Journal of Alzheimer's Disease - Volume 62, issue 1

Authors: Overk, Cassia | Masliah, Eliezer

Article Type: Review Article

Abstract:  It has been a year since we lost Dale Schenk on September 30, 2016. Dale’s visionary work resulted in the remarkable discovery in 1999 that an experimental amyloid-β (Aβ) vaccine reduced the neurodegeneration in a transgenic model of Alzheimer’s disease (AD). Following Dale’s seminal work, several active and passive immunotherapies have since been developed and tested in the clinic for AD, Parkinson’s disease (PD), and other neurodegenerative disorders. Here we provide a brief overview of the current state of development of immunotherapy for AD, PD, and other neurodegenerative disorders in the context of this anniversary. The next steps in the …development of immunotherapies will require combinatorial approaches mixing antibodies against various targets (e.g., Aβ, α-syn, Tau, and TDP43) with small molecules that block toxicity, aggregation, inflammation, and promote cell survival. Show more

Keywords: Alzheimer’s disease, immunotherapy, Potamkin Prize, synucleinopthy, tauopathy

DOI: 10.3233/JAD-171071

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 1-13, 2018

Authors: Jha, Niraj Kumar | Jha, Saurabh Kumar | Sharma, Renu | Kumar, Dhiraj | Ambasta , Rashmi K. | Kumar, Pravir

Article Type: Review Article

Abstract: For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2 ) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2 . On the contrary, hypoxia to …the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration. Show more

Keywords: Angiogenesis, energy metabolism, hypoxia, neurodegeneration, neurogenesis, therapeutics

DOI: 10.3233/JAD-170589

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 15-38, 2018

Authors: Lang, Brittany | Kindy, Mark S. | Kozel, F. Andrew | Schultz, Susan K. | Taheri, Saeid

Article Type: Review Article

Abstract: Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from …different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory. Show more

Keywords: Biomarkers, cerebrovascular diseases, clustering, neuroimaging, vascular cognitive impairment, vascular dementia

DOI: 10.3233/JAD-170733

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 39-60, 2018

Authors: Ihara, Masafumi | Washida, Kazuo

Article Type: Review Article

Abstract: Many studies have shown a relationship between atrial fibrillation (AF) and vascular dementia. AF is a major risk factor for stroke, and stroke is the greatest risk factor for vascular dementia. However, the relationship between Alzheimer’s disease (AD), the leading cause of dementia, and AF remains unclear. At least four epidemiological studies have reported AF significantly raises the risk of AD 1.5- to 2.5-fold. Chronic cerebral hypoperfusion, resulting from persistent AF, could explain the link as hypoperfusion may mechanistically exacerbate amyloid-β (Aβ) neuropathology, such as senile plaques and amyloid angiopathy, by upregulating Aβ-producing enzymes and lowering Aβ clearance efficiency. In …addition, hypoperfusion may exacerbate tau pathology directly through upregulation of tau-phosphorylating enzymes and indirectly via the amyloid cascade. However, most neuropathological studies do not support the direct link between AD pathology and AF but rather suggests vascular neuropathology is related to, or coexistent with, AF and lowers the threshold for clinically-evident AD. Vascular neuropathology may thus mediate the link between AD and AF. From a treatment perspective, an observational study has shown that catheter ablation is associated with less incidence of AD in AF patients, suggesting rhythm-control suppresses hypoperfusion-induced AD neuropathology. In addition, rate-control may lower the rate of cognitive decline in cognitively impaired elderly subjects with AF. Further studies are warranted to clarify the mechanisms underlying the linkage between AF and AD. However, anticoagulation and rhythm-/rate-control against AF may hold promise even for AD patients. Show more

Keywords: Alzheimer’s disease, anticoagulant, atrial fibrillation, catheter ablation, dementia, hypoperfusion, rhythm control

DOI: 10.3233/JAD-170970

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 61-72, 2018

Authors: Hashimoto, Makoto | Ho, Gilbert | Sugama, Shuei | Takamatsu, Yoshiki | Shimizu, Yuka | Takenouchi, Takato | Waragai, Masaaki | Masliah, Eliezer

Article Type: Research Article

Abstract:  Currently, the physiological roles of amyloidogenic proteins (APs) in human brain, such as amyloid-β and α-synuclein, are elusive. Given that many APs arose by gene duplication and have been resistant against the pressures of natural selection, APs may be associated with some functions that are advantageous for survival of offspring. Nonetheless, evolvability is the sole physiological quality of APs that has been characterized in microorganisms such as yeast. Since yeast and human brain may share similar strategies in coping with diverse range of critical environmental stresses, the objective of this paper was to discuss the potential role of evolvability of …APs in aging-associated neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Given the heterogeneity of APs in terms of structure and cytotoxicity, it is argued that APs might be involved in preconditioning against diverse stresses in human brain. It is further speculated that these stress-related APs, most likely protofibrillar forms, might be transmitted to offspring via the germline, conferring preconditioning against forthcoming stresses. Thus, APs might represent a vehicle for the inheritance of the acquired characteristics against environmental stresses. Curiously, such a characteristic of APs is reminiscent of Charles Darwin’s ‘gemmules’, imagined molecules of heritability described in his pangenesis theory. We propose that evolvability might be a physiological function of APs during the reproductive stage and neurodegenerative diseases could be a by-product effect manifested later in aging. Collectively, our evolvability hypothesis may play a complementary role in the pathophysiology of APs with the conventional amyloid cascade hypothesis. Show more

Keywords: Alzheimer’s disease, amyloidogenic proteins, cancers, evolvability, neurodegenerative disease, stress, γ-synuclein, transmission, yeast prion

DOI: 10.3233/JAD-170894

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 73-83, 2018

Authors: Xie, Long | Das, Sandhitsu R. | Wisse, Laura E.M. | Ittyerah, Ranjit | Yushkevich, Paul A. | Wolk, David A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Short Communication

Abstract: Neurofibrillary tangle (NFT) pathology is linked to neurodegeneration in the medial temporal lobe (MTL). Using a tailored pipeline, we correlated atrophy rate, as measured from retrospective longitudinal MRI, with NFT burden, measured from 18 F-AV-1451 PET, within MTL regions of earliest NFT pathology. In amyloid-β positive but not amyloid-β negative individuals, we found significant correlation between 18 F-AV-1451 uptake and atrophy rate that was strongest in the transentorhinal cortex, the first region with NFT pathology. This supports the role of NFTs in driving neurodegeneration and the utility of 18 F-AV-1451 PET and structural measurement of transentorhinal cortex in tracking early …tau-mediated disease progression. Show more

Keywords: Alzheimer’s disease, amyloid, 18F-AV-1451 PET, medial temporal lobe, structural atrophy

DOI: 10.3233/JAD-170945

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 85-92, 2018

Authors: Berg, Jody-Lynn | Durant, January | Léger, Gabriel C. | Cummings, Jeffrey L. | Nasreddine, Ziad | Miller, Justin B.

Article Type: Short Communication

Abstract: The Montreal Cognitive Assessment (MoCA) has become widely used as a brief test of cognitive function in patients with neurological disease. More convenient application of the MoCA might increase its use and enhance its utility. An electronic version of the MoCA has recently been developed. To establish validity of the electronic version (eMoCA), discrepancy scores, concordance correlation coefficients (CCC), and root mean squared differences (RMSD) were calculated between each administration method in a sample of 43 new adult patients presenting with primary memory complaints. The CCC was 0.84 and the RMSD was 2.27, with 76% of the sample having a …difference score within 2 points. Overall, this study establishes adequate convergent validity between the MoCA and eMoCA among an adult population presenting with memory concerns. Show more

Keywords: Cognition, handheld computers, neuropsychological tests, reproducibility of results

DOI: 10.3233/JAD-170896

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 93-97, 2018

Authors: Backhouse, Tamara | Camino, Julieta | Mioshi, Eneida

Article Type: Research Article

Abstract: Background: Behavioral crises in dementia are represented by a wide variety of symptoms, regularly require external intervention from professionals, and are reported as a risk factor for hospital admission. Little is known about the factors that are associated with them. Objective: To determine the factors associated with dementia-related behavioral crises. Methods: We searched MEDLINE, CINAHL, PsycINFO, EMBASE, and AMED databases. An additional lateral search including reference lists was conducted. Two researchers screened all records for potential eligibility. Narrative synthesis was used to bring together the findings. Results: Out of the 5,544 records identified, 24 …articles (18 distinct studies) met the eligibility criteria. Aggression and agitation were the most common behaviors present at crises. Delusions, wandering/absconding, and hallucinations were also key behaviors contributing to crises. Behavioral crises predominantly happened in the severe stages of dementia (according to MMSE scores), in people with dementia residing in their own homes and in long-term care, and were the catalyst for admissions to psychiatric inpatient settings, specialist-care units, long-term care settings, or for referrals to psychiatric community services. Lack of consistency in assessment of behavior, and management of agitation/aggression in dementia crises were evident. Conclusion: Interventions to reduce the likelihood of people with dementia-related behaviors reaching crisis point need to focus on both family and care home settings and incorporate aggression and agitation management. Future research should focus on determining the factors that could be addressed to prevent behavioral crises and the interventions and models of care that may help to prevent crises. Show more

Keywords: Behavior, behavioral symptoms, crisis intervention, dementia, hospitalization, institutionalization

DOI: 10.3233/JAD-170679

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 99-113, 2018

Authors: Mahady, Laura | Nadeem, Muhammad | Malek-Ahmadi, Michael | Chen, Kewei | Perez, Sylvia E. | Mufson, Elliott J.

Article Type: Research Article

Abstract: Although the frontal cortex plays an important role in cognitive function and undergoes neuronal dysfunction in Alzheimer’s disease (AD), the factors driving these cellular alterations remain unknown. Recent studies suggest that alterations in epigenetic regulation play a pivotal role in this process in AD. We evaluated frontal cortex histone deacetylase (HDAC) and sirtuin (SIRT) levels in tissue obtained from subjects with a premortem diagnosis of no-cognitive impairment (NCI), mild cognitive impairment (MCI), mild to moderate AD (mAD), and severe AD (sAD) using quantitative western blotting. Immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a …decrease in sAD compared to NCI. HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in MCI and mAD, but not in sAD compared to NCI. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to NCI. HDAC1 levels negatively correlated with perceptual speed, while SIRT1 positively correlated with perceptual speed, episodic memory, global cognitive score, and Mini-Mental State Examination. HDAC1 positively, while SIRT1 negatively correlated with cortical neurofibrillary tangle counts. These findings suggest that dysregulation of epigenetic proteins contribute to neuronal dysfunction and cognitive decline in the early stage of AD. Show more

Keywords: Alzheimer’s disease, frontal cortex, histone deacetylase, epigenetics, mild cognitive impairment, neuropathology, sirtuins

DOI: 10.3233/JAD-171032

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 115-131, 2018

Authors: Marra, Angela | Naro, Antonino | Chillura, Antonino | Bramanti, Alessia | Maresca, Giuseppa | De Luca, Rosaria | Manuli, Alfredo | Bramanti, Placido | Calabrò, Rocco Salvatore

Article Type: Research Article

Abstract: Background: Identifying the patients with mild cognitive impairment (MCI) who may develop dementia (MDC) is challenging. The study of peripersonal space (PPS) by using functional transcranial Doppler (fTCD) could be used for this purpose. Objective: To identify changes in cerebral blood flow (CBF) during motor tasks targeting PPS, which can predict MDC. Methods: We evaluated the changes in CBF in 22 patients with MCI and 23 with dementia [Alzheimer’s disease (AD) and vascular dementia (VaD)] during a motor task (passive mobilization, motor imagery, and movement observation) in which the hand of the subject moved forward and …backward the face. Results: CBF increased when the hand approached the face and decreased when the hand moved from the face in the healthy controls (HCs). CBF changed were detectable only in patients with MCI but not in those with the AD and those who were MDC after 8-month follow-up. On the other hand, the patients with VaD presented a paradoxical response to the motor task (i.e., a decrease of CBF rather than an increase, as observed in HCs and MCI). Therefore, we found a modulation of PPS-related CBF only in HCs and patients with stable MCI (at the 8-month follow-up). Conclusions: fTCD may allow preliminarily differentiating and following-up the patients with MCI and MDC, thus allowing the physician to plan beforehand more individualized cognitive rehabilitative training. Show more

Keywords: Dementia, functional transcranial Doppler, mild cognitive impairment, MCI-to-dementia conversion, peripersonal space

DOI: 10.3233/JAD-170973

Citation: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 133-143, 2018