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

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