia, primary progressive aphasia

DOI: 10.3233/JAD-150806

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 359-371, 2016

Authors: Deochand, Chetram | Tong, Ming | Agarwal, Amit R. | Cadenas, Enrique | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer’s disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. Objective: This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery …(CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. Results: CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312 -IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased Aβ PP-Aβ , and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. Conclusion: Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal. Show more

Keywords: Alzheimer’s disease, cigarette smoke, insulin resistance, mouse model, neurodegeneration

DOI: 10.3233/JAD-150664

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 373-386, 2016

Authors: Wimo, Anders | Sjölund, Britt-Marie | Sköldunger, Anders | Qiu, Chengxuan | Klarin, Inga | Nordberg, Gunilla | von Strauss, Eva

Article Type: Research Article

Abstract: Background: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare. Objectives: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area. Methods: Participants were from the 1995-1998 Nordanstig Project (NP) (n  = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n  = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds …ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death. Results: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48–1.04) in SNAC-N; the OR was 0.47 (0.24–0.90) for men and 0.88 (0.54–1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39–0.99) and in men (0.34; 0.15–0.79), but not in women (0.81; 0.46–1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population. Conclusions: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men. Show more

Keywords: Dementia, mortality, prevalence, rural population

DOI: 10.3233/JAD-150708

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 387-396, 2016

Authors: Weissmann, Robert | Hüttenrauch, Melanie | Kacprowski, Tim | Bouter, Yvonne | Pradier, Laurent | Bayer, Thomas A. | Kuss, Andreas W. | Wirths, Oliver

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain …transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses. Show more

Keywords: Alzheimer’s disease, amyloid, differential gene expression, next-generation sequencing, transcriptome, transgenic mice

DOI: 10.3233/JAD-150745

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 397-409, 2016

Authors: Chang, Yu-Ling | Yen, Yu-Shiuan | Chen, Ta-Fu | Yan, Sui-Hing | Tseng, Wen-Yih Isaac

Article Type: Research Article

Abstract: This study investigated the putative changes in regional gray matter and cingulum bundle segments in mild cognitive impairment (MCI) by using two diagnostic criteria. Participants comprised 50 older adults with MCI and 22 healthy older controls (HC). The older adults with MCI were further divided into two groups defined by a global Clinical Dementia Rating (CDR) score of 0.5 and with (the CDR/NPT MCI group) or without (the CDR MCI group) objective cognitive impairments determined using neuropsychological tests (NPTs). Comparable regional gray matter integrity was observed among the three groups. However, the integrity of the right inferior segment of the …cingulum bundle in the two MCI groups was more reduced than that in the HC group, and the CDR/NPT MCI group exhibited additional disruption in the left inferior cingulum bundle. The results also demonstrated that neuropsychological measures have greater predictive value for changes in white matter beyond the contribution of an informant-based instrument alone. Overall, the findings confirm the utility of informant-based assessment in detecting microstructural brain changes in high-risk older adults, even before objective cognitive impairment is evident. The findings also suggest that combining the neuropsychological measures with the informant-based assessment provided the greatest predictive value in assessing white matter disruption. The essential role of the white matter measurement as a biomarker for detecting individuals at a high risk of developing dementia was highlighted. Show more

Keywords: Alzheimer’s disease, cognition, diffusion magnetic resonance imaging, early diagnosis, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-150599

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 411-423, 2016

Authors: Dermody, Nadene | Hornberger, Michael | Piguet, Olivier | Hodges, John R. | Irish, Muireann

Article Type: Research Article

Abstract: Background: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown. Objective: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). Methods: Twelve AD, 12 bvFTD, and 12 healthy older Control participants …completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI. Results: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy were found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes. Conclusion: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient’s daily life. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, episodic memory, frontal lobe, hippocampus, parietal lobe, prospective memory

DOI: 10.3233/JAD-150871

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 425-441, 2016

Authors: Hoffmann, Kristine | Sobol, Nanna A. | Frederiksen, Kristian S. | Beyer, Nina | Vogel, Asmus | Vestergaard, Karsten | Brændgaard, Hans | Gottrup, Hanne | Lolk, Annette | Wermuth, Lene | Jacobsen, Søren | Laugesen, Lars P. | Gergelyffy, Robert G. | Høgh, Peter | Bjerregaard, Eva | Andersen, Birgitte B. | Siersma, Volkert | Johannsen, Peter | Cotman, Carl W. | Waldemar, Gunhild | Hasselbalch, Steen G.

Article Type: Research Article

Abstract: Background: Studies of physical exercise in patients with Alzheimer’s disease (AD) are few and results have been inconsistent. Objective: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. Methods: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, …ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. Results: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: –3.5, 95% confidence interval (CI) –5.8 to –1.3, p  = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p  = 0.028), suggesting a dose-response relationship between exercise and cognition. Conclusions: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, cognition, exercise, randomized controlled trial

DOI: 10.3233/JAD-150817

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 443-453, 2016