Journal of Alzheimer's Disease - Volume 46, issue 1

Authors: Balconi, Michela | Cotelli, Maria | Brambilla, Michela | Manenti, Rosa | Cosseddu, Maura | Premi, Enrico | Gasparotti, Roberto | Zanetti, Orazio | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Previous studies have reported significant deficits in emotion recognition among individuals along the frontotemporal dementia (FTD) spectrum. The basis of emotional impairment is still poorly understood and explicit (emotion appraisal) and implicit (autonomic system activity) responses have not been carefully evaluated. Objective: We investigated explicit evaluation of emotions by testing valence and arousal using self-report measures and we also assessed automatic responses to emotional cues, using autonomic measures (skin conductance response and heart rate). Methods: 16 behavioral variant FTD and 12 agrammatic variants of primary progressive aphasia patients were included. The performance of these …patients was compared to a group of 14 patients with Alzheimer’s disease and 20 healthy controls. Each subject was required to observe and evaluate affective pictures while autonomic parameters were recorded. Results: FTD patients preserved a functional general competency in terms of valence (correct positive versus negative attribution) and arousal (correct dichotomy between high versus low arousal category) distinction. These patients showed significant changes in autonomic implicit response compared to the other groups. The mismatch between explicit and implicit responsiveness to emotional cues was found both in behavioral variant FTD and in agrammatic variants of primary progressive aphasia. Emotional responsiveness was related to the severity of behavioral abnormalities as measured by the Frontal Behavioral Inventory and associated with atrophy of the left putamen. Conclusion: The present findings indicate that FTD patients are able to explicitly “appraise” the emotion, but they cannot implicitly “feel” the emotion. This mismatch between the two levels may help explain the general emotional behavior impairment found in these patients. Show more

Keywords: Basal ganglia, dementia, emotional disturbances, putamen

DOI: 10.3233/JAD-142826

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 211-225, 2015

Authors: Nijholt, Diana A.T. | Ijsselstijn, Linda | van der Weiden, Marcel M. | Zheng, Ping-Pin | Sillevis Smitt, Peter A. E. | Koudstaal, Peter J. | Luider, Theo M. | Kros, Johan M.

Article Type: Research Article

Abstract: Increased levels of pregnancy zone protein (PZP) were found in the serum of persons who later developed Alzheimer’s disease (AD) in comparison to controls who remained dementia free. We suggested that this increase is due to brain derived PZP entering the blood stream during the early phase of the disease. Here we investigate the possible involvement of PZP in human AD pathogenesis. We observed increased PZP immunoreactivity in AD postmortem brain cortex compared to non-demented controls. In the AD cortex, PZP immunoreactivity localized to microglial cells that interacted with senile plaques and was occasionally observed in neurons. Our data link …the finding of elevated serum PZP levels with the characteristic AD pathology and identify PZP as a novel component in AD. Show more

Keywords: Alzheimer’s disease, microglia, pregnancy zone protein

DOI: 10.3233/JAD-131628

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 227-238, 2015

Authors: Liu, Huanliang | Jin, Xiaoxia | Yin, Xiaomin | Jin, Nana | Liu, Fei | Qian, Wei

Article Type: Research Article

Abstract: Accumulated and abnormally hyperphosphorylated tau aggregates into neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). cAMP response binding protein (CREB), a constitutively expressed nuclear transcription factor, is a critical component of the neuroprotective transcriptional network. Numerous studies have shown that cAMP-dependent protein kinase (PKA)-CREB signaling is down-regulated in AD brain. In the present study, we studied the regulation of tau expression by PKA-CREB signaling. We found that the promoter of human tau gene contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2, and CRE3. Overexpression of CREB or activation of PKA significantly suppressed the expression of …tau at mRNA and protein levels. ChIP (Chromatin immunoprecipitation) and EMSA (electrophoretic mobility shift assay) revealed that CREB interacted with these three CRE cis-element and that CRE1, among the three elements, plays the most important role in the suppression of tau expression. Furthermore, upregulation of PKA-CREB signaling suppressed expression of endogenous tau. Collectively, these results suggest that PKA-CREB signaling down-regulates tau expression by reducing tau transcription, which may provide a novel insight into the regulation of tau expression and a molecular mechanism involved in tau pathogenesis in AD. Show more

Keywords: CRE, CREB, PKA, tau, transcriptional regulation

DOI: 10.3233/JAD-142610

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 239-248, 2015

Authors: Kim, Hak-Su | Moon, Sohee | Paik, Jin-Hwe | Shin, Dong Wun | Kim, Lindsay S. | Park, Chang-Shin | Ha, Joohun | Kang, Ju-Hee

Article Type: Research Article

Abstract: The 5′-AMP-activated protein kinase (AMPK), which is a sensor of cellular energy, regulates neuronal survival and energy homeostasis. However, the roles of AMPK in the pathogenesis of Alzheimer's disease (AD) are unclear. The senescence-accelerated mouse prone 8 (SAMP8) strain is characterized by deficits in learning and memory, exhibits pathological characteristics of AD as early as 5 months of age, and is being increasingly recognized as a model of AD. Here, we investigated the relationship between AMPK activation and phosphorylation of the tau protein in the brain of young (2-month-old) SAMP8 animals and in differentiated SH-SY5Y cells. Upregulation of p-AMPK, p-ACC, …and p-GSK3βS9 and downregulation of p-tau396 and sirtuin 1 (Sirt1) were observed in the cerebral cortex of young SAMP8 mice compared with that of age-matched SAMR1 animals. The hippocampal levels of p-AMPK and p-tau396 in SAMP8 animals were not significantly different from those of SAMR1, whereas upregulation of p-GSK3βS9 and downregulation of sirt1 was observed in the hippocampus of SAMP8 mice. Consistent with in vivo findings in the cortex, AMPK activation in SH-SY5Y cells upregulated p-GSK3βS9 but downregulated p-tau396 , whereas it had no significant effect on p-tau262 expression. In addition, the AMPK-mediated inhibition of p-tau396 expression was attenuated by okadaic acid, a protein phosphatase 2A (PP2A) inhibitor. Taken together, our data showed that AMPK activation inhibits p-tau396 expression in a GSK3β- and PP2A-dependent manner, and suggest that differential regulation of tau phosphorylation in young SAMP8 mice by AMPK plays a compensatory role against accelerated senescence in this AD animal model. Show more

Keywords: 5′-AMP-activated protein kinase, GSK3β, p-tau, protein phosphatase 2A, senescence-accelerated mice, sirtuin 1, tau protein

DOI: 10.3233/JAD-150035

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 249-259, 2015

Authors: Herukka, Sanna-Kaisa | Rummukainen, Jaana | Ihalainen, Jouni | von und zu Fraunberg, Mikael | Koivisto, Anne M. | Nerg, Ossi | Puli, Lakshman K. | Seppälä, Toni T. | Zetterberg, Henrik | Pyykkö, Okko T. | Helisalmi, Seppo | Tanila, Heikki | Alafuzoff, Irina | Hiltunen, Mikko | Rinne, Jaakko | Soininen, Hilkka | Jääskeläinen, Juha E. | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ1 - 42 ), total tau (T-tau), and phosphorylated tau (P-tau181 ) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer’s disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical …brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n  = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r  = 0.70, p  = 0.017) and P-tau181 (r  = 0.64, p  = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, normal pressure hydrocephalus, tau

DOI: 10.3233/JAD-142862

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 261-269, 2015

Authors: Petersen, Robert B. | Lissemore, Frances M. | Appleby, Brian | Aggarwal, Neelum | Boyatzis, Richard | Casadesus, Gemma | Cummings, Jeff | Jack, Anthony | Perry, George | Safar, Jiri | Sajatovic, Martha | Surewicz, Witold K. | Wang, Yanming | Whitehouse, Peter | Lerner, Alan

Article Type: Brief Report

Abstract: The term “brain health” integrates general health and well-being with cognitive fitness, in the context of an environment that includes the spectrum of positive and negative factors affecting the individual. Brain health incorporates the effects of neurodegeneration in an ecological sense and the effects of environment and health practices on brain function. It also provides a framework for understanding and maximizing cognitive function across the lifespan. Despite decades of research into the pathogenesis of neurodegenerative disorders, our understanding of how to treat them is relatively rudimentary. Unidimensional approaches, such as medication monotherapies, have generally produced negative results in treatment trials. …New integrative paradigms that cut across the molecular and cellular level to the individual and societal level may provide new approaches to understand and treat these disorders. This report on proceedings of a multi-disciplinary conference held in Cleveland, Ohio, in October 2013 summarizes research progress in understanding neurodegenerative disorders in a brain health context. A new “brain health” paradigm is essential to finally understand neurodegenerative disorders such as Alzheimer’s disease and overcome the relative stand-still in therapeutics research that has characterized the last decade. The authors summarize progress in these emerging areas with the aim of producing new integrated scientific models for understanding brain health, potentially modifying disease course and advancing care for individuals and families affected by neurodegenerative conditions. Show more

Keywords: Alzheimer’s disease, brain health, neurodegeneration, Parkinson’s disease, psychosocial approaches

DOI: 10.3233/JAD-150043

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 271-283, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150239

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 285-287, 2015