Journal of Alzheimer's Disease - Volume 67, issue 2

Authors: Escobar, Iris | Xu, Jing | Jackson, Charles W. | Perez-Pinzon, Miguel A.

Article Type: Review Article

Abstract: Cerebral ischemia remains a leading cause of mortality worldwide. Although the incidence of death has decreased over the years, surviving patients may suffer from long-term cognitive impairments and have an increased risk for dementia. Unfortunately, research aimed toward developing therapies that can improve cognitive outcomes following cerebral ischemia has proved difficult given the fact that little is known about the underlying processes involved. Nevertheless, mechanisms that disrupt neural network activity may provide valuable insight, since disturbances in both local and global networks in the brain have been associated with deficits in cognition. In this review, we suggest that abnormal neural …dynamics within different brain networks may arise from disruptions in synaptic plasticity processes and circuitry after ischemia. This discussion primarily concerns disruptions in local network activity within the hippocampus and other extra-hippocampal components of the Papez circuit, given their role in memory processing. However, impaired synaptic plasticity processes and disruptions in structural and functional connections within the Papez circuit have important implications for alterations within the global network, as well. Although much work is required to establish this relationship, evidence thus far suggests there is a link. If pursued further, findings may lead toward a better understanding of how deficits in cognition arise, not only in cerebral ischemia, but in other neurological diseases as well. Show more

Keywords: Cognition, heart arrest, hippocampus, ischemia, long-term potentiation, neuronal plasticity, stroke

DOI: 10.3233/JAD-180875

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 425-446, 2019

Authors: Castellani, Rudy J. | Perry, George

Article Type: Review Article

Abstract: There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical …in controlling tau’s binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the “tau prion”. Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members. Show more

Keywords: Dementia pugilistica, phosphorylated tau, repetitive head trauma, tau, tauopathy

DOI: 10.3233/JAD-180721

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 447-467, 2019

Authors: Wright, John W. | Harding, Joseph W.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive neuron losses in memory-associated brain structures that rob patients of their dignity and quality of life. Five drugs have been approved by the FDA to treat AD but none modify or significantly slow disease progression. New therapies are needed to delay the course of this disease with the ultimate goal of preventing neuron losses and preserving memory functioning. In this review we describe the renin-angiotensin II (AngII) system (RAS) with specific regard to its deleterious contributions to hypertension, facilitation of neuroinflammation and oxidative stress, reduced cerebral blood flow, tissue remodeling, …and disruption of memory consolidation and retrieval. There is evidence that components of the RAS, AngIV and Ang(1–7), are positioned to counter such damaging influences and these systems are detailed with the goal of drawing attention to their importance as drug development targets. Ang(1–7) binds at the Mas receptor, while AngIV binds at the AT4 receptor subtype, and these receptor numbers are significantly decreased in AD patients, accompanied by declines in brain aminopeptidases A and N, enzymes essential for the synthesis of AngIV. Potent analogs may be useful to counter these changes and facilitate neuronal functioning and reduce apoptosis in memory associated brain structures of AD patients. Show more

Keywords: Alzheimer’s disease, Ang(1–7)/Mas receptor system, angiotensin II/AT1 receptor system, angiotensin IV/AT4 receptor system, insulin-regulated aminopeptidase (IRAP), renin-angiotensin system (RAS)

DOI: 10.3233/JAD-181035

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 469-480, 2019

Authors: Oeckl, Patrick | Halbgebauer, Steffen | Anderl-Straub, Sarah | Steinacker, Petra | Huss, André M. | Neugebauer, Hermann | von Arnim, Christine A.F. | Diehl-Schmid, Janine | Grimmer, Timo | Kornhuber, Johannes | Lewczuk, Piotr | Danek, Adrian | Consortium for Frontotemporal Lobar Degeneration German | Ludolph, Albert C. | Otto, Markus

Article Type: Short Communication

Abstract: Reliable blood biomarkers for Alzheimer’s disease (AD) are missing. We measured astroglial GFAP in patients with AD (n  = 28), frontotemporal dementia (bvFTD, n  = 35), Parkinson’s disease (n  = 11), Lewy body dementias (n  = 19), and controls (n  = 34). Serum GFAP was increased in AD (p  < 0.001) and DLB/PDD (p  < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p  < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r = –0.42, p  < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be …the first blood biomarker in the differential diagnosis of AD and bvFTD. Show more

Keywords: Alzheimer’s disease, astrocyte, biomarker, cerebrospinal fluid, differential diagnosis, frontotemporal dementia, GFAP, Lewy body dementia, Parkinson’s disease, serum

DOI: 10.3233/JAD-180325

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 481-488, 2019

Authors: Kaskikallio, Alar | Karrasch, Mira | Rinne, Juha O. | Tuokkola, Terhi | Parkkola, Riitta | Grönholm-Nyman, Petra

Article Type: Short Communication

Abstract: We examined whether cerebrovascular white matter pathology is related to cognition as measured by the compound score of CERAD neuropsychological battery in cognitively normal older adults, patients with mild cognitive impairment, and patients with Alzheimer’s disease (total n  = 149), controlling for age and education. Trend-level effects of white matter pathology on cognition were only observed in patients with Alzheimer’s disease (p  = 0.062, η 2  = 0.052), patients with severe frontal white matter pathology performed notably worse than those with milder pathology. This indicates that frontal cerebrovascular pathology may have an additive negative effect on cognition in Alzheimer’s disease.

Keywords: Alzheimer’s disease, cognition, mild cognitive impairment, white matter

DOI: 10.3233/JAD-180554

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 489-493, 2019

Authors: Gallacher, John | de Reydet de Vulpillieres, Frederic | Amzal, Billy | Angehrn, Zuzanna | Bexelius, Christin | Bintener, Christophe | Bouvy, Jacoline C. | Campo, Laura | Diaz, Carlos | Georges, Jean | Gray, Alastair | Hottgenroth, Antje | Jonsson, Pall | Mittelstadt, Brent | Potashman, Michele H. | Reed, Catherine | Sudlow, Cathie | Thompson, Robin | Tockhorn-Heidenreich, Antje | Turner, Andrew | van der Lei, Johan | Visser, Pieter Jelle | the ROADMAP Consortium

Article Type: Editorial

Abstract: ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer’s disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit.

Keywords: Alzheimer’s disease, data sharing, data systems, health policy, patient outcome assessment, real-world clinical trials, systems integration

DOI: 10.3233/JAD-180370

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 495-501, 2019

Authors: Barton, Shawn M. | Janve, Vaibhav A. | McClure, Richard | Anderson, Adam | Matsubara, Joanne A. | Gore, John C. | Pham, Wellington

Article Type: Research Article

Abstract: The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer’s disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here, we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected …with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, drug delivery, iron oxide nanoparticles, lipopolysaccharide

DOI: 10.3233/JAD-180755

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 503-513, 2019

Authors: Meng, Lanxia | He, Mingyang | Xiong, Min | Zhang, Xingyu | Nie, Shuke | Xiong, Jing | Hu, Dan | Zhang, Zhaohui | Mao, Ling | Zhang, Zhentao

Article Type: Research Article

Abstract: The etiology and pathogenesis of Alzheimer’s disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-β (DNA pol-β) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-β inhibitor 2′,3′– Dideoxycytidine (DDC) in AD models both in vitro and in vivo . DDC protected primary neurons from amyloid-β (Aβ)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol– β. Chronic oral administration of DDC alleviated Aβ deposition and memory deficits in …the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD. Show more

Keywords: 2′,3′– Dideoxycytidine, Alzheimer’s disease, DNA polymerase-β, synapse

DOI: 10.3233/JAD-180798

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 515-525, 2019

Authors: Zwingmann, Ina | Michalowsky, Bernhard | Esser, Alexander | Kaczynski, Anika | Monsees, Jessica | Keller, Armin | Hertel, Johannes | Wucherer, Diana | Thyrian, Jochen René | Eichler, Tilly | Kilimann, Ingo | Teipel, Stefan | Dreier Wolfgramm, Adina | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Caregivers providing informal care for people with dementia (PwD) often report unmet needs, burden, and health impairments. Optimal support for family dementia caregivers will likely benefit from better understanding and assessment of the prevalence and types of caregivers’ unmet needs and associated socio-demographic and clinical characteristics. Objective: The present study investigates 1) the number and types of caregivers’ unmet needs, 2) socio-demographic and clinical characteristics of both PwD and caregivers, and 3) caregivers’ burden and health-related outcomes that are related to caregivers’ unmet needs. Methods: The present analyses are based on cross-sectional …data of n  = 226 dyads of caregivers and their community-dwelling PwD participating in a comprehensive standardized, computer-based caregivers’ needs assessment within a general practitioner (GP)-based, cluster-randomized intervention trial. Results: A total of n  = 505 unmet needs were identified for n  = 171 caregivers from the intervention group at baseline. Only 24.3% caregivers reported no unmet need (n  = 55), whereas 75.7% caregivers had at least one unmet need (n  = 171). Caregivers had on average 2.19 unmet needs (mean  = 2.19, SD  = 2.15). Specifically, 53.1% of caregivers had one up to three unmet needs (n  = 120), 18.6% (n  = 42) had three up to six unmet needs, and 4.0% (n  = 9) had more than six unmet needs. Discussion: Our results underline the importance of a comprehensive needs assessment for family dementia caregivers to develop and implement concepts that can provide family dementia caregivers with optimal support. Show more

Keywords: Caregiver burden, caregiver interventions, caregiver supporting groups, caregiver unmet needs, randomized controlled trial

DOI: 10.3233/JAD-180244

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 527-539, 2019

Authors: Winston, Charisse N. | Aulston, Brent | Rockenstein, Edward M. | Adame, Anthony | Prikhodko, Olga | Dave, Kishan N. | Mishra, Priyanka | Rissman, Robert A. | Yuan, Shauna H.

Article Type: Research Article

Abstract: Progressive accumulation of aggregation-prone proteins, amyloid-β (Aβ ) and hyperphosphorylated tau (p-tau), are the defining hallmarks of Alzheimer’s disease (AD). The mechanisms by which Aβ and p-tau are transmitted throughout the diseased brain are not yet completely understood. Interest in exosome research has grown dramatically over the past few years, specifically due to their potential role as biomarkers for staging of neurodegenerative diseases, including AD. Despite their diagnostic utility, the pathogenic potential of exosomes has yet to be fully elucidated. In this study, we use a series of recombinant tau antibodies to characterize a new model of human …tau in vivo. Exosome suspensions derived from neuronally-differentiated, human induced pluripotent stem cells that express the repeat domain of tau P301L and V337M mutations (NiPSCEs) were injected into the wild-type mouse brain and pathological changes were characterized by immunostaining at one- (1 m) and two-month (2 m) post-injection. We found that tau inclusions were present throughout the brain at 2 m post-injection, which were detectable using antibodies raised against full-length tau (K9JA) and misfolded tau (MC1). Furthermore, we found that phosphorylated tau immunoreactivity was elevated 1 m post-injection, which was surprisingly normalized after 2 m. Finally, we observed extensive degeneration of neuronal dendrites in both ipsilateral and contralateral hippocampi in NiPSCE treated mice. In summary, we demonstrate that exosomes are sufficient to cause long-distance propagation of tau pathology and neurodegeneration in vivo . These novel findings support an active role of exosomes in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, exosomes, induced pluripotent stem cells, tau propagation

DOI: 10.3233/JAD-180776

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 541-553, 2019