Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Zupanic, Eva | Kramberger, Milica G. | von Euler, Mia | Norrving, Bo | Winblad, Bengt | Secnik, Juraj | Fastbom, Johan | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Recurrent ischemic stroke (IS) increases the risk of cognitive decline. To lower the risk of recurrent IS, secondary prevention is essential. Objective: Our aim was to compare post-discharge secondary IS prevention and its maintenance up to 3 years after first IS in patients with and without Alzheimer’s disease and other dementia disorders. Methods: Prospective open-cohort study 2007–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who experienced an IS (n  = 1410; 332 [23.5%] with Alzheimer’s disease) were compared with matched non-dementia IS patients (n  = 7150). We …analyzed antiplatelet, anticoagulant, blood pressure lowering, and statin treatment as planned medication initiation at discharge and actual dispensation of medications at first, second, and third year post-stroke. Results: At discharge, planned initiation of medication was higher in patients with dementia compared to non-dementia patients for antiplatelets (OR with 95% CI for fully adjusted models 1.23 [1.02–1.48]) and lower for blood pressure lowering medication (BPLM; 0.57 [0.49–0.67]), statins (0.57 [0.50–0.66]), and anticoagulants (in patients with atrial fibrillation – AF; 0.41 [0.32–0.53]). When analysis for antiplatelets was stratified according to the presence of AF, ORs for receiving antiplatelets remained significant only in the presence of AF (in the presence of AF 1.56 [1.21–2.01], in patients without AF 0.99 [0.75–1.33]). Similar trends were observed in 1st, 2nd, and 3rd year post-stroke. Conclusions: Dementia was a predictor of lower statin and BPLM use. Patients with dementia and AF were more likely to be prescribed antiplatelets and less likely to receive anticoagulants. Show more

Keywords: Alzheimer’s disease, anticoagulants, antihypertensive agents, cohort studies, dementia, hydroxymethylglutaryl-CoA reductase inhibitors, ischemic stroke, platelet aggregation inhibitors, secondary prevention

DOI: 10.3233/JAD-191011

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Santos-Mandujano, Rosalía A. | Ryan, Natalie S. | Chávez-Gutiérrez, Lucía | Sánchez-Torres, Carmen | Meraz-Ríos, Marco Antonio

Article Type: Research Article

Abstract: Presenilin 1 gene (PSEN1 ) mutations are the most common cause of familial Alzheimer’s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory …dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes. Show more

Keywords: A431E, familial Alzheimer’s disease, posterior cortical atrophy, Presenilin 1, spastic paraparesis, white matter hyperintensities

DOI: 10.3233/JAD-190978

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Musa, Gada | Slachevsky, Andrea | Muñoz-Neira, Carlos | Méndez, Carolina | Villagra, Roque | González-Billault, Christian | Ibáñez, Agustín | Hornberger, Michael | Lillo, Patricia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the most common neurodegenerative early-onset dementias. Despite the fact that both conditions have a very distinctive clinical pattern, they present with an overlap in their cognitive and behavioral features that may lead to misdiagnosis or delay in diagnosis. The current review intends to summarize briefly the main differences at the clinical, neuropsychological, and behavioral levels, in an attempt to suggest which aspects would facilitate an adequate diagnosis in a clinical setting, especially in Latin American and low- and middle-income countries, where the resources needed for a differential diagnosis (such as MRI or …biomarkers) are not always available. A timely diagnosis of AD and FTD have significant implications for the medical management and quality of life of patients and careers. Show more

Keywords: Alzheimer’s disease, cognitive neuropsychology, differential diagnosis, frontotemporal dementia, young onset dementia

DOI: 10.3233/JAD-190924

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Fischer, Corinne E. | Ismail, Zahinoor | Youakim, James M. | Creese, Byron | Kumar, Sanjeev | Nuñez, Nicolas | Darby, Ryan R. | Di Vita, Antonella | D’Antonio, Fabrizia | de Lena, Carlo | McGeown, William J. | Ramit, Ravona | Rasmussen, Jill | Bell, Joanne | Wang, Huali | Bruneau, Marie-Andrée | Panegyres, Peter K. | Lanctôt, Krista L. | Agüera-Ortiz, Luis | Lyketsos, Kostas | Cummings, Jeffrey | Jeste, Dilip V. | Sano, Mary | Devanand, Dev P. | Sweet, Robert A. | Ballard, Clive

Article Type: Research Article

Abstract: Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to …capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders , 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders. Show more

Keywords: Alzheimer’s disease, criteria, delusions, hallucinations, mild cognitive impairment, psychosis

DOI: 10.3233/JAD-190828

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Sun, Miao | Ma, Kai | Wen, Jie | Wang, Guangxian | Zhang, Changliang | Li, Qi | Bao, Xiaofeng | Wang, Hui

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of “senile” plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to …as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a “lost link” in understanding and treating AD and call for future work. Show more

Keywords: Alzheimer’s disease, dementia, gut microbiome, neurodegenerative disorders

DOI: 10.3233/JAD-190872

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Surmak, Andrew J. | Wong, Koon-Pong | Cole, Graham B. | Hirata, Kenji | Aabedi, Alexander A. | Mirfendereski, Omid | Mirfendereski, Payam | Yu, Amy S. | Huang, Sung-Cheng | Ringman, John M. | Liebeskind, David S. | Barrio, Jorge R.

Article Type: Research Article

Abstract: Background: 2-(4’- [11 C]Methylaminophenyl)-6-hydroxybenzothiazole ([11 C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. Objective: In this work, we use positron emission tomography (PET) imaging with [11 C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Methods: Ten moyamoya subjects and five control patients were evaluated with [11 C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11 C]-PiB PET scans before and after steroidal and immunomodulatory …therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Results: Increased [11 C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p  < 0.005). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11 C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11 C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Conclusion: Strong [11 C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11 C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques. Show more

Keywords: Inflammation, moyamoya, PET, PIB, sulfotransferase

DOI: 10.3233/JAD-190559

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Cao, Qing | Tan, Chen-Chen | Xu, Wei | Hu, Hao | Cao, Xi-Peng | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Dementia is a severe neurodegenerative disorder and it can be categorized into several subtypes by different pathogenic causes. We sought to comprehensively analyzed the prevalence of dementia from perspectives of geographic region (Asia, Africa, South America, and Europe/North America), age, and gender. We searched PubMed and EMBASE for relevant articles on dementia published from January 1985 to August 2019. In these studies, analyses were stratified by geographic region, age, and gender. Meta-regression was conducted to identify if there were significant differences between groups. We included forty-seven studies. Among the individuals aged 50 and over in the community, the pooled prevalence …for all-cause dementia, Alzheimer’s disease, and vascular dementia were 697 (CI95% : 546–864) per 10,000 persons, 324 (CI95% : 228–460) per 10,000 persons, and 116 (CI95% : 86–157) per 10,000 persons, respectively. In our study, the prevalence of all-type dementia in individuals aged 100 years and older (6,592 per 10,000 cases) is 2.415 times higher than in those aged 50–59 (27 per 10,000 cases). The number of people living with dementia approximately doubles every five years. The prevalence was greater in women than in men (788 cases versus 561 cases per 10,000 persons) in overall analysis. In individuals aged 60 to 69 years, AD prevalence in females was 1.9 times greater than that in males (108 cases versus 56 cases per 10,000 persons), while the prevalence of VaD was 1.8 times greater in males than in females (56 cases versus 32 cases per 10,000 persons). Prevalence rate was higher in Europe and North America than in Asia, Africa, and South America. Show more

Keywords: Alzheimer’s disease, dementia, prevalence, vascular dementia

DOI: 10.3233/JAD-191092

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Cogliati, Sebastián | Clementi, Victoria | Francisco, Marcos | Crespo, Cira | Argañaraz, Federico | Grau, Roberto

Article Type: Research Article

Abstract: Multiple causes, apart from genetic inheritance, predispose to the production and aggregation of amyloid-β (Aβ) peptide and Alzheimer’s disease (AD) development in the older population. There is currently no therapy or medicine to prevent or delay AD progression. One novel strategy against AD might involve the use of psychobiotics, probiotic gut bacteria with specific mental health benefits. Here, we report the neuronal and behavioral protective effects of the probiotic bacterium Bacillus subtilis in a Caenorhabditis elegans AD model. Aging and neuronal deterioration constitute important risk factors for AD development, and we showed that B. subtilis significantly delayed …both detrimental processes in the wild-type C. elegans strain N2 compared with N2 worms colonized by the non-probiotic Escherichia coli OP50 strain. Importantly, B. subtilis alleviated the AD-related paralysis phenotype of the transgenic C. elegans strains CL2120 and GMC101 that express, in body wall muscle cells, the toxic peptides Aβ3-42 and Aβ1-42 , respectively. B. subtilis -colonized CL2355 worms were protected from the behavioral deficits (e.g., poor chemotactic response and decreased body bends) produced by pan-neuronal Aβ1-42 expression. Notably, B. subtilis restored the lifespan level of C. elegans strains that express Aβ to values similar to the life expectancy of the wild-type strain N2 fed on E. coli OP50 cells. The B. subtilis proficiencies in quorum-sensing peptide (i.e., the Competence Sporulation Factor, CSF) synthesis and gut-associated biofilm formation (related to the anti-aging effect of the probiotic) play a crucial role in the anti-AD effects of B. subtilis . These novel results are discussed in the context of how B. subtilis might exert its beneficial effects from the gut to the brain of people with or at risk of developing AD. Show more

Keywords: Aβ42 , Alzheimer’s disease, B. subtilis , healthy aging, neuroprotection, probiotics, psychobiotics

DOI: 10.3233/JAD-190837

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Rundek, Tatjana | Gardener, Hannah | Dias Saporta, Anita Seixas | Loewenstein, David A. | Duara, Ranjan | Wright, Clinton B. | Dong, Chuanhui | Levin, Bonnie | Elkind, Mitchell S.V. | Sacco, Ralph L.

Article Type: Research Article

Abstract: Background: Modifiable vascular risk factors (VRF) have been implicated in cognitive impairment. Objective: We compared the prediction of cognitive performance between the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score, a validated tool to estimate dementia risk using VRF, and the Northern Manhattan Study (NOMAS) global vascular risk score (GVRS), created to predict vascular events. Methods: The CAIDE and GVRS scores were calculated based on baseline VRF among 1,290 stroke-free participants in the prospective population-based NOMAS MRI cohort (mean age 64±8 years, 60% women; 66% Hispanic, 17% Black, 15% White; 46% completed …high school). Domain-specific Z-scores were derived for episodic and semantic memory, executive function, and processing speed, and averaged to calculate global cognition. Results: The CAIDE score was associated with worse global cognition at initial assessment (Beta per SD = –0.347, p  < 0.0001), and with greater decline over time (Beta per SD = –0.033, p  = 0.02). These associations were largely due to age and education, and the association with cognitive decline was not significant after adjusting for age, sex, and education. The GVRS was inversely associated with global cognition at initial testing (Beta per SD = –0.247, p  < 0.0001) and greater decline over time (Beta per SD = –0.127, p  < 0.0001), which persisted after adjusting for sociodemographics. The associations for both scores with initial cognitive performance were driven by executive function and processing speed, and the GVRS was associated with decline in episodic memory and processing speed. Conclusions: The GVRS was a stronger predictor of cognitive decline than the CAIDE in a multi-ethnic urban cohort. The inclusion of glucose and smoking in the GVRS, which are absent in CAIDE, likely explains the better performance of the GVRS. Show more

Keywords: Cognition, dementia, epidemiology, risk score, vascular risk factors

DOI: 10.3233/JAD-190925

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Liu, Hanxiang | Reynolds, Gavin P. | Wei, Xianwen

Article Type: Research Article

Abstract: Uric acid (UA) is a major contributor to naturally-occurring antioxidant activity and is thought to have protective effects against neurodegenerative processes. However, UA is also implicated as a risk factor in vascular, including cerebrovascular, disease. Its association with, and role in, dementia and its component diseases including Alzheimer’s disease (AD) and vascular dementia (VaD) remains unclear and inconsistently studied. Changes in blood lipids, particularly cholesterol measures, have also been implicated in dementias although the relationship or interactions with UA have been little studied. We have measured plasma UA and lipids taken from 187 subjects first attending a general hospital …neurology department for symptoms associated with dementia, and from a series of 79 healthy control subjects. Diagnoses of AD and VaD were made following neuroimaging; laboratory measures were compared between dementia and control groups and between AD and VaD subgroups. No overall change in UA was seen in dementia, although a substantial and highly significant reduction was found in the AD patients. Reduced values in total cholesterol, HDL, and LDL were found in dementia, independent of statin treatment. Further investigation found a significant reduction of HDL only in the VaD group, while total cholesterol was significantly reduced in both AD and VaD subjects. These findings indicate that in our Chinese sample, UA deficits are specifically associated with AD, while deficits in HDL cholesterol found in dementia tend to be greater in VaD. Show more

Keywords: Alzheimer’s disease, antioxidant, cerebrovascular disease, cholesterol, HDL, LDL, neurodegeneration, uric acid, vascular dementia

DOI: 10.3233/JAD-191111

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019