Journal of Alzheimer's Disease - Volume 54, issue 2

Authors: Arosio, Beatrice | Casati, Martina | Gussago, Cristina | Ferri, Evelyn | Abbate, Carlo | Scortichini, Valeria | Colombo, Elena | Rossi, Paolo Dionigi | Mari, Daniela

Article Type: Review Article

Abstract: As the European population gets older, the incidence of neurological disorders increases with significant impact on social costs. Despite differences in disease etiology, several brain disorders in the elderly (e.g., Alzheimer’s disease, vascular dementia, normal pressure hydrocephalus) share dementia as a common clinical feature. The current treatment for the majority of these diseases is merely symptomatic and does not modify the course of the illness. Symptoms of normal pressure hydrocephalus are the only ones that can be modified if they are recognized in time and treated appropriately. Therefore, an important clinical strategy may be disclosed by pathogenic pathways that can …be modified and to find drugs that can slow down or even arrest disease progression. Possibly a way to answer this question could be by re-examining all the molecules which have so far succeeded in improving many aspects of cognitive deterioration in some neurodegenerative conditions, that were not considered because of controversial opinions. The main purpose of this summary is to further substantiate the hypothesis that the pathway of adenosine type A2A receptor could be used as a potential target to develop new/old therapeutic strategies. Show more

Keywords: Adenosine, adenosine receptors, elderly, neurodegeneration

DOI: 10.3233/JAD-160324

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 417-425, 2016

Authors: Vijayan, Murali | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Stroke is a brain disease that occurs when blood flow stops, resulting in reduced oxygen supply to neurons. Stroke occurs at any time and at any age, but increases after the age of 55. It is the second leading cause of death and the third leading cause of disability-adjusted, life-years. The pathophysiology of ischemic stroke is complex and recent molecular, cellular, and animal models and postmortem brain studies have revealed that multiple cellular changes have been implicated, including oxidative stress/mitochondrial dysfunction, inflammatory responses, micro RNA alterations, and marked changes in brain proteins. These cellular changes provide new information for developing …therapeutic strategies for ischemic stroke treatment. Research also revealed that stroke increases with a number of modifiable factors and most strokes can be prevented and/or controlled through pharmacological or surgical interventions and lifestyle changes. Ischemic stroke is the major risk factor for vascular dementia and Alzheimer’s disease. This review summarizes the latest research findings on stroke, including causal factors and molecular links between stroke and vascular disease/Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, hemorrhage, inflammatory responses, ischemic stroke, magnetic resonance imaging, vascular dementia

DOI: 10.3233/JAD-160527

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 427-443, 2016

Authors: Goldwaser, Eric L. | Acharya, Nimish K. | Sarkar, Abhirup | Godsey, George | Nagele, Robert G.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and diabetes mellitus (DM) are among the most pervasive and devastating disorders that afflict people throughout the world. Although typically associated with older demographics, recent epidemiologic studies have reported parallel trends in decreasing age of onset and increasing incidence of these conditions. Promising research continues to implicate the cerebrovasculature and blood-brain barrier (BBB) as playing key roles in AD pathoetiology. Similarly, complications accompanying DM, such as diabetic nephropathy/retinopathy, cardiovascular disease, and stroke, have been rooted in vascular compromise. Not surprisingly, DM is now considered a major risk factor for AD. The purpose of this review is to …highlight investigations into the role of the cerebrovasculature in the development and progression of AD. We give particular attention to studies on humans and a variety of animal model systems that have demonstrated a link between BBB dysfunction and pathological changes in the brain consistent with aging and AD. Together, these studies suggest that the vascular complications associated with chronic, poorly managed DM can lead to subclinical BBB breakdown that precedes and drives the pathological changes progressing to symptomatic AD, providing a common mechanistic thread connecting these two disorders. Furthermore, this emphasizes the need to focus on the vasculature as a potential therapeutic target with the intent of limiting BBB breakdown involved in disease initiation and progression. In conclusion, AD may be more than just an associated comorbidity of DM, and instead another manifestation of the underlying vascular pathology that is common to both. Show more

Keywords: Alzheimer’s disease, amyloid, blood-brain barrier, dementia, diabetes complications, diabetes mellitus

DOI: 10.3233/JAD-160284

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 445-456, 2016

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Shear distortion of amyloid-beta (Aβ) solutions accelerates amyloid cascade reactions that may yield different toxic oligomers than those formed in quiescent solutions. Recent experiments indicate that cerebrospinal fluid (CSF) and interstitial fluid (ISF) containing Aβ flow through narrow brain perivascular pathways and brain parenchyma. This paper suggests that such flow causes shear distortion of Aβ molecules involving conformation changes that may be one of the initiating events in the etiology of Alzheimer’s disease. Aβ shearing can occur in or around brain arteries and arterioles and is suggested as the origin of cerebral amyloid angiopathy deposits in cerebrovascular walls. Comparatively low …flow rates of ISF within the narrow extracellular spaces (ECS) of the brain parenchyma are suggested as a possible initiating factor in both the formation of neurotoxic Aβ42 oligomers and amyloid fibrils. Aβ42 in slow-flowing ISF can gain significant shear energy at or near the walls of tortuous brain ECS flow paths, promoting the formation of a shear-distorted, excited state hydrophobic Aβ42 * conformation. This Aβ42 * molecule could possibly be involved in one of two paths, one involving rapid adsorption to a brain membrane surface, ultimately forming neurotoxic oligomers on membranes, and the other ultimately forming plaque within the ECS flow pathways. Rising Aβ concentrations combined with shear at or near critical brain membranes are proposed as contributing factors to Alzheimer’s disease neurotoxicity. These hypotheses may be applicable in other neurodegenerative diseases, including tauopathies and alpha-synucleinopathies, in which shear-distorted proteins also may form in the brain ECS. Show more

Keywords: Amyloid-β, cerebral amyloid angiopathy, cerebrospinal fluid, extracellular space, glymphatic system, interstitial fluid, protein conformation, protein misfolding

DOI: 10.3233/JAD-160027

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 457-470, 2016

Authors: López-González, Irene | Palmeira, Andre | Aso, Ester | Carmona, Margarita | Fernandez, Liana | Ferrer, Isidro

Article Type: Short Communication

Abstract: FOXP2 is altered in a variety of language disorders. We found reduced mRNA and protein expression of FOXP2 in frontal cortex area 8 in Pick’s disease, and frontotemporal lobar degeneration-tau linked to P301L mutation presenting with language impairment in comparison with age-matched controls and cases with parkinsonian variant progressive supranuclear palsy. Foxp2 mRNA and protein are also reduced with disease progression in the somatosensory cortex in transgenic mice bearing the P301S mutation in MAPT when compared with wild-type littermates. Our findings support the presence of FOXP2 expression abnormalities in sporadic and familial frontotemporal degeneration tauopathies.

Keywords: FOXP2, frontotemporal lobar degeneration, language, Pick’s disease, P301S transgenic mice, tauopathy

DOI: 10.3233/JAD-160274

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 471-475, 2016

Authors: Varghese, Merina | Santa-Maria, Ismael | Ho, Lap | Ward, Libby | Yemul, Shrishailam | Dubner, Lauren | Księżak-Reding, Hanna | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: The release of paired helical filaments (PHFs) from neurons into the extracellular space may contribute to the propagation of tau pathology across brain regions in Alzheimer’s disease (AD) and other tauopathies. The majority of available mechanistic studies exploring the pathologic role of extracellular PHFs are conducted in proliferating cell lines. Here, we compare how extracellular PHFs induce tauopathy in mitotic cells and in post-mitotic brain neurons. In a mitotic cell line (HEK 293T), extracellular exposure to AD PHFs leads to an intracellular “aggresomal” type deposition of tau, coincidental with redistribution of dynein, a retrograde motor protein. We also observed that …PHFs impaired proteasome degradation, but not autophagy. Exposure of cells to proteasome inhibitors was sufficient to induce intracellular tau aggregate formation as well as reorganization of dynein and the intermediate filament protein, vimentin. Thus, in mitotic cells, extracellular PHFs promote cellular tau aggregation, in part, by interfering with cellular proteasome degradation processes. In contrast with our observations with proliferating cells, exposure of post-mitotic primary neuronal cultures to AD PHFs did not promote “aggresomal” tau deposition, but instead resulted in a widespread accumulation of phosphorylated tau-immunoreactive swellings in neuritic processes, characterized by disturbed cytoskeletal organization of dynein and vimentin. Collectively, our observations suggest that extracellular PHFs may contribute to the propagation of tau pathology by independent mechanisms in post-mitotic and mitotic brain cells. These outcomes indicate that in addition to post-mitotic brain neurons, mitotic brain cells should also be considered as targets for therapeutic interventions to attenuate propagation of tauopathy. Show more

Keywords: Alzheimer’s disease, neuropathology, proteasome, tau

DOI: 10.3233/JAD-160166

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 477-496, 2016

Authors: Cushman, Mary | Callas, Peter W. | McClure, Leslie A. | Unverzagt, Frederick W. | Howard, Virginia J. | Gillett, Sarah R. | Thacker, Evan L. | Wadley, Virginia G.

Article Type: Research Article

Abstract: Background: Improved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people. Objective: To study the association of NT-proBNP with risk of incident cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured …in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up. Results: Adjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33 pg/ml) had a 1.69-fold increased odds (95% CI 1.11–2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele. Conclusion: Higher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimer’s disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction. Show more

Keywords: Biomarkers, brain, cognition disorders, natriuretic peptide, prospective study, risk factors

DOI: 10.3233/JAD-160328

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 497-503, 2016

Authors: Stevnsborg, Lea | Jensen-Dahm, Christina | Nielsen, Thomas R. | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Previous studies demonstrated lower quality diagnostic assessment of dementia in immigrant populations, but knowledge about the quality of treatment and care for dementia is still lacking. Objective: To conduct a nationwide registry-based study to determine whether inequality exists regarding access to anti-dementia treatment and care between immigrant and Danish-born patients with dementia. Methods: A cross-sectional register-based study was conducted in the entire elderly (60≥years) population with dementia in Denmark in 2012 (n  = 34,877). The use of anti-dementia drugs and residency in a nursing home were compared among Danish-born and Western and non-Western immigrants with …dementia. Logistic regression analysis was done with adjustment for age, sex, comorbidity, marital status, basis of inclusion, and time since dementia diagnosis. Results: Immigrant background was associated with a significantly lower likelihood of receiving anti-dementia drug therapy (odds ratio (OR) [95% confidence interval (CI)]): non-Western = 0.70 [0.56–0.87]; Western = 0.74 [0.63–0.87]). No significant differences were found in type or amount of anti-dementia medication dispensed between the population groups (proxy measure for adherence). Non-Western immigrants were significantly less likely to live in a nursing home (0.52 [0.41–0.65]). Conclusion: This nationwide registry-based study indicated a worrisome difference in access to anti-dementia treatment and care for dementia patients with an immigrant background, but similar levels of adherence compared with the Danish-born population. Further research is necessary to pinpoint barriers to access to suitable healthcare among elderly immigrants with dementia but also to identify and develop culturally sensitive methods for their treatment and care. Show more

Keywords: Dementia, drug therapy, emigrants and immigrants and, healthcare disparities, medication adherence, nursing homes

DOI: 10.3233/JAD-160124

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 505-514, 2016

Authors: El Haj, Mohamad | Antoine, Pascal

Article Type: Research Article

Abstract: Reminiscence, or the process of thinking or telling about past experience, is thought to serve social, instrumental, and integrative functions. Our paper investigated these functions in Alzheimer’s disease (AD). Twenty-six participants with a clinical diagnosis of probable mild AD and 28 control older adults filled in a French adaptation of the Reminiscence Functions Scale. Eight specific functions were assessed: death preparation, identity, problem-solving, teaching/informing, conversation, boredom reduction, bitterness revival, and intimacy maintenance. Both older adults and AD participants reported reminiscence about their past to prepare themselves for the idea of their own mortality. All participants also reported reminiscence “to reduce …boredom” and “for something to do”. However, reminiscence for death preparation and boredom reduction was reported more by AD participants than by older adults. In all participants, the death preparation function of reminiscence was significantly correlated with depression. Individuals with AD seem to reminiscence to cope with thoughts about their own mortality. This helps them to see that they have lived a full life and can therefore accept death more calmly. Individuals with AD also seem to cope with boredom by using reminiscence, probably as a tool to fill time or simply to create ease of conversation. Show more

Keywords: Alzheimer’s disease, depression, reminiscence

DOI: 10.3233/JAD-160497

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 515-523, 2016

Authors: Binukumar, B.K. | Pelech, Steven L. | Sutter, Catherine | Shukla, Varsha | Amin, Niranjana D. | Grant, Philip | Bhaskar, Manju | Skuntz, Suzanne | Steiner, Joseph | Pant, Harish C.

Article Type: Research Article

Abstract: Cyclin-dependent kinase 5 (CDK5) is a multifunctional serine/threonine kinase that regulates a large number of neuronal processes essential for nervous system development and function with its activator p35 CDK5R1. Upon neuronal insults, p35 is proteolyzed and cleaved to p25 producing deregulation and hyperactivation of CDK5 (CDK5/p25), implicated in tau hyperphosphorylation, a pathology in some neurodegenerative diseases. A truncated, 24 amino acid peptide, p5, derived from p35 inhibits the deregulated CDK5 phosphotransferase activity and ameliorates Alzheimer’s disease (AD) phenotypes in AD model mice. In the present study, we have screened a diverse panel of 70 human protein kinases for their sensitivities …to p5, and a subset of these to p35. At least 16 of the tested protein kinases exhibited IC50 values that were 250 μM or less, with CAMK4, ZAP70, SGK1, and PIM1 showing greater sensitivity to inhibition by p5 than CDK5/p35 and CDK5/p25. In contrast, the p5 peptide modestly activated LKB1 and GSK3β . A sub set of kinases screened against p35 showed that activity of CAMK4 in the absence of calcium and calmodulin was also markedly inhibited by p35. The Cyclin Y-dependent kinases PFTK1 (CDK14) and PCTK1 (CDK16) were activated by p35 at least 10-fold in the absence of Cyclin Y and by approximately 50% in its presence. These findings provide additional insights into the mechanisms of action for p5 and p35 in the regulation of protein phosphorylation in the nervous system. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase 5 activator, p35 CDK5R1, tau phosphorylation

DOI: 10.3233/JAD-160458

Citation: Journal of Alzheimer's Disease, vol. 54, no. 2, pp. 525-533, 2016