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

Authors: Xiao, Shuo | Song, Lin-Lin | Li, Jiang-Tao | Wang, He | Yu, Na | Wang, Zi-Qi | Zhang, Ying | He, Jin-Sheng | Hung, Tao

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia, characterized by amyloid-β peptide (Aβ) aggregates, phosphorylated tau protein (p -tau), and progressive neurodegeneration. Amyloid-β peptide 42 (Aβ42 ) is considered an early trigger of AD pathogenesis. We have previously reported that Aβ N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aβ in brain of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1Δ E9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 treatment …group had a shorter escape latency than the control groups in the place navigation test and the probe trial (p  < 0.05). Moreover, immunohistochemistry showed decreased levels of both Aβ and p -tau in the brains of APP/PS1 mice. Regarding Aβ levels, western blot results showed that Aβ42 oligomer (p  < 0.01) but not Aβ40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231 ) (p  < 0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (p  < 0.01) density of synapses and a reduction of abnormally enlarged mitochondria (p  < 0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, immunotherapy, Morris water maze test, phosphorylated tau protein, synapse

DOI: 10.3233/JAD-190874

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

Authors: Rogers, Nicole K. | Romero, Cesar | SanMartín, Carol D. | Ponce, Daniela P. | Salech, Felipe | López, Mercedes N. | Gleisner, Alejandra | Tempio, Fabián | Behrens, María I.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the adult population. There is evidence of an inverse epidemiological relationship between AD and cancer, another prevalent age-related disease. This has led to hypothesize that there could be a common biological mechanism, deregulated in opposite directions that might explain the phenomenon of mutual protection. The immunological system and its regulatory checkpoints are good candidates to explain why having survived a cancer could protect from developing AD. During cancerous growth, the neoplastic cells induce immune tolerance to block the host’s immunity system that would prevent tumor growth. This has led to …the development of drugs that block distinct immune checkpoints, such as Programmed Death 1 (PD-1) and its major ligand PD-L1, that have shown great promise in treating diverse types of cancer. We propose that in those individuals who survived a cancer, the immune system is left in a state of diminished tolerance or proinflammatory systemic milieu, after its successful attempt to fight the cancer, that protects them from developing AD. Show more

Keywords: Alzheimer’s disease, cancer, immune checkpoint, inflammation

DOI: 10.3233/JAD-190839

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Wang, Yan-Li | Chen, Wei | Cai, Wen-Jie | Hu, Hao | Xu, Wei | Wang, Zuo-Teng | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI-2 dataset from August 2010 to May 2017. Cross-sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI-EF), and memory function (ADNI-Mem). The association analyses were …performed using multiple linear regression models, linear mixed models, Spearman rank correlation, and Kaplan-Meier survival curves. The volumes of WMHs were greater in patients with Alzheimer’s disease (AD) dementia compared with controls (p  < 0.001) and mild cognitive impairment (p  = 0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS-Cog13 and ADNI-EF (p  = 0.029; p  = 0.003) at baseline and MMSE, MoCA, CDRSB, ADAS-Cog13, FAQ, and ADNI-Mem (overall p  < 0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ɛ 4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction, and diagnosis. Additionally, the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI-EF, and ADNI-Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia. The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, cognition, white matter hyperintensities

DOI: 10.3233/JAD-191005

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

Authors: Wu, Wanqing | Ding, Ding | Zhao, Qianhua | Wang, Ruru | Liang, Xiaoniu | Xiao, Zhenxu | Luo, Jianfeng | Guo, Qihao | Hong, Zhen

Article Type: Research Article

Abstract: Background: There is significant evidence that physical activity has profound effects on the neurochemistry and plasticity of the brain and may prevent cognitive decline. Objective: This study aimed to determine the association between physical activity and incident dementia among older Chinese adults. Methods: In the prospective phase of the Shanghai Aging Study, 1,648 community-dwellers aged 60 years or older were followed for an average of 5 years. Their physical activity was assessed based on questionnaires. The physical activities were further transformed into metabolic equivalent values. A consensus diagnosis of incident dementia was ascertained based on medical, …neurological, and neuropsychological data and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Results: We identified 166 incident dementia cases; the incidence rate was 19.4 per 1000 person-years. A multivariate Cox regression model indicated that compared to low levels of physical activity, medium-to-high levels of physical activity were associated with a reduced risk of dementia (hazard ratio, 95% confidence interval = 0.62, 0.44–0.89) after adjusting for age, sex, years of education, apolipoprotein E ɛ 4, and other confounders. Conclusion: Our findings demonstrate that medium-to-high level of physical activity is protective against dementia in older adults. Show more

Keywords: Chinese, cognition, cohort studies, dementia, incidence, physical activity

DOI: 10.3233/JAD-190937

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Fani, Lana | Hilal, Saima | Sedaghat, Sanaz | Broer, Linda | Licher, Silvan | Arp, Pascal P. | van Meurs, Joyce B.J. | Ikram, M. Kamran | Ikram, M. Arfan

Article Type: Research Article

Abstract: There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer’s disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of …Alzheimer’s disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer’s disease. We found a U-shaped association between telomere length and risk of Alzheimer’s disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13–2.23) for the lowest tertile and 1.47 (1.03–2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer’s disease in the general population. Show more

Keywords: Alzheimer’s disease, dementia, population-based, prospective cohort study, telomere

DOI: 10.3233/JAD-190759

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Kumar, Rajnish | Pavlov, Pavel F. | Winblad, Bengt

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-β (Aβ) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. Recently, we have shown that GMP-1, a 2-(methoxymethyl)pyrimido [1, 2-a ] benzimidazol-4-ol, protects mitochondrial function in drosophila and mice models of AD, and improved memory and behavior indicating neuroprotective effect of GMP-1 treatment. Here, we have found that GMP-1 specifically binds to copper and zinc, …metals that are dysregulated in AD brain. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aβ fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aβ. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models. Show more

Keywords: Alzheimer’s disease, metal chelation, multi-target-directed ligands, treatment strategies

DOI: 10.3233/JAD-190695

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

Authors: Fransquet, Peter D. | Ritchie, Karen | Januar, Vania | Saffery, Richard | Ancelin, Marie-Laure | Ryan, Joanne

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n  = 769) and buccal samples during follow-up (n  = 1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ 4. Multivariable logistic regression analyses determined the association between BDNF methylation and …both prevalent and incident dementia. Adjustment for gender, age, education, APOE ɛ 4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ–0.5%, 95% CI:–0.9,–0.04, p  = 0.03, p  = 0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p  = 0.02, p  = 0.14 adjusted and Δ–1.5%, OR:0.85, SE:0.06, p  = 0.03, p  = 0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r =–0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing. Show more

Keywords: BDNF, biomarkers, blood, dementia, DNA methylation, epigenetics

DOI: 10.3233/JAD-190738

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

Authors: Zuelsdorff, Megan | Okonkwo, Ozioma C. | Norton, Derek | Barnes, Lisa L. | Graham, Karen L. | Clark, Lindsay R. | Wyman, Mary F. | Benton, Susan F. | Gee, Alexander | Lambrou, Nickolas | Johnson, Sterling C. | Gleason, Carey E.

Article Type: Research Article

Abstract: Background: It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer’s and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. Objective: We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Methods: Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life …event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. Results: African Americans (N = 50) reported more stressful life events than Whites (N = 1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. Conclusions: Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course. Show more

Keywords: African Americans, Alzheimer’s disease, life course, stress

DOI: 10.3233/JAD-190439

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Fuller-Thomson, Esme | Deng, ZhiDi

Article Type: Research Article

Abstract: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease whose clinical presentation mimics that of Alzheimer’s disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what they are …today. Thus, each successive birth cohort entering old age has had less cumulative life exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE. Show more

Keywords: Alzheimer’s disease, FTLD with TDP-43 pathology, lead poisoning, nervous system, TDP-43 proteinopathies, tetraethyl lead

DOI: 10.3233/JAD-190943

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Wang, Longcai | Qiao, Yanchun | Zhang, Haihua | Zhang, Yan | Hua, Jiao | Jin, Shuilin | Liu, Guiyou

Article Type: Research Article

Abstract: Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer’s disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin …D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and to forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents. Show more

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D

DOI: 10.3233/JAD-190713

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

Authors: He, Jin-Ting | Zhao, Xin | Xu, Lei | Mao, Cui-Ying

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and …microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction. Show more

Keywords: Alzheimer’s disease, amyloid-β , blood-brain barrier, inflammation, ischemia, metabolic syndrome, oxidative stress, p-tau

DOI: 10.3233/JAD-190764

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2019

Authors: Yoon, Bora | Choi, Seong Hye | Jeong, Jee Hyang | Park, Kyung Won | Kim, Eun-Joo | Hwang, Jihye | Jang, Jae-Won | Kim, Hee Jin | Hong, Jin Yong | Lee, Jong-Min | Kang, Ju-Hee | Yoon, Soo Jin

Article Type: Research Article

Abstract: Background: Balance impairments are common in patients with Alzheimer’s disease (AD) dementia. Objective: We sought to determine the stage along the AD spectrum during which balance impairments appear and identify factors associated with a decline in balance function. Methods: Our cross-sectional study included 295 participants; 71 were cognitively normal, 96 reported subjective cognitive decline (SCD), 72 had amnestic mild cognitive impairment (MCI), and 56 had AD dementia. The balance and mobility function was assessed using the Timed Up and Go test (TUG) and the One-Leg Standing Test (OLST). Results: Participants in the MCI and …AD dementia groups were older than those in the cognitively normal and SCD groups. TUG and OLST test scores were linearly correlated with Mini-Mental Status Examination-Korean Version score (MMSE-KC). TUG score increased with greater AD spectrum severity (all p  < 0.001), whereas OLST score showed a precipitous impairment starting in the SCD group (all p  < 0.001), even after adjusting for age, sex, MMSE-KC, Geriatric depression scale, and body mass index. Based on subgroup analyses, in females and apolipoprotein E (APOE ) ɛ 4 carriers, there was significant balance/mobility impairment in the SCD group when compared to the CN group. Conclusion: Our results suggest that balance/mobility is related to cognitive function and that balance/mobility impairment can be observed beginning in the SCD stage. Furthermore, CN females and APOE ɛ 4 carriers had better balance and mobility when compared to females and APOE ɛ 4 carriers along the ADD spectrum/with cognitive impairment respectively. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cognition, female, postural balance, subjective cognitive decline

DOI: 10.3233/JAD-190601

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Naismith, Sharon L. | Duffy, Shantel L. | Cross, Nathan | Grunstein, Ron | Terpening, Zoe | Hoyos, Camilla | D’Rozario, Angela | Lagopoulos, Jim | Osorio, Ricardo S. | Shine, James M. | McKinnon, Andrew C.

Article Type: Research Article

Abstract: Background: Obstructive sleep apnea is associated with an increased risk of developing mild cognitive impairment and dementia. Intermittent nocturnal hypoxemia in obstructive sleep apnea is associated with brain changes in key regions that underpin memory. Objective: To determine whether older adults with severe nocturnal hypoxemia would exhibit reduced functional connectivity within these regions, with associated deficits in memory. Methods: Seventy-two participants 51 years and over underwent polysomnography with continuous blood oxygen saturation recorded via oximetry. The oxygen desaturation index (ODI, 3% dips in oxygen levels per hour) was the primary outcome measure. ODI was split into …tertiles, with analyses comparing the lowest and highest tertiles (N = 48). Thirty-five of the 48 participants from these two tertiles had mild cognitive impairment. Participants also underwent resting-state fMRI and comprehensive neuropsychological, medical, and psychiatric assessment. Results: The highest ODI tertile group demonstrated significantly reduced connectivity between the left and right parahippocampal cortex, relative to the lowest ODI tertile group (t(42) = –3.26, p  = 0.041, beta = –1.99).The highest ODI tertile group also had poorer working memory performance. In the highest ODI tertile group only, higher left-right parahippocampal functional connectivity was associated with poorer visual memory recall (between-groups z = –2.93, p  = 0.0034). Conclusions: Older adults with severe nocturnal hypoxemia demonstrate impaired functional connectivity in medial temporal structures, key regions involved in sleep memory processing and implicated in dementia pathophysiology. Oxygen desaturation and functional connectivity in these individuals each relate to cognitive performance. Research is now required to further elucidate these findings. Show more

Keywords: Default mode network, memory, mild cognitive impairment, obstructive sleep apnea

DOI: 10.3233/JAD-190747

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

Authors: de Oliveira, Jade | Engel, Daiane F. | de Paula, Gabriela C. | Melo, Helen M. | Lopes, Samantha C. | Ribeiro, Camila Tiefensee | Delanogare, Eslen | Moreira, José Claudio Fonseca | Gelain, Daniel Pens | Prediger, Rui D. | Gabilan, Nelson H. | Moreira, Eduardo Luiz G. | Ferreira, Sergio T. | de Bem, Andreza F.

Article Type: Research Article

Abstract: Familial hypercholesterolemia (FH) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. FH patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/- ), an animal model of FH. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer’s disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein …1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/- mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels. Show more

Keywords: Amyloid-β, apoptosis, familial hypercholesterolemia, LDLr-/- mice, memory impairment

DOI: 10.3233/JAD-190742

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Eckerström, Carl | Eckerström, Marie | Göthlin, Mattias | Molinder, Anna | Jonsson, Michael | Kettunen, Petronella | Svensson, Johan | Rolstad, Sindre | Wallin, Anders

Article Type: Research Article

Abstract: Background: Research has shown that mixed dementia is more common than previously believed but little is known of its early stages. Objective: To examine if incipient mixed dementia can be differentiated from incipient Alzheimer’s disease (AD) and subcortical ischemic vascular dementia (SVD) using neuropsychological tests, cerebrospinal fluid (CSF) markers, and magnetic resonance imaging markers. Methods: We included 493 patients and controls from the Gothenburg MCI study and used the dementia groups for marker selection (CSF total-tau (T-tau), phospho-tau (P-tau), and amyloid-β42 (Aβ42 ), 11 neuropsychological tests, and 92 regional brain volumes) and to obtain cut-off …values which were then applied to the MCI groups. Results: Incipient mixed dementia was best differentiated from incipient AD by the Word fluency F-A-S test and the Trail making test A. CSF T-tau, P-tau, and Aβ42 differentiated incipient mixed dementia from incipient SVD. Conclusion: Incipient mixed dementia is characterized by an AD-like biomarker profile and an SVD-like cognitive profile. Incipient mixed dementia can be separated from incipient AD and incipient SVD using CSF markers and cognitive testing. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, magnetic resonance imaging, mild cognitive impairment, neuropsychological test, vascular dementia

DOI: 10.3233/JAD-190651

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

Authors: Emrani, Sheina | Lamar, Melissa | Price, Catherine C. | Wasserman, Victor | Matusz, Emily | Au, Rhoda | Swenson, Rodney | Nagele, Robert | Heilman, Kenneth M. | Libon, David J.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called ‘mixed’ dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called ‘pure’ AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological …underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other. Show more

Keywords: Alzheimer’s disease, episodic memory, executive control, mixed dementia, vascular dementia

DOI: 10.3233/JAD-190654

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

Authors: Carbonell, Felix | Zijdenbos, Alex P. | Bedell, Barry J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOE ɛ 4 genotype. It has been reported that APOE ɛ 4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer’s disease (AD) pathology. Objective: We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI). …Methods: We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18 F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18 F]florbetapir PET, from the Alzheimer’s Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ. Results: From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition. Conclusions: Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOE ɛ 4 genotype or global measures of Aβ burden. Show more

Keywords: Alzheimer’s disease, amyloid-β , cross-correlation, glucose metabolism, positron emission tomography, singular value decomposition

DOI: 10.3233/JAD-190560

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Tarumi, Takashi | Thomas, Binu P. | Tseng, Benjamin Y. | Wang, Ciwen | Womack, Kyle B. | Hynan, Linda | Lu, Hanzhang | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Cerebral white matter (WM) represents the structural substrate of neuronal communications which is damaged by Alzheimer’s disease (AD). Aerobic exercise training (AET) may improve WM integrity in cognitively normal older adults, but its efficacy remains unknown in patients with amnestic mild cognitive impairment (MCI), a prodromal phase of AD dementia. Therefore, we conducted a proof-of-concept study that randomized 70 amnestic MCI patients to a 1-year program of AET or a non-aerobic stretching and toning (SAT), active control group. Thirty-six patients completed both baseline and follow-up MRI scans, and cerebral WM integrity was measured by WM lesion volume and diffusion characteristics …using fluid-attenuated-inversion-recovery and diffusion tensor imaging respectively. Peak oxygen uptake (VO2peak ) and neuropsychological function were also measured. At baseline and 1-year follow-up, WM lesion volume and diffusion characteristics were similar between the AET and SAT groups, although VO2peak significantly improved after AET. The AET group showed slight improvement in neuropsychological performance. When analyzing individual data, tract-based spatial statistics demonstrated that VO2peak improvements are associated with attenuated elevations in mean and axial diffusivities, particularly the anterior WM fiber tracts (e.g., genu of corpus callosum). In patients with amnestic MCI, we found that although AET intervention did not improve WM integrity at group level analysis, individual cardiorespiratory fitness gains were associated with improved WM tract integrity of the prefrontal cortex. Show more

Keywords: Aerobic exercise, cardiorespiratory fitness, diffusion tensor imaging, mild cognitive impairment, white matter integrity

DOI: 10.3233/JAD-190875

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Brown, Monique J. | Patterson, Robert

Article Type: Research Article

Abstract:  The risk of dementia and mild cognitive impairment between older adults in same-sex relationships and those in opposite-sex relationships have been found to be statistically not different. However, studies examining subjective cognitive decline (SCD) among sexual and gender minority populations (SGM) are lacking. The primary objective was to determine if SGM report greater SCD compared to non-SGM populations in a U.S. population-based sample of non-institutionalized adults aged 45 and older. The secondary objective was to assess the association between gender and SCD. Cross-sectional data were obtained from the 2016 Behavioral Risk Factor Surveillance System (n  = 36,734). There were 1,094 SGM …adults in the sample. Descriptive statistics examined sociodemographic characteristics and their distribution by SCD and SGM status. Crude and multivariable logistic regression models were used to determine the association between SGM status, gender, and SCD. Adjusted models controlled for age, race/ethnicity, income, education, employment, marital status, depression, and diabetes. Statistically significant differences in SGM status and SCD existed by age, race/ethnicity, education, employment, marital status, and depression. Differences in SCD also existed by income and diabetes status. There was no statistically significant association between SGM status and SCD (OR: 0.88; 95% CI: 0.63–1.24). However, men had 64% higher odds (OR: 1.64; 95% CI: 1.44–1.88) of reporting SCD compared to women. Future studies examining the potential reasons for this null association, including resilience and/or premature aging are warranted. Future research assessing potential reasons for gender differences in SCD, whether physiological or environmental, is also needed. Show more

Keywords: Cognitive dysfunction, GLBT persons, health status disparities, men, women

DOI: 10.3233/JAD-190869

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

Authors: Bouji, Marc | Lecomte, Anthony | Gamez, Christelle | Blazy, Kelly | Villégier, Anne-Sophie

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of neurodegenerative disease leading to dementia. Several studies suggested that mobile phone radiofrequency electromagnetic field (RF-EMF) exposures modified AD memory deficits in rodent models. Objective: Here we aimed to test the hypothesis that RF-EMF exposure may modify memory through corticosterone and oxidative stress in the Samaritan rat model of AD. Methods: Long-Evans male rats received intracerebroventricular infusion with ferrous sulphate, amyloid-beta 1-42 peptide, and buthionine-sufloximine (AD rats) or with vehicle (control rats). To mimic cell phone use, RF-EMF were exposed to the head for 1 month (5 …days/week, in restraint). To look for hazard thresholds, high brain averaged specific absorption rates (BASAR) were tested: 1.5 W/Kg (15 min), 6 W/Kg (15 min), and 6 W/Kg (45 min). The sham group was in restraint for 45 min. Endpoints were spatial memory in the radial maze, plasmatic corticosterone, heme oxygenase-1 (HO1), and amyloid plaques. Results: Results indicated similar corticosterone levels but impaired memory performances and increased cerebral staining of thioflavine and of HO1 in the sham AD rats compared to the controls. A correlative increase of cortical HO1 staining was the only effect of RF-EMF in control rats. In AD rats, RF-EMF exposures induced a correlative increase of hippocampal HO1 staining and reduced corticosterone. Discussion: According to our data, neither AD nor control rats showed modified memory after RF-EMF exposures. Unlike control rats, AD rats showed higher hippocampal oxidative stress and reduced corticosterone with the higher BASAR. This data suggests more fragility related to neurodegenerative disease toward RF-EMF exposures. Show more

Keywords: Alzheimer’s disease, corticosterone, memory, mobile phone, oxidative stress, radiofrequency

DOI: 10.3233/JAD-190593

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

Authors: Reimand, Juhan | Groot, Colin | Teunissen, Charlotte E. | Windhorst, Albert D. | Boellaard, Ronald | Barkhof, Frederik | Nazarenko, Sergei | van der Flier, Wiesje M. | van Berckel, Bart N.M. | Scheltens, Philip | Ossenkoppele, Rik | Bouwman, Femke

Article Type: Research Article

Abstract: Background: Amyloid-β PET and cerebrospinal fluid (CSF) Aβ42 are considered interchangeable for clinical diagnosis of Alzheimer’s disease. Objective: To explore the clinical reasoning for requesting additional amyloid-β PET after performing CSF biomarkers. Methods: We retrospectively identified 72 memory clinic patients who underwent amyloid-β PET after CSF biomarkers analysis for clinical diagnostic evaluation between 2011 and 2019. We performed patient chart reviews to identify factors which led to additional amyloid-β PET. Additionally, we assessed accordance with appropriate-use-criteria (AUC) for amyloid-β PET. Results: Mean patient age was 62.0 (SD = 8.1) and mean Mini-Mental State Exam score …was 23.6 (SD = 3.8). CSF analysis conflicting with the clinical diagnosis was the most frequent reason for requesting an amyloid-β PET scan (n  = 53, 74%), followed by incongruent MRI (n  = 16, 22%), unusual clinical presentation (n  = 11, 15%) and young age (n  = 8, 11%). An amyloid-β PET scan was rarely (n  = 5, 7%) requested in patients with a CSF Aβ+/tau+ status. Fifteen (47%) patients with a post-PET diagnosis of AD had a predominantly non-amnestic presentation. In n  = 11 (15%) cases, the reason that the clinician requested amyloid-β was not covered by AUC. This happened most often (n  = 7) when previous CSF analysis did not support current clinical diagnosis, which led to requesting amyloid-β PET. Conclusion: In this single-center study, the main reason for requesting an amyloid-β PET scan after performing CSF biomarkers was the occurrence of a mismatch between the primary clinical diagnosis and CSF Aβ/tau results. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography, tau proteins

DOI: 10.3233/JAD-190836

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

Authors: Schnaider, Lee | Arnon, Zohar | Gazit, Ehud

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is the most common cause of dementia. Despite substantial investment in research, there are no current effective treatments to prevent or delay the onset and development of AD and the exact molecular mechanism of AD pathogenesis is still not fully understood. Researchers have long suspected that microbial infections may play a role in AD; however, this hypothesis has been greatly overlooked for decades, only recently gaining a traction and recognition within the broad scientific community due to new overwhelming evidence on the association of various pathogenic microbes and AD. Here, we provide our perspective on the significance …of these findings, which shed light on the interplay between molecular self-assembly, neurodegeneration, and antimicrobial peptides, as well as propose an amendment to the amyloid cascade hypothesis. It is important to note that this association does not yet prove a causal link, but these reports warrant a thorough investigation into the microbial infection-AD hypothesis which might in turn deliver the elusive therapeutic target the scientific community has been so desperately searching for. Show more

Keywords: Alzheimer’s disease, antimicrobial peptides, infectious diseases, neurodegeneration, self-assembly

DOI: 10.3233/JAD-190765

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Francis, Nikita | Robison, Lisa S. | Popescu, Dominique L. | Michaelos, Michalis | Hatfield, Joshua | Xu, Feng | Zhu, Xiaoyue | Davis, Judianne | Anderson, Maria E. | Anderson, Brenda J. | Van Nostrand, William E. | Robinson, John K.

Article Type: Research Article

Abstract: Exercise has been shown to be protective against the risk of dementias, including Alzheimer’s disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study …is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0 h, 1 h, 3 h, and 12 h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities. Show more

Keywords: Amyloid, behavior, dementia, exercise, transgenic

DOI: 10.3233/JAD-190810

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

Authors: Feng, Maoxiao | Cui, Donghai | Li, Yi | Shi, Jian | Xiang, Lan | Bian, Hong | Ma, Zhiyong | Xia, Wen | Wei, Guangwei

Article Type: Research Article

Abstract: The cell surface level of apolipoprotein E receptor 2 (ApoER2) increases by cyclic transport of ApoER2 and then activates Reelin signaling pathway to exert neuroprotective function in AD. ApoER2 ligand Apolipoprotein E4 (ApoE4) inhibits the recycling of ApoER2 to the cell surface rendering neurons unresponsive to Reelin. Carnosic acid (CA) is proven to possess neuroprotective and neurotrophic functions in Alzheimer’s disease (AD) mouse model. However, there are no reports about how ApoE4 impairs the recycling of ApoER2 and if CA can affect the cyclic transport of ApoER2. In this study, we demonstrated that ApoE4 attenuates the binding of sorting nexin …17 (SNX17) to ApoER2 and inhibits the recycling of ApoER2, resulting in decreased cell surface level of ApoER2. Further, we found that CA enhances the binding of SNX17 to ApoER2, counteracts the negative effects of ApoE4 on the cell surface level of ApoER2 to reverse the ApoE4-induced reduction in Reelin signaling activation by increasing the phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) and cAMP-response element-binding protein (CREB) and the expression of Gria2. Thus, CA promotes neurite growth inhibited by ApoE4. Our work suggests that CA may be a potential approach to attenuate the risk of ApoE4-associated AD. Show more

Keywords: Apolipoprotein E receptor 2, Apolipoprotein E4, carnosic acid, Reelin signaling pathway, sorting nexin 17

DOI: 10.3233/JAD-190914

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Yin, Ping | Wang, Shuang | Wei, Yafen | Wang, Xu | Zhang, Jingdian | Yin, Xiang | Feng, Jiachun | Zhu, Mingqin

Article Type: Research Article

Abstract: Inflammation resolution is regulated by specialized pro-resolving lipid mediators (SPMs) and the levels of SPMs are found decreased in Alzheimer’s disease (AD) brain. We have previously found that one of the SPMs, Maresin1 (MaR1), improved neuronal survival and increase microglial phagocytosis of amyloid-β 1-42 (Aβ42 ); however, the mechanisms underlying the protective mechanism remain further investigation. We aim to investigate the effects of MaR1 on microglial chemotaxis and activation in this study. Both indirect and direct primary neuron and microglia co-culture system was used in this study. Our results showed MaR1 downregulated the increased microglial chemotaxis induced by Aβ42 . …The microglial inactivation marker CD200R was downregulated by Aβ42 and upregulated by MaR1. Pro-inflammatory cytokines secretion such as tumor necrosis factor (TNF)-α were increased by Aβ42 and these changes were revised by MaR1 treatment. In addition, the levels of chemokine monocyte chemoattractant protein (MCP)-1 were increased while the levels of anti-inflammatory factor IL-10 secretion were decreased by Aβ42 , and these changes were abolished by MaR1 treatment. Moreover, by proteomics analysis, we identified cell signaling pathways affected by MaR1 were not only limited to inflammation-related pathways such as P38, but also in pathways involved in cell survival, autophagy, axon formation, and apoptosis, including PI3K/AKT, mTOR, ERK, caspase3, Cdc42, and p75NTR. In conclusion, MaR1 promoted inflammation resolution by inhibiting chemotaxis and regulating activation of microglia. MaR1 played a neuroprotective role by affecting cell signaling pathways involving inflammation, cell survival, autophagy, axon formation, and apoptosis inhibition. Show more

Keywords: Alzheimer’s disease, chemotaxis, Maresin1, microglia, proteomics, resolution of inflammation

DOI: 10.3233/JAD-190682

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Robinson, Andrew C. | Chew-Graham, Stephen | Davidson, Yvonne S. | Horan, Michael A. | Roncaroli, Federico | Minshull, James | du Plessis, Daniel | Pal, Piyali | Payton, Antony | Pendleton, Neil | Mann, David M.A.

Article Type: Research Article

Abstract: In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie , to collect brains from both demented and non-demented individuals for …the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer’s disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more ‘polarized’, being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had ‘naturally’ evolved in the brains of both demented and non-demented participants. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, cohort studies, dementia, longitudinal studies, neuropathology

DOI: 10.3233/JAD-190580

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

Authors: Reas, Emilie T. | Hagler Jr. , Donald J. | Kuperman, Joshua M. | Wierenga, Christina E. | Galasko, Douglas | White, Nathan S. | Dale, Anders M. | Banks, Sarah J. | McEvoy, Linda K. | Brewer, James B.

Article Type: Research Article

Abstract: Background: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer’s disease, their independent or synergistic effects on cognitive decline are unclear. Objective: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. Methods: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer’s disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations …of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. Results: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. Conclusion: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognitive decline, dementia, diffusion imaging, magnetic resonance imaging, memory, mild cognitive impairment

DOI: 10.3233/JAD-190871

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

Authors: Chen, Haoyu | Liang, Lu | Xu, Hua | Xu, Jia | Yao, Leyi | Li, Yanling | Tan, Yufan | Li, Xiaofen | Huang, Qingtian | Yang, Zhenjun | Wu, Jiawen | Chen, Jinghong | Huang, Hongbiao | Wang, Xuejun | Zhang, Chang-E. | Liu, Jinbao

Article Type: Research Article

Abstract: Hyperbilirubinemia may increase the risk of Alzheimer’s disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased Aβ production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several …protein kinases (GSK-3β, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of AβPP γ -secretase PS2 and decreased the expression of α -secretase ADAM17, which were positively correlated with Aβ production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD. Show more

Keywords: AβPP, α-secretase, Alzheimer’s disease, amyloid-β, bilirubin, γ-secretase, protein kinase, spatial learning and memory injury, tau hyperphosphorylation, tau protein

DOI: 10.3233/JAD-190945

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Agca, Cansu | Klakotskaia, Diana | Stopa, Edward G. | Schachtman, Todd R. | Agca, Yuksel

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most devastating and costly diseases, and prevalence of AD increases with age. Furthermore, females are twice as likely to suffer from AD compared to males. The cessation of reproductive steroid hormone production during menopause is hypothesized to cause this difference. Two rodent AD models, APP21 and APP+PS1, and wild type (WT) rats underwent an ovariectomy or sham surgery. Changes in learning and memory, brain histology, amyloid-β (Aβ) deposition, levels of mRNAs involved in Aβ production and clearance, and synaptic and cognitive function were determined. Barnes maze results showed that regardless of ovariectomy status, …APP+PS1 rats learned slower and had poor memory retention. Ovariectomy caused learning impairment only in the APP21 rats. High levels of Aβ42 and very low levels of Aβ40 were observed in the brain cortices of APP+PS1 rats indicating limited endogenous PS1. The APP+PS1 rats had 43-fold greater formic acid soluble Aβ42 than Aβ40 at 17 months. Furthermore, levels of formic acid soluble Aβ42 increased 57-fold in ovariectomized APP+PS1 rats between 12 and 17 months of age. The mRNA encoding Grin1 significantly decreased due to ovariectomy whereas levels of Bace1, Chat, and Prkcb all decreased with age. The expression levels of mRNAs involved in Aβ degradation and AβPP cleavage (Neprilysin, Ide, Adam9, and Psenen) were found to be highly correlated with each other as well as hippocampal Aβ deposition. Taken together, these results indicate that both ovariectomy and genotype influence AD markers in a complex manner. Show more

Keywords: Alzheimer’s disease, amyloid-β , estrogen, gene expression, ovarian hormones, ovariectomy, progesterone, rat, transgenic

DOI: 10.3233/JAD-190935

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Bastrup, Joakim | Kastaniegaard, Kenneth | Asuni, Ayodeji A. | Volbracht, Christiane | Stensballe, Allan

Article Type: Research Article

Abstract: Amyloid plaques are one of the hallmarks of Alzheimer’s disease (AD). The main constituent of amyloid plaques is amyloid-β peptides, but a complex interplay of other infiltrating proteins also co-localizes. We hypothesized that proteomic analysis could reveal differences between amyloid plaques and adjacent control tissue in the transgenic mouse model of AD (APPPS1-21) and in similar regions from non-transgenic littermates. Our microproteomic strategy included isolation of regions of interest by laser capture microdissection and analysis by liquid chromatography mass spectrometry-based label-free relative quantification. We consistently identified 183, 224, and 307 proteins from amyloid plaques, adjacent control and non-tg samples, respectively. …Pathway analysis revealed 27 proteins that were significantly regulated when comparing amyloid plaques and corresponding adjacent control regions. We further elucidated that co-localized proteins were subjected to post-translational modifications and are the first to report 193 and 117 unique modifications associated to amyloid plaques and adjacent control extracts, respectively. The three most common modifications detected in proteins from the amyloid plaques were oxidation, deamidation, and pyroglutamylation. Together, our data provide novel information about the biological processes occurring within and around amyloid plaques in the APPPS1-21 mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid plaque, mass spectrometry, microdissection, pyroglutamate

DOI: 10.3233/JAD-190652

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Chosy, E. Julia | Gross, Noele | Meyer, Marnie | Liu, Catherine | Edland, Steven D. | Launer, Lenore J. | White, Lon R.

Article Type: Research Article

Abstract: Background: Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes. Objective: Examine the relationship between head injury and later cognitive impairment. Methods: A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared. Results: Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance …in the adjusted model (OR = 1.320, CI: 0.90–1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR = 1.462, CI: 0.68–3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR = 1.003, CI: 1.00–1.01). Conclusion: We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they However could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury. Show more

Keywords: Alzheimer’s disease, brain lesions, cognitive dysfunction, dementia, Honolulu-Asia Aging Study, neuropathology, traumatic brain injury

DOI: 10.3233/JAD-190053

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

Authors: Arfanakis, Konstantinos | Evia, Arnold M. | Leurgans, Sue E. | Cardoso, Luis F.C. | Kulkarni, Arman | Alqam, Nabil | Lopes, Lucas F. | Vieira, Diego | Bennett, David A. | Schneider, Julie A.

Article Type: Research Article

Abstract: Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo . All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for …demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. Results: WMH burden in the whole group was associated with both vascular and Alzheimer’s disease (AD) pathologies: arteriolosclerosis (p  < 10–4 ), gross (p  < 10–4 ), and microscopic infarcts (p  = 0.04), and amyloid-β plaques (p  = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p  = 10–4 ) and arteriolosclerosis (p  < 10–4 ), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p  = 8×10–4 ) and arteriolosclerosis (p  = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p  = 0.038) and non-demented (p  = 0.006) groups. Conclusion: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices. Show more

Keywords: Cognition, magnetic resonance imaging, pathology, white matter hyperintensities

DOI: 10.3233/JAD-190687

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Agarwal, Puja | Brockman, John D. | Wang, Yamin | Schneider, Julie A. | Morris, Martha C.

Article Type: Research Article

Abstract: Background: Bromine is a naturally occurring element that is widely present in the human environment in various chemical forms primarily as flame retardants, pesticides, and water treatments. Objective: In this exploratory study, we investigated the association of brain bromine concentrations on Alzheimer’s disease (AD) neuropathology, cerebral infarcts, and Lewy bodies. Methods: The study was conducted in 215 deceased participants of the Memory and Aging Project, a clinical-pathologic cohort study. Brain bromine levels were measured using instrumental neutron activation analysis. Multiple brain regions were assessed for diffuse and neuritic plaques, neurofibrillary tangles, cerebral macro-and microinfarcts, and Lewy …bodies. Standardized measures of AD pathology (Braak, CERAD, NIA-Reagan, global AD pathology) were computed. Results: In linear regression models, the higher brain bromine levels were associated with more AD neuropathology (Braak (p trend = 0.01); CERAD (p trend = 0.02); NIA-Reagan (p trend = 0.02). Conclusion: Bromine accumulation in the brain is associated with higher level of AD neuropathology. The potential deleterious effects of this element on AD need further exploration. Show more

Keywords: Alzheimer’s disease, bromine, metals, neuropathology

DOI: 10.3233/JAD-190646

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Song, Shasha | Chen, Jingjiong | Xiao, Pinpin | Duan, Hao | Zhou, Yajun | Wang, Feng | Wang, Hongmei | Zhao, Yuwu | Geng, Zhi

Article Type: Research Article

Abstract: Continuous epileptic seizures hallmark status epilepticus, leading to preferential neuronal cell loss in the hippocampus that can progress into Alzheimer’s disease. Previous studies have shown that status epilepticus prompts an overproduction of nitric oxide (NO) by upregulation of NO synthase II (NOS II) to induce apoptosis of neuronal cells in the hippocampus, in a nuclear factor-kappaB (NF-κ B) signaling dependent manner. Here, in an experimental rat model for status epilepticus, elicitation of sustained seizure activity was achieved by microinjection of kainic acid (KA) into the hippocampal CA3 subfield. We found that KA induced features of status epilepticus, which could be …attenuated by blocking NF-κ B signaling through a specific inhibitor. Interestingly, infiltration of macrophages of primarily pro-inflammatory subtype was detected in the hippocampal CA3 region immediately after KA injection. Experimental elimination of macrophages by an anti-CD115 antibody significantly attenuated the features of status epilepticus, likely through suppressing activation of NF-κ B signaling. Together, these data suggest that macrophages play a critical role in NF-κ B signaling-mediated status epilepticus that predisposes to Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, kainic acid, macrophages, NF-κB, status epilepticus

DOI: 10.3233/JAD-190994

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Kuroda, Eriko | Takata, Kazuyuki | Nishimura, Kaneyasu | Oka, Hikaru | Sueyoshi, Mari | Aitani, Mayu | Kouda, Atsushi | Satake, Shiho | Shima, Chiaki | Toda, Yuki | Nakata, Susumu | Kitamura, Yoshihisa | Ashihara, Eishi

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulation in the brain triggers the onset of Alzheimer’s disease (AD), and its prevention and elimination are high priorities for anti-AD therapeutic strategies. Microglia, the resident immune cells in the brain, promote Aβ clearance by phagocytosis. Previously, we demonstrated that injection of primary cultured rat microglia and mouse bone marrow-derived microglia-like cells into the brain decreases the level of Aβ and that intrahippocampal injection of these cells ameliorates cognitive impairment in a mouse model of AD. To advance this cell therapeutic strategy to the clinical stage, less invasive ways of preparing autologous microglia-like cells from elderly patients are …required. In this study, we demonstrated that hematopoietic stem cells mobilized from the bone marrow to peripheral blood by administering granulocyte colony-stimulating factor and a CXCR4 antagonist to mice differentiated into microglia-like cells upon stimulation with colony-stimulating factor 1 and interleukin-34. The peripheral blood-derived microglia-like (PBDML) cells expressed microglial markers and engaged in Aβ phagocytosis. Although PBDML cells were in an anti-inflammatory state under nonstimulated conditions, they expressed mRNAs encoding proinflammatory cytokines following lipopolysaccharide treatment. PBDML cells injected into the hippocampi of a mouse AD model survived for at least 36 days while phagocytosing Aβ, contributed to a reduction in brain Aβ burden, and ameliorated cognitive impairment in the mice. These results strongly suggest that PBDML cells are a promising source for the development of a novel cell therapy against AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , cell therapy, cognitive impairment, intrahippocampal injection, microglia, Morris water maze, novel object recognition test, peripheral blood, stereology

DOI: 10.3233/JAD-190974

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

Authors: Yeh, Tian-Shin | Wang, Jung-Der | Ku, Li-Jung

Article Type: Research Article

Abstract: Background: People with early onset Alzheimer’s disease (EOAD) seem to suffer greater impact. But there is a lack of population-based studies on loss of life expectancy (LE) and lifetime healthcare costs. Objectives: We conducted this study to estimate LE, expected years of life lost (EYLL), and lifetime healthcare costs for Alzheimer’s disease (AD) in Taiwan stratified by onset age and gender, using a method which integrates the product of the survival function and the mean cost function over a lifetime horizon. Methods: We linked the National Health Insurance datasets with the National Mortality Registry and extrapolated …the survival to lifetime to estimate the mean cumulative costs since the date of the first AD diagnosis using medical claims between 2001 and 2012. Results: A total of 21,615 mild to moderate severe AD patients (including 20,358 late-onset (LOAD) and 1,257 EOAD) were recruited. The average onset age for EOAD was 61 years old, while that of LOAD was 78. Although the LE of EOAD was 4.8 years longer than that of LOAD due to younger age, the EYLL for the former was 8.7 years versus 1.7 years for the latter. EOAD also had higher lifetime healthcare costs than the LOAD group (USD$37,957±2,403 versus 33,809±786). Conclusions: Since EOAD patients had both higher EYLL and lifetime healthcare costs than LOAD, future studies should pay more attention to the needs of EOAD patients. Show more

Keywords: Early-onset Alzheimer’s disease, healthcare costs, late-onset Alzheimer’s disease, life expectancy

DOI: 10.3233/JAD-181060

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

Authors: Tarraf, Wassim | Kaplan, Robert | Daviglus, Martha | Gallo, Linda C. | Schneiderman, Neil | Penedof, Frank J. | Perreira, Krista M. | Lamar, Melissa | Chai, Albert | Vásquez, Priscilla M. | González, Hector M.

Article Type: Research Article

Abstract: Background: Cardiovascular disease is linked to cognitive decline and disorders (e.g., dementia). The evidence is based largely on older non-Latino White cohorts. Objective: Examine the association between global vascular risk and cognitive function among Hispanics/Latinos in the United States. Methods: We used data from a large sample of stroke- and cardiovascular disease-free, middle-aged and older Hispanics/Latinos with diverse backgrounds (n =7,650) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We compared associations between two measures of cardiovascular risk (CVR), the Framingham Cardiovascular Risk Score (FCRS) and the multiethnic Global Vascular Risk Score (GVRS), and cognitive …performance using measures of global and domain specific cognitive function, and tested for modification by sex and age. Results: Higher FCRS and GVRS were associated with lower global cognition and higher probability of low mental status, after covariates adjustment. Both CVR indices were associated with lower performances in learning and memory, verbal fluency, and psychomotor speed. Higher GVRS presented stronger associations with lower cognitive function compared to the FCRS. Women and younger age (45–64 years) exhibited more pronounced associations between higher CVR and worse cognition, particularly so with the GVRS. Discussion: CVR is also a risk for compromised cognitive function and evident in middle-age among Hispanics/Latinos. The multiethnic GVRS, tailored to specific risks based on racial/ethnic background, is feasible to use in primary care settings and can provide important insight on cognitive risk. Even modest shifts in population toward cardiovascular health in the high-risk Hispanic/Latino population can have important positive impacts on healthy cognitive aging. Show more

Keywords: cardiovascular risk, cognition, HCHS/SOL, Hispanics/Latinos, neuroepidemiology, neuropsychology

DOI: 10.3233/JAD-190830

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

Authors: Tsunoda, Keiichiro | Yamashita, Toru | Osakada, Yosuke | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Nomura, Emi | Morihara, Ryuta | Nakano, Yumiko | Takahashi, Yoshiaki | Hatanaka, Noriko | Shang, Jingwei | Sato, Kota | Takemoto, Mami | Hishikawa, Nozomi | Ohta, Yasuyuki | Abe, Koji

Article Type: Research Article

Abstract: The world is rapidly aging and facing an increase in the number of dementia patients, so it is important to detect the preclinical stage of dementia in such countries. We examined both cognitive and affective functions among cognitively normal control (n  = 218), mild cognitive impairment (MCI, n  = 146), and Alzheimer’s disease (AD, n  = 305) subjects using two evaluation tools for behavioral and psychological symptoms of dementia (BPSD) [Abe’s BPSD score (ABS) and mild behavioral impairment (MBI)]. BPSD were present in 12.4% (ABS) and 9.6% (MBI) of cognitively normal people, 34.9% and 32.2% in MCI subjects, and 66.2% and 51.1% in …AD patients. Both ABS (§ p<0.05) and MBI (§§ p  <  0.01) score showed worse score with cognitive decline of the Mini-Mental State Examination in the AD group in BPSD-positive participants. Similar correlations were found in all participants in AD group (|||| p  <  0.01 versus ABS and MBI). Among the subscales in BPSD-positive participants, an apathy/indifference score of ABS and a decreased motivation of MBI showed significant differences in AD patients compared to the control and MCI subjects (**p<0.01). In addition, subscale analyses further showed a downward trend from the control to MCI and AD subjects in four ABS subscales and three MBI subscales. The present study showed the preclinical presence of BPSD in cognitively normal people, more so in MCI subjects, and ABS detected BPSD more sensitively than MBI in all three groups. Show more

Keywords: Affective symptoms, behavioral symptoms, cognitive dysfunction, dementia

DOI: 10.3233/JAD-190669

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

Authors: Davidowitz, Eliot J. | Krishnamurthy, Pavan K. | Lopez, Patricia | Jimenez, Heidy | Adrien, Leslie | Davies, Peter | Moe, James G.

Article Type: Research Article

Abstract: Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer’s disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms …of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation. Show more

Keywords: Alzheimer’s disease, drug therapy, pathological, protein aggregation, tau protein

DOI: 10.3233/JAD-190465

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Wada-Isoe, Kenji | Kikuchi, Takashi | Umeda-Kameyama, Yumi | Mori, Takahiro | Akishita, Masahiro | Nakamura, Yu | on behalf of the ABC Dementia Scale Research Group

Article Type: Research Article

Abstract: The course of Alzheimer’s disease (AD) varies between individuals, and the relationship between cognitive and functional decline and the deterioration of behavioral and psychological symptoms of dementia (BPSD) is still poorly understood. Until recently, it was challenging to monitor subsequent changes in these symptoms because there was no single composite scale available that could simultaneously evaluate activities of daily living (ADL), BPSD, and cognitive function (CF) states. The present authors developed a new, brief assessment scale, the “ABC Dementia Scale” (ABC-DS), which is based on item response theory and facilitates concurrent measurement of ADL, BPSD, and CF states. We previously …presented the reliability, construct validity, concurrent validity, and responsiveness of the ABC-DS. We obtained the evidence through three clinical trials featuring 1,400 subjects in total. In the present study, we performed a secondary analysis of the data obtained in the previous study. We conducted hierarchical cluster analyses that allowed us to classify 197 AD patients in terms of similarities regarding ADL, BPSD, and CF domain scores, as measured by the ABC-DS. Consequently, the scale identified subgroups of patients with global clinical dementia ratings of 1, 2, and 3. Considering our results in conjunction with the clinical experiences of the AD expert among the present authors regarding longitudinal changes in ADL, BPSD, and CF, we were able to propose potential progression pathways of AD in the form of a hypothetical roadmap. Show more

Keywords: ABC dementia scale, activities of daily living, Alzheimer’s disease, cognitive function, cluster analysis, psychological symptoms of dementia

DOI: 10.3233/JAD-190767

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

Authors: Vergouw, Leonie J.M. | Bosman, Brechje | van de Beek, Marleen | Salomé, Mariet | Hoogers, Susanne E. | van Steenoven, Inger | Roks, Gerwin | Bonifati, Vincenzo | van Swieten, John C. | Lemstra, Afina W. | de Jong, Frank Jan

Article Type: Research Article

Abstract: It is currently unknown whether patients with dementia with Lewy bodies (DLB) with relatives with dementia or Parkinson’s disease (familial DLB patients) have a different phenotype than sporadic DLB patients. In this study, we aimed to examine disease onset, rate of cognitive decline, survival, and Alzheimer’s disease (AD) biomarkers in patients with familial DLB (n  = 154) and sporadic DLB (n  = 137), using linear mixed model analysis and Cox regression analysis, among others. Familial patients had a shorter survival (8.0 years) and more often elevated cerebrospinal fluid AD biomarkers (47%) than sporadic patients (9.0 years; p ≤0.001; 30%, p  = 0.037). Our …findings suggest that genetic factors are important in DLB and that the identification of new genetic factors will probably improve the prediction of prognosis. Show more

Keywords: Dementia with Lewy bodies, family history, phenotype, survival

DOI: 10.3233/JAD-190825

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

Authors: Abe, Koji | Shang, Jinwei | Shi, Xiaowen | Yamashita, Toru | Hishikawa, Nozomi | Takemoto, Mami | Morihara, Ryuta | Nakano, Yumiko | Ohta, Yasuyuki | Deguchi, Kentaro | Ikeda, Masaki | Ikeda, Yoshio | Okamoto, Koichi | Shoji, Mikio | Takatama, Masamitsu | Kojo, Motohisa | Kuroda, Takeshi | Ono, Kenjiro | Kimura, Noriyuki | Matsubara, Etsuro | Osakada, Yosuke | Wakutani, Yosuke | Takao, Yoshiki | Higashi, Yasuto | Asada, Kyoichi | Senga, Takehito | Lee, Liang-Ja | Tanaka, Kenji

Article Type: Research Article

Abstract: Background: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer’s disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established. Objective: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology. Methods: With only 1.5μ l of …serum, we examined a new target plate “BLOTCHIP® ” plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n  = 100), MCI (n  = 60), and AD (n  = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains. Results: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (*** p  < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains. Conclusion: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage. Show more

Keywords: Alzheimer’s disease, biomarker, coagulation, complement, MALDI-TOF, mild cognitive impairment, neuroinflammation, peptidome, plasticity

DOI: 10.3233/JAD-191016

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

Authors: Elias, Alby | Cummins, Tia | Lamb, Fiona | Tyrrell, Regan | Dore, Vincent | Williams, Rob | Rosenfeld, Jeffrey V. | Hopwood, Malcolm | Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: Epidemiological studies suggest a relationship between posttraumatic stress disorder (PTSD) and dementia. Objective: This study assessed whether Alzheimer’s disease (AD) imaging biomarkers were elevated in Vietnam veterans with PTSD. Methods: The study compared cognition, amyloid-β, tau, regional brain metabolism and volumes, and the effect of APOE in 83 veterans with and without PTSD defined by the Clinician’s Administered PTSD Scale. Results: The PTSD group had significantly lower education, predicted premorbid IQ, total intracranial volume, and Montreal Cognitive Assessment score compared with the controls. There was no difference between the two groups in …the imaging or genetic biomarkers for AD. Conclusion: Our findings do not support an association between AD pathology and PTSD of up to 50 years duration. Measures to assess cognitive reserve, a factor that may delay the onset of dementia, were lower in the PTSD group compared with the controls and this may account for the previously observed higher incidence of dementia with PTSD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, positron emission tomography, posttraumatic stress disorder, tau

DOI: 10.3233/JAD-190913

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

Authors: Imai, Masamichi | Tanaka, Mika | Sakata, Muneyuki | Wagatsuma, Kei | Tago, Tetsuro | Toyohara, Jun | Sengoku, Renpei | Nishina, Yuji | Kanemaru, Kazutomi | Ishibashi, Kenji | Murayama, Shigeo | Ishii, Kenji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are often misdiagnosed with each other because of similar symptoms including progressive memory loss. The metabolic network topology that describes inter-regional metabolic connections can be generated using fluorodeoxyglucose positron emission tomography (FDG-PET) data with the graph-theoretical method. We hypothesized that different metabolic connectivity underlies the symptoms of AD patients, DLB patients, and cognitively normal (CN) individuals. Objective: This study aimed to generate metabolic connectivity using FDG-PET data and assess the network topology to differentiate AD patients, DLB patients, and CN individuals. Methods: This study included 45 …AD patients, 18 DLB patients, and 142 CN controls. We analyzed FDG-PET data using the graph-theoretical method and generated the network topology in AD patients, DLB patients, and CN individuals. We statistically assessed the topology with global and nodal parameters. Results: The whole metabolic network was preserved in CN; however, diffusely decreased connection was found in AD and partially but more deeply decreased connection was observed in DLB. The metabolic topology revealed that the right posterior cingulate and the left transverse temporal gyrus were significantly different between AD and DLB. Conclusion: The present findings indicate that metabolic connectivity decreased in both AD and DLB, compared with CN. DLB was characterized restricted but deeper stereotyped network disruption compared with AD. The right posterior cingulate and the left transverse temporal gyrus are significant regions in the metabolic connectivity for differentiating AD from DLB. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, fluorodeoxyglucose, graph theory, network analysis, neuroimaging biomarkers, positron emission tomography

DOI: 10.3233/JAD-190843

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

Authors: Cechova, Katerina | Andel, Ross | Angelucci, Francesco | Chmatalova, Zuzana | Markova, Hana | Laczó, Jan | Vyhnalek, Martin | Matoska, Vaclav | Kaplan, Vojtech | Nedelska, Zuzana | Ward, David | Hort, Jakub

Article Type: Research Article

Abstract:  Apolipoprotein (APOE ) ɛ 4 is a well-known risk factor for late-onset Alzheimer’s disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF ) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age = 72.2) were recruited from the Czech Brain Aging Study and, based …on APOE and BDNF genes polymorphisms, were divided into four groups: ɛ 4– BDNF Val/Val (n  = 37), ɛ 4– BDNF Met (n  = 19), ɛ 4+ BDNF Val/Val (n  = 35), and ɛ 4+ BDNF Met (n  = 16). All patients underwent clinical examination, magnetic resonance imaging, and complex neuropsychological battery. The combination of APOE ɛ 4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ɛ 4+ BDNF Met group. Our findings suggest that carriage of ɛ 4+ BDNF Met is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOE ɛ 4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, Apolipoprotein E, brain-derived neurotrophic factor, cognition, gene polymorphism

DOI: 10.3233/JAD-190464

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

Authors: Brewer, Gregory J. | Herrera, Robert A. | Philipp, Stephan | Sosna, Justyna | Reyes-Ruiz, Jorge Mauricio | Glabe, Charles G.

Article Type: Research Article

Abstract:  This work provides new insight into the age-related basis of Alzheimer’s disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD …than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45 , and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, autophagosomes, endosomes, lysosomes, mitochondria

DOI: 10.3233/JAD-190835

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

Authors: Marcon, Gabriella | Manganotti, Paolo | Tettamanti, Mauro

Article Type: Short Communication

Abstract: The number of people reaching old age is growing dramatically and centenarians are among the fastest growing age groups. Since no epidemiological study on Parkinson’s disease (PD) in this age class is present in the medical literature, we estimated PD prevalence in the Centenari a Trieste (CaT) study. Participating centenarians were examined by a neurologist, who also retrieved their remote and pharmacological anamnesis. Ninety centenarians received a neurological examination. No subject had PD clinical signs. Moreover, none had a previous diagnosis of PD or had taken or was taking anti-Parkinson treatment. This simple but consistent clinical observation permits some physio-pathological …hypotheses. Show more

Keywords: Alpha-synuclein, centenarians, Parkinson’s disease, prevalence

DOI: 10.3233/JAD-190717

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Briceño, Emily M. | Mehdipanah, Roshanak | Gonzales, Xavier | Heeringa, Steven | Levine, Deborah A. | Langa, Kenneth M. | Garcia, Nelda | Longoria, Ruth | Morgenstern, Lewis B.

Article Type: Research Article

Abstract: Background: As the Mexican American (MA) population grows and ages, there is an urgent need to estimate the prevalence of cognitive impairment or dementia (CID), cognitive trajectories, and identify community resource needs. The Brain Attack Surveillance in Corpus Christi (BASIC)-Cognitive project is a population-based study to address these issues among older MAs and non-Hispanic whites (NHW) and their informal care providers. Objective: Present the methodology and initial recruitment findings for the BASIC-Cognitive project. Method: Random, door-to-door case ascertainment is used in Nueces County, Texas, to recruit community-dwelling and nursing home residents ≥65 and informal care providers. …Households are identified from a two-stage area probability sample, using Census data to aim for equal balance of MAs and NHWs. Individuals with cognitive screens indicative of possible CID complete neuropsychological assessment (Harmonized Cognitive Assessment Protocol from the Health and Retirement Study). Informal care providers complete comprehensive interview and needs assessment. Study pairs repeat procedures at 2-year follow-up. Asset and concept mapping are performed to identify community resources and study care providers’ perceptions of needs for individuals with CID. Results: 1,030 age-eligible households were identified, or 27% of households for whom age could be determined. 1,320 individuals were age-eligible, corresponding to 1.3 adults per eligible household. Initial recruitment yielded robust participation in the MA eligible population (60% of 689 individuals that completed cognitive screening). Conclusion: The BASIC-Cognitive study will provide critical information regarding the prevalence of CID in MAs, the impact of caregiving, and allocation of community resources to meet the needs of this population. Show more

Keywords: Caregivers, dementia, epidemiology, health resources, mild cognitive impairment, Mexican American

DOI: 10.3233/JAD-190761

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Lee, Tsung-Lin | Liu, Chi-Hung | Chang, Yu-Ming | Lin, Tien-Yu | Chien, Chung-Yao | Chen, Chih-Hung | Tsai, Kuen-Jer | Lin, Sheng-Hsiang | Sung, Pi-Shan

Article Type: Research Article

Abstract: Background: Antiplatelet use on the risk of intracerebral hemorrhage (ICH) in patients with Alzheimer’s disease (AD) has not yet been completely elucidated. Objective: This large epidemiologic study aims to estimate the risk of ICH in AD patients treated with antiplatelet therapy (APT). Methods: Using data from Taiwan’s National Health Insurance Research Database, ICH risk in APT-treated AD patients with a validated diagnosis (N = 824) was determined. AD without APT and non-AD with and without APT comparison cohorts were selected. To adjust for confounders and competing risk of death, inverse probability of treatment weighting using propensity scores and …competing risks regression (CRR) were applied. Cox proportional hazards regression analysis estimated ICH risk in all cohorts comparing with non-AD without APT. Results: Among the 824 AD patients with APT, 79.6% were prescribed aspirin. ICH incidence rates in the AD (with/without APT) and non-AD (with/without APT) cohorts were 2.88/2.70 and 2.24/1.20 per 1,000 person-years, respectively. Overall, AD with (adjusted hazards ratio (aHR), 2.29; 95% CI, 1.19–4.38) and without (aHR, 1.97; 95% CI, 1.08–3.61) APT and non-AD with APT (aHR, 1.80; 95% CI, 1.34–2.42) were at a higher risk and had elevated subdistribution HR obtained from CRR than non-AD without APT controls. However, the risk was comparable between the AD cohorts with and without APT (HR, 1.16; 95% CI, 0.51–2.66). Conclusions: Our study indicated both the APT and non-APT users in AD population yielded higher ICH risks. However, whether APT use potentiate the risk of ICH in AD patients may warrant further evaluation. Show more

Keywords: Alzheimer’s disease, antiplatelet therapy, aspirin, intracranial hemorrhage, risk

DOI: 10.3233/JAD-190762

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

Authors: Nerius, Michael | Haenisch, Britta | Gomm, Willy | Doblhammer, Gabriele | Schneider, Anja

Article Type: Research Article

Abstract: Background: Recent evidence indicates an important role for neuroinflammation in the pathological cascade of Alzheimer’s disease (AD), and neuroinflammation is increasingly being recognized as a potential therapeutic target. Objective: To assess the impact of glucocorticoids on the risk of developing dementia. Methods: We used health insurance data of the largest German health insurer from 2004–2013 with a baseline sample of 176,485 persons aged 50 years and older to study the association of glucocorticoid treatment and incidence of dementia. Cox proportional-hazard models were calculated adjusting for sex, age, and comorbidities known to be major risk factors for …dementia and were given as hazard ratios (HR) with 95% confidence intervals (CI). We further stratified glucocorticoid treatment by route of application and treatment duration. Results: Of the 176,485 dementia-free persons, 19,938 were diagnosed with dementia by the end of 2013. The risk of suffering from dementia was significantly lower for glucocorticoid users compared to non-users (HR = 0.81, CI = 0.78–0.84). The lowest risk was found among users of inhaled glucocorticoid (HR = 0.65, CI = 0.57–0.75), followed by nasal (HR = 0.76, CI = 0.66–0.87), other (HR = 0.84, CI = 0.80–0.88), and oral users (HR = 0.83, CI = 0.78–0.88). We found no difference in risk reduction between long- and short-term-users. Conclusion: Longitudinal German health insurance data indicate that the use of glucocorticoids is associated with a lower risk of dementia. Prospective clinical trials will be necessary to determine whether glucocorticoids can have a positive impact on neuroinflammation and thus protect persons against dementia. Show more

Keywords: Administrative claims, cohort studies, dementia, epidemiology, glucocorticoids, inflammation

DOI: 10.3233/JAD-190444

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

Authors: Jensen-Dahm, Christina | Christensen, Ane Nørgaard | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Opioids are used with increasing frequency. Elderly with dementia are prescribed opioids more frequent than elderly without. One possible explanation is that opioids may be used not only to treat pain but also behavioral symptoms. Objective: To test the hypothesis that strong opioid use, especially transdermal formulations, had increased, especially in elderly with dementia, in parallel with a decrease in antipsychotic use. Methods: Population-based cross-sectional study conducted using nationwide Danish registers with data on Denmark’s entire elderly population age ≥65 (2000: n  = 802,106; 2015: n  = 1,056,476). The registers were used to identify elderly with and …without dementia and filled prescriptions for opioids and antipsychotics. Annual prevalence of opioid and antipsychotic use from 2000–2015 was calculated. Results: Prevalence of opioid use increased by 35% (24.2 to 32.5%) among elderly with dementia and by 13% among elderly without (14.9 to 16.8%) from 2000–2015. The disproportionate increase in opioid use among elderly with dementia was mainly driven by an increase in strong opioids (dementia: 11.7 to 23.1%; without dementia: 5.9 to 7.4%). Use of antipsychotics decreased during the same period (dementia: 31.3 to 19.3%; no dementia: 4.5 to 2.7%). Conclusion: From 2000–2015, use of opioids among the elderly increased with a disproportionately higher increase among elderly with dementia. The parallel decrease in the use of antipsychotics may suggest that opioids to some extent have replaced antipsychotics in managing behavioral symptoms, despite safety concerns and lack of evidence for effect of opioids. Future research should focus on potential risks associated with increased opioid use. Show more

Keywords: Antipsychotic, behavioral symptoms, dementia, drug use, opioid, pain

DOI: 10.3233/JAD-190787

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

Authors: Babić Leko, Mirjana | Nikolac Perković, Matea | Klepac, Nataša | Švob Štrac, Dubravka | Borovečki, Fran | Pivac, Nela | Hof, Patrick R. | Šimić, Goran

Article Type: Research Article

Abstract: The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O -methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine β-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called –1021C/T or –970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether …these polymorphisms are associated with cerebrospinal fluid AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181 , p-tau199 , and p-tau231 ), amyloid-β42 (Aβ42 ), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aβ42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t -tau and p -tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aβ42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p -tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD. Show more

Keywords: Alzheimer’s disease, biomarkers, COMT, DBH, dopamine, MAOB, noradrenaline, polymorphisms

DOI: 10.3233/JAD-190991

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

Authors: Khan, Hafiz | Rafiq, Aamrin | Shabaneh, Obadeh | Gittner, LisaAnn S. | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: Dementia and hypertension are chronic diseases that affect elderly populations worldwide. The prevalence of these diseases increases each year, especially in rural and underserved rural communities like West Texas. The purpose of this study was to find risk factors of dementia and their impact on West Texans. Data was provided by the Project FRONTIER for rural West Texas counties. The SPSS software package was used for statistical analysis. Pearson’s chi-squared test was also utilized to determine relationships between the risk factors considering a level of significance (α )  = 0.05. The findings have shown that age group had significant associations with …hypertension, cerebral, neurologic disease, Romberg test, and muscle strength for both males and females (p ≤0.002). Hypertension was significantly associated with cognitive disorder and diabetes in both males and females (p ≤0.011). Age group in females was significantly associated with parkinsonism (p  = 0.02), neurological stroke (p  = 0.002), reflexes (p  = 0.003), and sensory intact (hands/feet) (p  = 0.004), respectively, whereas age for males was not significantly associated with those variables (p  = 0.29, p  = 0.05, p  = 0.56, and p  = 0.76, respectively). Hypertension in females was significantly associated with cardiovascular disease (p  = 0.001) and depression (p  = 0.001) but was not found to be significant for males (p  = 0.30 and p  = 0.09, respectively). Both males and females in Hispanic and non-Hispanic groups were found to be significantly associated with Alzheimer’s disease (p  = 0.0001 and p  = 0.045, respectively). Hispanic and non-Hispanic females were found to be significantly associated with hypertension (p  = 0.026). Gender-specific differences in dementia risk factors exist and integrating such variables may guide relevant policymaking to reduce dementia incidence in rural West Texas. Show more

Keywords: Cardiovascular disease, cognitive disorder, dementia, FRONTIER database, hypertension, statistical methods

DOI: 10.3233/JAD-190893

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

Authors: Sawant, Neha | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: The purpose of our article is to critically assess the role of phosphorylated tau in Huntington’s disease (HD) progression and pathogenesis. HD is a fatal and pure genetic disease, characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. HD is caused by expanded polyglutamine (polyQ or CAG) repeats within the exon 1 of the HD gene. HD has an autosomal dominant pattern of inheritance with genetic anticipation. Although the HD gene was discovered 16 years ago, there is no complete understanding of how mutant huntingtin (mHTT) selectively targets medium spiny projection neurons in the basal …ganglia of the brain in patients with HD. Several years of intense research revealed that multiple cellular changes are involved in disease process, including transcriptional dysregulation, mitochondrial abnormalities and impaired bioenergetics, defective axonal transport, calcium dyshomeostasis, synaptic damage and caspase, and NMDAR activations. Recent research also revealed that phosphorylated tau and defective GSK-3β signaling are strongly linked to progression of the disease. This article summarizes the recent developments of cellular and pathological changes in disease progression of HD. This article also highlights recent developments in phosphorylated tau and defective GSK-3β signaling and the involvement of calcineurin in HD progression and pathogenesis. Show more

Keywords: Huntington’s disease, hyperphosphorylated tau, medium spiny projection neurons, mitochondrial abnormalities, mutant huntingtin, polyglutamine repeats

DOI: 10.3233/JAD-190851

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Hays, Chelsea C. | Zlatar, Zvinka Z. | Meloy, M.J. | Osuna, Jessica | Liu, Thomas T. | Galasko, Douglas R. | Wierenga, Christina E.

Article Type: Research Article

Abstract: Evidence suggests the ɛ 4 allele of the apolipoprotein E gene (APOE ) may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE -related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ɛ 4+, ɛ 4–) on FreeSurfer-derived …CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE , CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ɛ 4+, whereas these relationships were not evident in ɛ 4–. In the rACC, higher CSF tau was associated with higher CTH for both ɛ 4+ and ɛ 4–, and with lower CBF only in ɛ 4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer’s disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ɛ 4+ and a positive relationship in ɛ 4–. Findings suggest the presence of an ɛ 4–related pattern of increased CTH and CBF reduction in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition. Show more

Keywords: Aging, Alzheimer’s disease, APOE , cerebral blood flow, cognition, cognitive decline, grey matter, magnetic resonance imaging, tau proteins

DOI: 10.3233/JAD-190504

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Yare, Katrine | Woodward, Michael

Article Type: Review Article

Abstract: Numerous observational studies have suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and Alzheimer’s disease (AD). However, because of the significant disparity between results, especially those between observational and randomized controlled trials (RCT), this postulate remains unproven. A significant contributing factor to these inconsistencies is the loose use of the generic definitions of estrogens and progestogens with most studies not delineating the clear differences between non-endogenous and endogenously identical (bioidentical) hormones, their molecular binding affinities and actions, and resultant metabolites. This is highlighted by the generalized terminological use of HT, which is often used to encompass …significantly disparate hormonal formulations without clear demarcation. This has impacted and continues to significantly influence interpretations of data, meta-analyses, observational studies, etc., relevant to AD. To progress forward and allow unbiased interpretation, it is no longer acceptable to group HT formulations together as a homogenous group. This will also allow differentiation between compounds that exhibit beneficial actions and those that do not and whether these effects are specific or generalized. The role of the endogenous hormones, 17 beta-oestradiol (E2) and progesterone (P4), in the development of sporadic AD in postmenopausal women is also examined. Show more

Keywords: Alzheimer’s disease, 17 beta-oestradiol, conjugated equine estrogens, hormone therapy, progesterone, progestins

DOI: 10.3233/JAD-190896

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Newkirk, Lori A. | Dao, Virginia L. | Jordan, Joshua T. | Alving, Loren I. | Davies, Helen D. | Hewett, Linda | Beaudreau, Sherry A. | Schneider, Logan D. | Gould, Christine E. | Chick, Christina F. | Hirst, Rayna B. | Rose, Sophia Miryam Schüssler-Fiorenza | Anker, Lauren A. | Tinklenberg, Jared R. | O’Hara, Ruth

Article Type: Research Article

Abstract: Background: Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services. Objective: To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use. Methods: California Alzheimer’s Disease Center patients with AD (n  = 220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were …also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users. Results: Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p  < 0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p  < 0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services. Conclusion: Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use. Show more

Keywords: Activities of daily living, Alzheimer’s disease, caregiver burnout, dementia, family caregivers, respite care, spouse caregivers, support group

DOI: 10.3233/JAD-190438

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

Authors: Shimizu, Soichiro | Takenoshita, Naoto | Inagawa, Yuta | Tsugawa, Akito | Hirose, Daisuke | Kaneko, Yoshitsugu | Ogawa, Yusuke | Serisawa, Shuntaro | Sakurai, Shu | Hirao, Kentaro | Kanetaka, Hidekazu | Kanbayashi, Takashi | Imanishi, Aya | Sakurai, Hirofumi | Hanyu, Haruo

Article Type: Research Article

Abstract: Background: Recently, many studies have investigated the association between orexin A and Alzheimer’s disease (AD). However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A levels and cognitive function has not been reported to date. Objective: The aim of this study was to identify whether there is a direct association between the orexinergic system and cognitive function in AD. Methods: For this study, we included 22 patients with AD and 25 …control subjects who underwent general physical, neurological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], Aβ42 , and Aβ42 /Aβ40 ) were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were analyzed. Results: There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores: r  = 0.591, p  = 0.04, MoCA score: r  = 0.571, p  = 0.006) in AD patients. Conclusion: This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for cognitive function In AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid Alzheimer’s disease biomarker, cognitive function, hypocretin 1, orexin A

DOI: 10.3233/JAD-190958

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

Authors: Parvand, Mahraz | Rankin, Catharine H.

Article Type: Review Article

Abstract: As we age, our olfactory function declines. In addition to occurring in normal aging, more rapid decrement of olfactory decline has been associated with several neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). It has been argued that since olfactory deficits occur less frequently or are absent in diseases such as progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, olfactory deficits can be used for differential diagnoses of AD and PD. The purpose of this review is to provide a survey of current knowledge about the molecular bases and differential patterns of olfactory deficits present in normal …aging, AD, and PD. As substantial research has been conducted in this area, the majority of the content of this review focuses on articles published in the past decade. We hypothesize that olfactory deficits in normal aging, AD, and PD may have different underlying causes, and propose the use of model organisms with small, tractable nervous systems and/or easy to manipulate genomes to further investigate the cellular mechanisms responsible for these deficits. Show more

Keywords: Aging, Alzheimer’s disease, olfaction, Parkinson’s disease, Smell

DOI: 10.3233/JAD-190636

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2019

Authors: Hegde, Vijay | Dhurandhar, Nikhil V. | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Type 2 diabetes mellitus (T2D), which is often accompanied by hyperinsulinemia and insulin resistance, is associated with an increased risk for developing mild cognitive impairment and Alzheimer’s disease (AD); however, the underlying mechanisms for this association are still unclear. Recent findings have shown that hyperinsulinemia and insulin resistance can coexist or be independent events. This makes it imperative to determine the contribution of these individual conditions in impacting AD. This literature review highlights the recent developments of hyperinsulinemia and insulin resistance involvement in the progression and pathogenesis of AD.

Keywords: Alzheimer’s disease, amyloid plaques, hyperglycemia, hyperinsulinemia, insulin resistance, tau phosphorylation

DOI: 10.3233/JAD-190808

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

Authors: Defrancesco, Michaela | Marksteiner, Josef | Kemmler, Georg | Dal-Bianco, Peter | Ransmayr, Gerhard | Benke, Thomas | Mosbacher, Jochen | Höller, Yvonne | Schmidt, Reinhold

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer’s disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI). Objective: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression. Methods: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for …Alzheimer’s dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster). Results: Out of the 662 included patients (mean age 76.4±8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time. Conclusion: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression. Show more

Keywords: Alzheimer’s disease, disease progression, Neuropsychiatric Inventory, neuropsychiatric symptoms

DOI: 10.3233/JAD-190662

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

Authors: Kang, David E. | Woo, Jung A.

Article Type: Review Article

Abstract:  The defining pathological hallmarks of Alzheimer’s disease (AD) are proteinopathies marked by the amyloid-β (Aβ) peptide and hyperphosphorylated tau. In addition, Hirano bodies and cofilin-actin rods are extensively found in AD brains, both of which are associated with the actin cytoskeleton. The actin-binding protein cofilin known for its actin filament severing, depolymerizing, nucleating, and bundling activities has emerged as a significant player in AD pathogenesis. In this review, we discuss the regulation of cofilin by multiple signaling events impinging on LIM kinase-1 (LIMK1) and/or Slingshot homolog-1 (SSH1) downstream of Aβ. Such pathophysiological signaling pathways impact actin dynamics to regulate synaptic …integrity, mitochondrial translocation of cofilin to promote neurotoxicity, and formation of cofilin-actin pathology. Other intracellular signaling proteins, such as β-arrestin, RanBP9, Chronophin, PLD1, and 14-3-3 also impinge on the regulation of cofilin downstream of Aβ. Finally, we discuss the role of activated cofilin as a bridge between actin and microtubule dynamics by displacing tau from microtubules, thereby destabilizing tau-induced microtubule assembly, missorting tau, and promoting tauopathy. Show more

Keywords: Alzheimer’s disease, amyloid, β-arrestin, chronophin, cofilin, cytoskeleton, F-actin, LIMK1, microtubule, mitochondria, PLD1, slingshot, SSH1, tau

DOI: 10.3233/JAD-190585

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

Authors: Morsy, Ahmed | Trippier, Paul C.

Article Type: Review Article

Abstract: No cure or disease-modifying therapy for Alzheimer’s disease (AD) has yet been realized. However, a multitude of pharmacological targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathological hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N -methyl-D -aspartate receptor blockade treatments that are clinically approved …for the symptomatic treatment of AD. Additional targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of ‘sensitive targets’ that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target’s function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our analysis to targets that have emerged in the last decade and targets that have been validated using small molecules in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and critical targets suitable for small molecule drug intervention. Show more

Keywords: Alzheimer’s disease, amyloid, drug discovery, therapeutics, toxicity

DOI: 10.3233/JAD-190744

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-32, 2019

Authors: Kumar, Subodh | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: MicroRNA-455-3p (miR-455-3p) is identify as a member of broadly conserved miRNA family expressed in most of the phylum and species. In humans, miR-455 is present on the human chromosome 9 at locus 9q32 and encoded by the human COL27A1 gene (collagen type XXVII alpha 1 chain). The role of miR-455 has been implicated in various human diseases such as cartilage development, adipogenesis, preeclampsia, and cancers, e.g., colon cancer, prostate cancer, hepatocellular carcinoma, renal cancer, oral squamous cancer, skin cancer, and non-small cell lung cancer. Recently, our laboratory discovered the biomarker and therapeutic relevance of miR-455-3p in Alzheimer’s disease (AD). Our …global microarray analysis of serum samples from AD patients, mild cognitive individuals (MCI), and healthy subjects unveiled the high level of miR-455-3p in AD patients relative to MCI and healthy controls. Further, validation analysis using different kinds of AD samples such as serum, postmortem brains, AD fibroblasts, AD B-lymphocytes, AD cell lines, AD mouse models, and AD cerebrospinal fluid confirmed the biomarker potential of miR-455-3p. The mechanistic link of miR-455-3p in AD was determined via modulation of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) levels. Luciferase reporter assay confirmed AβPP as validated target of miR-455-3p. Our study on mouse neuroblastoma cells revealed the protective role of miR-455-3p against Aβ-induced toxicities. We also noticed that miR-455-3p enhances cell survival and lifespan extension. High level of miR-455-3p reduces Aβ toxicity, enhances mitochondrial biogenesis and synaptic activity, and maintains healthy mitochondrial dynamics. Based on these evidences, we cautiously conclude that miR-455-3p is a promising peripheral biomarker and therapeutic candidate for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, microRNA-455-3p

DOI: 10.3233/JAD-190583

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

Authors: Ramasubramanian, Bhagavathi | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: The purpose of our article is to critically assess if TallyHo mice are a true mouse model for type 2 diabetes and Alzheimer’s disease. Diabetes is a lifestyle condition that is characterized by elevated blood glucose due to either insufficient amount of insulin or the body’s inability to use the produced insulin efficiently. Diabetes occurs in multiple forms, including type 1, type 2, type 3, neonatal, and gestational. Type 2 diabetes covers 95% of overall diabetes, found in individuals 65 years of age and above. Both modifiable and non-modifiable factors are involved in developing diabetes. In patients with diabetes, increased …blood glucose levels are reported to induce multiple complications, such as heart disease, stroke, kidney failure, foot ulcers, and damage to the eyes. However, the molecular basis of diabetes is not completely understood. Further, there are no accurate animal model(s) that mimic both type 1 and type 2 diabetes of humans. Multiple polygenic models are being used, including the Goto-Kakizaki rat, the Otzhka Long-Evans Tokushima Fatty rat, the Nagoya Shibata Yasuda mouse, the New Zealand obese mouse, the Tsumura-Suzuki obese diabetes mouse, leptin deficient ob /ob and the leptin receptor deficient db /db mouse models. In 2001, Kim and colleagues described the TallyHo mice that represent many features of type 2 diabetes of humans. Since then, several groups studied TallyHo mice. Only the male mice develop hyperglycemia and the females exhibit features of obesity. Thus, this model can be used to study both diabetes and obesity. The purpose of this article is to discuss recent developments in TallyHo mice research including diabetes onset and progression. Show more

Keywords: Alzheimer’s disease, diabetes, gestational diabetes, modifiable factors, obesity, TallyHo mice

DOI: 10.3233/JAD-190613

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: George, Elizabeth Kurudamannil | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Current healthcare costs for over 50 million people afflicted with AD are about $818 million and are projected to be $2 billion by 2050. Unfortunately, there are no drugs currently available that can delay and/or prevent the progression of disease in elderly individuals and in AD patients. Loss of synapses and synaptic damage are largely correlated with cognitive decline in AD patients. Women are at a higher lifetime risk of developing AD encompassing two-thirds of the total AD afflicted population. Only about 1-2% of …total AD patients can be explained by genetic mutations in APP , PS1 , and PS2 genes. Several risk factors have been identified, such as Apolipoprotein E4 genotype, type 2 diabetes, traumatic brain injury, depression, and hormonal imbalance, are reported to be associated with late-onset AD. Strong evidence reveals that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive function in elderly populations. Current available data on the use of antioxidants in mouse models of AD and antioxidant(s) supplements in diets of elderly individuals were investigated. The use of antioxidants in randomized clinical trials in AD patients was also critically assessed. Based on our survey of current literature and findings, we cautiously conclude that healthy diets, regular exercise, and improved lifestyle can delay dementia progression and reduce the risk of AD in elderly individuals and reverse subjects with mild cognitive impairment to a non-demented state. Show more

Keywords: Alzheimer’s disease, amyloid-beta, antioxidant enriched diet, healthcare cost, healthy diets, mitochondria, phosphorylated tau, reactive oxygen species, regular exercise

DOI: 10.3233/JAD-190232

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2019

Authors: Reddy, P. Hemachandra | Swerdlow, Russell H. | Culberson, John | Kang, David | Mitchell, Tedd L. | Smith, Quentin | Suneja, Sanoj | Ory, Marcia G. | Kumar, Subodh | Vijayan, Murali | Morsy, Ahmed | Arandia, Gabriela | Lawrence, J. Josh | George, Elizabeth | Oliver, Darryll | Pradeepkiran, Jangampalli Adi | Yin, Xiangling | Reddy, Arubala P. | Manczak, Maria | Cengiz, Pelin | Karamyan, Vardan T. | Kandimalla, Ramesh | Kuruva, Chandra Sekhar | Willms, Joshua | Ramasubramanian, Bhagavathi | Sawant, Neha | Burugu, Divya | Boles, Annette N. | Lopez, Veronica | Carrasco, Rocio | Aguirre, Cordelia | Thompson, Susan | Blackmon, Joan | Ament, Clay | Wang, Rui | Stephens, Emily R. | Hoang, Brittney | Bass, Kevin | Trippier, Paul C. | Hornback, Christopher | Kottapalli, Pratibha | Kottapalli, Kameswara Rao | Center Biotechnology and Genetics Core Facility | Oddo, Salvatore

Article Type: Abstract

Abstract: The purpose of the ‘First Regional Healthy Aging and Dementia Research Symposium’ was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24–25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members …involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion. Show more

DOI: 10.3233/JAD-190252

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2019

Authors: Oliver, Darryll M.A. | Reddy, P. Hemachandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. With the increased aging population, AD is a major health concern in society. Morphological and pathological studies revealed that AD is associated with the loss of synapses, defective mitochondria, and the proliferation of reactive astrocytes and microglia, in addition to the presence amyloid-β and phosphorylated tau in learning and memory regions of the brain in AD patients. AD occurs in two forms: early-onset familial and late-onset sporadic. Genetic mutations in APP , PS1 , and PS2 loci cause familial AD. Multiple factors are …reported to be involved in late-onset AD, including APOE4 genotype, polymorphisms in several gene loci and type 2 diabetes, traumatic brain injury, stroke, and age-related factors, including increased reactive oxygen species production and dysfunction in mitochondria. It is widely accepted that synaptic damage and mitochondrial dysfunction are early events in disease process. The purpose of this article is to highlight molecular triggers to the disease process. This article also reviews factors, including age, gender, lifestyle, epigenetic factors, and type 2 diabetes, that are involved in late-onset AD. This article also discusses recent developments in research of mitochondrial structure, function, physiology, dynamics, biogenesis, mitophagy, and mitochondrial DNA changes in healthy and diseased states. Show more

Keywords: Alzheimer’s disease, familial Alzheimer’s disease, mitochondria, mitochondrial biogenesis, mitophagy, reactive oxygen species

DOI: 10.3233/JAD-190048

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2019

Authors: Marino Gammazza, Antonella | Restivo, Vincenzo | Baschi, Roberta | Caruso Bavisotto, Celeste | Cefalù, Angelo B. | Accardi, Giulia | Conway de Macario, Everly | Macario, Alberto J.L. | Cappello, Francesco | Monastero, Roberto

Article Type: Research Article

Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma …levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Hsp60, Hsp70, Hsp90, molecular chaperones, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-180825

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018