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

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Salissou, Maibouge Tanko Mahamane | Lu, Youming | Hu, Fan | Zhou, Lan-Ting | Almansob, Yusra A.M. | Liu, Dan

Article Type: Research Article

Abstract: Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice …are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α -synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro . Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT. Show more

Keywords: Alpha-synuclein, behavior deficit, MPTP, neurotoxicity, oxidative stress, oxytocin, Parkinson’s disease

DOI: 10.3233/JAD-191091

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Marelli, Cecilia | Hourregue, Claire | Gutierrez, Laure-Anne | Paquet, Claire | Menjot de Champfleur, Nicolas | De Verbizier, Delphine | Jacob, Melissa | Dubois, Jonathan | Maleska, Aleksandra Maceski | Hirtz, Christophe | Navucet, Sophie | Bennys, Karim | Dumurgier, Julien | Cognat, Emmanuel | Berr, Claudine | Magnin, Eloi | Lehmann, Sylvain | Gabelle, Audrey

Article Type: Research Article

Abstract: Background: Memory troubles and hippocampal atrophy are considered more frequent and focal atrophy less severe in late-onset (>65 years) than in presenile behavioral variant frontotemporal dementia (bvFTD). Objective: To compare cerebrospinal fluid (CSF) and plasma biomarkers in late-onset and presenile bvFTD. Methods: Multicentric retrospective study (2007-2017) on patients with clinical diagnosis of bvFTD. Results: This study included 44 patients (67%) with presenile and 22 (33%) with late-onset bvFTD (comparable mean disease duration; n  = 11 with causal mutations). Hippocampal atrophy was more frequent (80% versus 25.8%) and severe in late-onset bvFTD (median Scheltens score: 3 …[0–4] versus 1 [0–3]), without difference after adjustment for age. Lobar atrophy and focal hypometabolism/hypoperfusion were not different between groups. The median CSF Aβ1-42 and phosphorylated tau (P-tau) concentrations were in the normal range and comparable between groups. Axonal neurodegeneration biomarkers were within the normal range (CSF T-tau; plasma T-tau in late-onset bvFTD) or higher (plasma neurofilament light chain (NFL); plasma T-tau in presenile bvFTD) than the normal values, but globally not different between bvFTD groups. Plasma glial fibrillary acid protein (GFAP) was strongly increased in both bvFTD groups compared with the values in controls of the same age. Conclusion: The CSF and plasma biomarker profiles did not suggest a more aggressive neurodegeneration in the presenile group (comparable T-tau, NFL, and GFAP levels) or the co-existence of Alzheimer’s disease in the late-onset group (comparable and within normal range CSF Aβ1-42 and P-tau). The severity of the neurodegenerative process seems comparable in presenile and late-onset bvFTD. Show more

Keywords: Biomarkers, cerebrospinal fluid, frontotemporal dementia, glial fibrillary acid protein, late-onset, neurofilament light chain

DOI: 10.3233/JAD-190378

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Pasha, Evan P. | Rutjes, Elmer | Tomoto, Tsubasa | Tarumi, Takashi | Stowe, Ann | Claassen, Jurgen A.H.R. | Munro Cullum, C. | Zhu, David C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: Vascular dysfunction has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the relationship of arterial stiffening with brain amyloid-β (Aβ) burden in at risk patients is unclear. Objective: We aimed to determine the relationship of aortic and carotid arterial stiffening with Aβ burden in patients with amnestic mild cognitive impairment (aMCI), a proposed transitional stage between normal aging and AD. Methods: Thirty-two older adults with aMCI underwent 18 Florbetapir PET amyloid imaging to ascertain Aβ burden via standardized uptake value ratio (SUVR). Carotid-femoral pulse wave velocity (cfPWV), which reflects aortic stiffness, …and carotid β stiffness index and distensibility, which reflect local cerebral arterial stiffness, thus having direct impact on the cerebral circulation, were measured using applanation tonometry and ultrasonography. Results: Region-of-interest based analysis showed that precuneus and mean cortex Aβ SUVR were correlated positively with carotid β stiffness index and negatively with carotid distensibility after adjusting for age, sex, mean arterial pressure (MAP), pulse pressure (PP), and APOE4 status. Whole-brain voxel-wise analysis showed that Aβ SUVR was positively correlated with carotid β stiffness index, and negatively with carotid distensibility at the precuneus/cingulate gyrus after multiple comparison correction. cfPWV was not correlated with Aβ SUVR. Conclusions: Carotid rather than aortic stiffening is independently associated with brain Aβ burden in patients with aMCI after adjusting for age, sex, MAP, PP, and APOE4 status. These findings provide evidence that arterial stiffening, particularly carotid artery stiffening, may contribute to AD pathology in patients with aMCI. Show more

Keywords: Arterial stiffness, amyloid, mild cognitive impairment, ClinicalTrials.gov identifier: NCT01146717

DOI: 10.3233/JAD-191073

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Zhu, Yi | Zhong, Qian | Ji, Jie | Ma, Jinhui | Wu, Han | Gao, Yaxin | Ali, Nawab | Wang, Tong

Article Type: Research Article

Abstract: Background: Regular aerobic exercises could improve global cognition in older adults with mild cognitive impairment (MCI), such as aerobic dance a type of commonly practiced aerobic exercises. However, its effects remain debatable in improving the cognitive function in patients with MCI. Objective: The aim of this systematic review and meta-analysis is to evaluate the effects of aerobic dance on cognitive function among older adults with MCI. Methods: We searched articles in the MEDLINE, PubMed, Embase, and The Cochrane Library databases from inception to 28 February 2019, with the following criteria: 1) randomized controlled trials; 2) older …adults with MCI; 3) aerobic dance intervention. Results: Five studies of 842 participants were identified. This meta-analysis showed that aerobic dance can significantly improve global cognition (Mini-Mental State Examination: MD = 1.43; 95% CI:[0.59, 2.27]; p  = 0.0009; Alzheimer’s Disease Assessment Scale-Cognitive Subscale: MD=–2.30; 95% CI:[–3.60, –1.00]; p  = 0.0005), and delayed recall ability (SMD = 0.46;95% CI: [0.30, 0.62]; p  < 0.00001) in older adults with MCI. In addition, have positive effects on improving executive function (Trial-Making Test A: MD = –2.37;95% CI:[–4.16, –0.58]; p  = 0.010; Trial-Making Test B: MD = –16.0; 95% CI: [–30.03, –2.11]; p  = 0.020) and immediate recall ability (SMD = 0.24;95% CI: [0.01, 0.46]; p  = 0.04). Conclusion: Aerobic dance significantly improves global cognitive function and memory in older adults with MCI. In addition, it also benefits executive function. However, due to the limitations as the review states, more randomized controlled trials with better study design and larger sample sizes should be conducted in the future research to make it much clearer. Show more

Keywords: Aerobic dance, cognition, executive function, memory, meta-analysis, mild cognitive function, randomized controlled trials

DOI: 10.3233/JAD-190681

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Sundström, Anna | Sörman, Daniel Eriksson | Hansson, Patrik | Ljungberg, Jessica Körning | Adolfsson, Rolf

Article Type: Short Communication

Abstract:  High mental demands at work was examined as a possible protective factor to reduce the risk of dementia in 1,277 initially dementia-free participants, aged 60 years and older. The cohort was followed for a mean of 13.6 years. During follow-up, 376 participants developed all-cause dementia (Alzheimer’s disease = 199; vascular dementia = 145). The association between mental demands at work and dementia was analyzed with Cox hazard models, adjusted for a range of covariates. The results revealed no significant association between mental demands at work and incidence of dementia. Based on the measures used in this study, it was concluded that high mental demands …at work may not reduce the risk of dementia later on in life. Show more

Keywords: Aging, Alzheimer’s disease, cognitive occupation complexity, cognitive reserve, dementia, mental demands at work, vascular dementia

DOI: 10.3233/JAD-190920

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Tabara, Yasuharu | Yamanaka, Mikihiro | Setoh, Kazuya | Segawa, Hiroaki | Kawaguchi, Takahisa | Kosugi, Shinji | Nakayama, Takeo | Matsuda, Fumihiko | the Nagahama Study Group

Article Type: Short Communication

Abstract: Accumulation of advanced glycation end products (AGEs) has been linked with cognitive decline as a risk factor based on the analysis in small populations. We investigated the association between skin autofluorescence of AGEs and global cognitive function in a Japanese older (≥60 years) population (n  = 4,041). The AGEs quartiles were inversely associated with the Revised Hasegawa’s Dementia Scale score (Q1: reference, Q2: β= –0.011, p  = 0.537, Q3: β= –0.043, p  = 0.016, Q4: β= –0.064, p  < 0.001) independent of major risk factors. Accumulation of AGEs was associated with lower cognitive performance in older adults.

Keywords: Advanced glycation end products, cognitive function, epidemiological studies, population at risk

DOI: 10.3233/JAD-190878

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Liu, Peng | Zhao, Beiyu | Wei, Meng | Li, Yanbo | Liu, Jie | Ma, Louyan | Shang, Suhang | Huo, Kang | Wang, Jin | Li, Rui | Qu, Qiumin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common age-associated neurodegenerative disease featured by progressive learning and memory deficit, and Aβ was identified as playing a key role in the process of AD and was theorized to be caused by the imbalance of production and clearance. Increasing evidence suggested an association between sleep deprivation and AD. Our recent study found that chronic sleep restriction (CSR) caused cognitive impairment and Aβ accumulation in rats, but the underlining mechanism was unclear. In the present study, we investigated the effects of inflammation on Aβ accumulation induced by CSR. We found that CSR significantly increased the …expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α ), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) in brain, and the inflammatory factors levels were positively correlated with Aβ42 deposition. Additionally, the inflammatory factors were correlated with BACE1, LRP-1, and RAGE levels in both the hippocampus and the prefrontal cortex. Furthermore, the plasma levels of IL-1β, TNF-α , and NO were elevated after CSR, and the concentration of plasma inflammatory mediators were correlated with plasma levels of sLRP1 and sRAGE. These results suggested that the inflammation in brain and plasma might be involved in the CSR-induced Aβ accumulation. Show more

Keywords: Alzheimer’s disease, amyloid-β, chronic sleep restriction, inflammation, risk factor

DOI: 10.3233/JAD-191317

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Silva, Dina | Cardoso, Sandra | Guerreiro, Manuela | Maroco, João | Mendes, Tiago | Alves, Luísa | Nogueira, Joana | Baldeiras, Inês | Santana, Isabel | de Mendonça, Alexandre

Article Type: Research Article

Abstract: Background: Diagnosis of Alzheimer’s disease (AD) confirmed by biomarkers allows the patient to make important life decisions. However, doubt about the fleetness of symptoms progression and future cognitive decline remains. Neuropsychological measures were extensively studied in prediction of time to conversion to dementia for mild cognitive impairment (MCI) patients in the absence of biomarker information. Similar neuropsychological measures might also be useful to predict the progression to dementia in patients with MCI due to AD. Objective: To study the contribution of neuropsychological measures to predict time to conversion to dementia in patients with MCI due to AD. …Methods: Patients with MCI due to AD were enrolled from a clinical cohort and the effect of neuropsychological performance on time to conversion to dementia was analyzed. Results: At baseline, converters scored lower than non-converters at measures of verbal initiative, non-verbal reasoning, and episodic memory. The test of non-verbal reasoning was the only statistically significant predictor in a multivariate Cox regression model. A decrease of one standard deviation was associated with 29% of increase in the risk of conversion to dementia. Approximately 50% of patients with more than one standard deviation below the mean in the z score of that test had converted to dementia after 3 years of follow-up. Conclusion: In MCI due to AD, lower performance in a test of non-verbal reasoning was associated with time to conversion to dementia. This test, that reveals little decline in the earlier phases of AD, appears to convey important information concerning conversion to dementia. Show more

Keywords: Alzheimer’s disease (AD), amyloid-β, cognitive impairment, dementia, mild cognitive impairment due to AD, neuropsychological assessment, prodromal AD, Raven Coloured Progressive Matrices

DOI: 10.3233/JAD-191133

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Zeghari, Radia | Manera, Valeria | Fabre, Roxane | Guerchouche, Rachid | König, Alexandra | Phan Tran, Minh Khue | Robert, Philippe

Article Type: Research Article

Abstract: Background: Apathy, a highly prevalent behavioral disorder in Alzheimer’s disease and other related disorders, is currently assessed using clinical scales as it is for all neuropsychiatric disorders. Objective: The aim of this study is to propose a new type of assessment using new technologies designed to assess loss of interest by a more implicit and indirect method. Methods: The Interest Game is a form of interactive self-report, where categories of interests are presented in order to quantify them and identify the activities that constitute them. Two indices can be extracted, the number of categories and the …number of activities selected. We compared the scores between three groups: Apathetic (A) and Non-Apathetic (NA) subjects (according to the Apathy Diagnostic Criteria) and controls with no objective cognitive impairment. Results: 95 subjects were included. Results showed that subjects from the A group had significantly less interests (both categories and images selected) than the NA group. As expected, the control group selected a higher number of categories than the other groups. The diagnosis (minor or major neurocognitive disorder) and level of education had also a significant effect on the number of categories selected. Furthermore, subjects with major neurocognitive disorder (NCD) had significantly less interests than minor NCD group. The number of categories measure was more sensitive than the number of images selected. Conclusion: The Interest Game is a promising tool to quantify and identify subject interests and differentiate between apathetic and non-apathetic subjects. Future studies should focus on including more apathetic subjects in the minor NCD group and validating this tool with the general population. Show more

Keywords: Apathy, interest, leisure activities, neurocognitive disorders, serious games

DOI: 10.3233/JAD-191282

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Moazzami, Kasra | Wittbrodt, Matthew T. | Lima, Bruno B. | Kim, Jeong Hwan | Hammadah, Muhammad | Ko, Yi-An | Obideen, Malik | Abdelhadi, Naser | Kaseer, Belal | Gafeer, M. Mazen | Nye, Jonathon A. | Shah, Amit J. | Ward, Laura | Raggi, Paolo | Waller, Edmund K. | Bremner, J. Douglas | Quyyumi, Arshed A. | Vaccarino, Viola

Article Type: Research Article

Abstract: Background: Circulating progenitor cells (CPC) have been associated with memory function and cognitive impairment in healthy adults. However, it is unclear whether such associations also exist in patients with coronary artery disease (CAD). Objective: To assess the association between CPCs and memory performance among individuals with CAD. Methods: We assessed cognitive function in 509 patients with CAD using the verbal and visual Memory subtests of the Wechsler memory scale-IV and the Trail Making Test parts A and B. CPCs were enumerated with flow cytometry as CD45med /CD34+ blood mononuclear cells, those co-expressing other epitopes representing populations …enriched for hematopoietic and endothelial progenitors. Results: After adjusting for demographic and cardiovascular risk factors, lower number of endothelial progenitor cell counts were independently associated with lower visual and verbal memory scores (p for all < 0.05). There was a significant interaction in the magnitude of this association with race (p  < 0.01), such that the association of verbal memory scores with endothelial progenitor subsets was present in Black but not in non-Black participants. No associations were present with the hematopoietic progenitor-enriched cells or with the Trail Making Tests. Conclusion: Lower numbers of circulating endothelial progenitor cells are associated with cognitive impairment in patients with CAD, suggesting a protective effect of repair/regeneration processes in the maintenance of cognitive status. Impairment of verbal memory function was more strongly associated with lower CPC counts in Black compared to non-Black participants with CAD. Whether strategies designed to improve regenerative capacity will improve cognition needs further study. Show more

Keywords: Circulating progenitor cells, cognitive impairment, coronary artery disease, dementia, memory, trail making tests, Wechsler Memory Scale

DOI: 10.3233/JAD-191063

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Teimouri, Elham | Rainey-Smith, Stephanie R. | Bharadwaj, Prashant | Verdile, Giuseppe | Martins, Ralph N.

Article Type: Review Article

Abstract:  There is currently no effective treatment for Alzheimer’s disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention strategies are currently the focus of much research. In the search for compounds that potentially confer benefit, the Amla fruit and its extracts have drawn attention. Amla preparations have been used for centuries in traditional Indian medicine systems such as Ayurveda, with various parts of the plant used to treat a variety of diseases. Here we review many animal-based studies, and some …clinical trials, which have shown that Amla, and its extracts, exert many positive effects on dyslipidemia, hyperglycemia, inflammation, oxidative stress, apoptosis, and autophagy, that contribute to AD risk. Collectively, this evidence suggests that Amla may be of value as part of an effective disease-delaying treatment for AD. Show more

Keywords: Amla, Alzheimer’s disease, anti-inflammatory, antioxidant, cardiovascular disease, type 2 diabetes

DOI: 10.3233/JAD-191033

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2020

Authors: Maasakkers, Carlijn M. | de Heus, Rianne A.A. | Thijssen, Dick H.J. | Melis, René J.F. | Gardiner, Paul A. | Claassen, Jurgen A.H.R.

Article Type: Research Article

Abstract: Background: Physicians are cautious to prescribe antihypertensive drugs in frail older adults because of the potential adverse effects, especially in those with cognitive complaints. Lifestyle aspects might provide safe targets to lower blood pressure in older adults. Objective: Our goal was to evaluate the associations between activity patterns and blood pressure in memory clinic patients. Methods: We used an observational cross-sectional study to measure activity patterns with the ActivPAL accelerometer, and simultaneous home blood pressure levels in memory clinic patients (age range 51–87 years old). Office blood pressure was assessed during routine clinical practice. …Results: 41 patients (mean age of 74.3 (7.7) years of age, 46% female) were included. Sedentary parameters were associated with higher mean home blood pressure, with the strongest correlation between more prolonged sitting bouts and higher SBP (r  = 0.58, p  < .0001). Physical activity parameters were negatively associated with mean home blood pressure. Adjusted regression estimates remained significant, showing, e.g., a 4.5 (95% CI = 1.6;7.4) mmHg increase in SBP for every hour of sitting per day and a –1.0 (95% CI = –1.8;–0.2) mmHg decrease in DBP for every additional 1000 steps per day. No strong correlations were found between any of the activity pattern variables and office blood pressure. Conclusion: Associations between activity pattern variables and blood pressure were only found with home blood pressure measurements, not with office measurements. Longitudinal evaluations of these associations are now needed to explore if reducing prolonged sedentary bouts and increasing step count indeed serve as safe targets to lower blood pressure. Show more

Keywords: Blood pressure, cognitive decline, dementia, hypertension, physical activity, sedentary behavior

DOI: 10.3233/JAD-191310

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Livny, Abigail | Schnaider Beeri, Michal | Heymann, Anthony | Moshier, Erin | Berman, Yuval | Mamistalov, Mary | Shahar, Danit-Rivka | Tsarfaty, Galia | Leroith, Derek | Preiss, Rachel | Soleimani, Laili | Silverman, Jeremy M. | Bendlin, Barbara B. | Levy, Andrew | Ravona-Springer, Ramit

Article Type: Research Article

Abstract: Backgrounds: The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. Objective: To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. Methods: Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n  = 24, Hp 2-1: n  = 77, Hp 2-2: n  = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, …controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. Results: Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus’ volume; p  = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p  = 0.0348), increased by 0.429% for Hp 2-1 (p  = 0.0457), and by 0.077% for Hp 2-2 (p  = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p  = 0.6011) and superior (p  = 0.2025) frontal gyri or for the middle temporal gyrus (p  = 0.503). Conclusions: The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype. Show more

Keywords: Brain volume, diabetes, haptoglobin genotype, vitamin E

DOI: 10.3233/JAD-191294

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Okafor, Maureen | Nye, Jonathon A. | Shokouhi, Mahsa | Shaw, Leslie | Goldstein, Felicia | Hajjar, Ihab

Article Type: Research Article

Abstract: Background: Tau positron emission tomography (PET) imaging is used in research, but its relation to cerebrospinal fluid (CSF) tau and other Alzheimer’s disease (AD)-related clinical measures is unclear in mild cognitive impairment with AD biomarkers (MCI-AD). Objective: To determine associations between 18 F-flortaucipir PET and CSF AD biomarkers, cognitive functioning, and neuroimaging measures in MCI-AD. Methods: In 29 participants 50 years or older with MCI-AD, 18 F-flortaucipir PET, CSF total tau (T-tau), phosphorylated tau181p (P-tau), amyloid-β (Aβ), structural MRI, and neuropsychological testing were collected as baseline assessments of an ongoing clinical trial. 11 C-Pittsburgh compound …B PET was simultaneously conducted in 20 participants. Associations between 18 F-flortaucipir PET and these measures were assessed by multiple linear regression adjusted for potential confounders and using global, lobar, and voxel-wise standardized uptake value ratio (SUVr). Results: Whole brain 18 F-flortaucipir SUVr was significantly associated with CSF T-tau (r  = 0.68, p  < 0.001) and P-tau (r  = 0.42, p  = 0.04) after adjusting for age, sex, race, and education, with strongest associations in the temporal region (T-tau: r  = 0.69, p  < 0.001; P-tau: r  = 0.49, p  = 0.02). Voxel-wise analysis confirmed these regional associations. 18 F-flortaucipir PET was also associated with CSF Aβ (r  = –0.45, p  = 0.03), episodic memory (r  = –0.61, p  = 0.001), visuospatial working memory (r  = –0.46, p  = 0.02), and brain cortical thickness (r  = –0.44, p  = 0.03) but not hippocampal volume. In the amyloid PET subset, although 11 C-PiB PET associated strongly with 18 F-flortaucipir (r  = 0.79, p ≤0.001), associations were stronger between 11 C-PiB and key outcomes, compared to 18 F-flortaucipir. Conclusion: 18 F-flortaucipir PET is moderately associated with CSF AD biomarkers and other AD-related phenotypes. The associations in this MCI-AD sample are stronger than previously described in other populations. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, cognitive function, cortical thickness, flortaucipir, mild cognitive impairment, positron emission tomography, tau PET

DOI: 10.3233/JAD-191330

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Patel, Hamel | Iniesta, Raquel | Stahl, Daniel | Dobson, Richard J.B. | Newhouse, Stephen J.

Article Type: Research Article

Abstract: Background: The typical approach to identify blood-derived gene expression signatures as a biomarker for Alzheimer’s disease (AD) have relied on training classification models using AD and healthy controls only. This may inadvertently result in the identification of markers for general illness rather than being disease-specific. Objective: Investigate whether incorporating additional related disorders in the classification model development process can lead to the discovery of an AD-specific gene expression signature. Methods: Two types of XGBoost classification models were developed. The first used 160 AD and 127 healthy controls and the second used the same 160 AD with …6,318 upsampled mixed controls consisting of Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, bipolar disorder, schizophrenia, coronary artery disease, rheumatoid arthritis, chronic obstructive pulmonary disease, and cognitively healthy subjects. Both classification models were evaluated in an independent cohort consisting of 127 AD and 687 mixed controls. Results: The AD versus healthy control models resulted in an average 48.7% sensitivity (95% CI = 34.7–64.6), 41.9% specificity (95% CI = 26.8–54.3), 13.6% PPV (95% CI = 9.9–18.5), and 81.1% NPV (95% CI = 73.3–87.7). In contrast, the mixed control models resulted in an average of 40.8% sensitivity (95% CI = 27.5–52.0), 95.3% specificity (95% CI = 93.3–97.1), 61.4% PPV (95% CI = 53.8–69.6), and 89.7% NPV (95% CI = 87.8–91.4). Conclusions: This early work demonstrates the value of incorporating additional related disorders into the classification model developmental process, which can result in models with improved ability to distinguish AD from a heterogeneous aging population. However, further improvement to the sensitivity of the test is still required. Show more

Keywords: Age-related memory disorders, Alzheimer’s disease, biomarkers, dementia, gene expression, human, machine learning, microarray analysis, neurodegenerative disorders

DOI: 10.3233/JAD-191163

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Cipollari, Eleonora | Szapary, Hannah J. | Picataggi, Antonino | Billheimer, Jeffrey T. | Lyssenko, Catherine A. | Ying, Gui-Shuang | Shaw, Leslie M. | Kling, Mitchel A. | Kaddurah-Daouk, Rima | Rader, Daniel J. | Praticò, Domenico | Lyssenko, Nicholas N. | for the Alzheimer’s Disease Metabolomics Consortium

Article Type: Research Article

Abstract: Background: Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer’s disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD. Objective: To devise and characterize an assay that can access intracellular cholesterol and cholesterol efflux in neural cells in living subjects. Methods: We modified the protocol for high-density lipoprotein cholesterol efflux capacity (CEC) from macrophages, a biomarker that accesses cholesterol in macrophages in atherosclerosis. To measure cerebrospinal fluid (CSF) CECs from neurons, microglia, and astrocytes, CSF …was exposed to, correspondingly, neuronal, microglial, and astrocytic cholesterol source cells. Human neuroblastoma SH-SY5Y, mouse microglial N9, and human astroglial A172 cells were used as the cholesterol source cells. CSF samples were screened for contamination with blood. CSF CECs were measured in a small cohort of 22 individuals. Results: CSF CECs from neurons, microglia, and astrocytes were moderately to moderately strongly correlated with CSF concentrations of cholesterol, apolipoprotein A-I, apolipoprotein E, and clusterin (Pearson’s r  = 0.53–0.86), were in poor agreement with one another regarding CEC of the CSF samples (Lin’s concordance coefficient rc  = 0.71–0.76), and were best predicted by models consisting of, correspondingly, CSF phospholipid (R2  = 0.87, p  < 0.0001), CSF apolipoprotein A-I and clusterin (R2  = 0.90, p  < 0.0001), and CSF clusterin (R2  = 0.62, p  = 0.0005). Conclusion: Characteristics of the CSF CEC metrics suggest a potential for independent association with AD and provision of fresh insight into the role of cholesterol in AD pathogenesis. Show more

Keywords: ABCA1, ABCG1, Alzheimer’s disease biomarkers, apolipoprotein A-I, apolipoprotein E, cell cholesterol efflux, clusterin (apolipoprotein J), SR-BI

DOI: 10.3233/JAD-191246

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Xia, Wenqing | Luo, Yong | Chen, Yu-Chen | Chen, Huiyou | Ma, Jianhua | Yin, Xindao

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) accelerates cognitive decline, which is believed to be triggered by aberrant neural activity. Objective: To explore how glucose fluctuations impact brain functional architecture and cognition in T2DM patients. Methods: T2DM patients were divided according to glycemic variability, forming two categories: patients with fluctuating glucose levels and patients with stable glucose levels. Degree centrality (DC) was calculated within the cerebral gray matter of each participant and was compared among the two patient groups and a healthy control group. The relationships between glucose fluctuations and aberrant DC and cognitive performance, as well …as the relationship between aberrant DC and cognitive performance, were further explored. Results: Compared with T2DM patients with stable glucose levels, T2DM patients with fluctuating glucose levels exhibited significantly worse performance on the Montreal Cognitive Assessment, Trail Making Test-B (TMT-B), and verbal fluency test (VFT), as well as significant decreases in DC in certain regions, most of which were within the default mode network. In the combined T2DM group, the mean amplitude of glycemic excursions (MAGE) was positively correlated with TMT-B scores and negatively correlated with VFT scores. Moreover, the MAGE was negatively correlated with DC in the left medial prefrontal cortex (mPFC). In addition, TMT-B scores were negatively correlated with reduced DC in the left mPFC. Conclusion: These findings further contribute to the mounting evidence of the effects of glycemic variability on the diabetic brain. Tightened control of glucose fluctuations might prevent cognitive decline and changes in brain functional architecture in T2DM individuals. Show more

Keywords: Brain, cognitive impairments, functional magnetic resonance imaging, type 2 diabetes mellitus

DOI: 10.3233/JAD-191217

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Sun, Lin | Cheng, Baoying | Zhou, Yuxun | Fan, Yating | Li, Wei | Qiu, Qi | Fang, Yuan | Xiao, Shifu | Zheng, Honghua | Li, Xia

Article Type: Research Article

Abstract: Background: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) includes a large spectrum of neurodegenerative disorders. Objective: To identify the relationship of ErbB4 mutation and ALS/FTD. Methods: Here, we report an atypical case of frontal variant behavioral abnormalities at the initial stage, a stable plateau stage of 5 years, and paralysis involving both upper and lower motor neurons followed by progressive cognitive dysfunction at the advanced stage. The clinical findings suggested a diagnosis of ALS/FTD, and genetic testing revealed erb-b2 receptor tyrosine kinase 4 (ErbB4 ) heterozygous mutation (c.2136 T>G, p.I712M), identified in an ALS pedigree previously. …We modeled mutant ErbB4 protein through the SWISS-MODEL Server, and speculated on the structural change caused by the mutation. We also identified that ErbB4 (I712M) mutation led to reduced auto-phosphorylation of ErbB4 upon neuregulin-1 (NRG1) stimulation. Results: A functional analysis of ErbB4 mutation demonstrated an obviously decreased auto-phosphorylation of ErbB4 involving in the pathogenesis of ALS/FTD. Conclusion: We firstly found ErbB4 mutation to be identified in ALS/FTD. Show more

Keywords: Amyotrophic lateral sclerosis, ErbB4, frontotemporal dementia, I712M, neuregulin-1

DOI: 10.3233/JAD-191230

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Zhang, Wei | Luo, Peng

Article Type: Research Article

Abstract: Cardiovascular disorders, e.g., atherosclerosis and hypertension, increase susceptibility to neurodegenerative diseases, like dementia and Alzheimer’s disease (AD), with undetermined mechanisms. Moreover, whether myocardial infarction (MI) may similarly increases occurrence of AD is unknown. In the current study, we performed a MI model in wild-type and AD-prone APP/PS1 mice and assessed the development of AD in these mice. We found that MI-treated mice of both wild-type and APP/PS1 behaved poorer in a social recognition test, the Morris water maze, and the plus-maze discriminative avoidance task, compared to sham-treated controls. Mechanistically, MI significantly increased the levels of reactive oxygen species, as well …as increased deposition of amyloid-β peptide aggregates and phosphorylation of tau protein in mouse brain, two signature pathological features for AD. Moreover, the microglia in the MI-mice appeared to alter polarization to a more proinflammatory phenotype. Together, our data suggest that MI may be a predisposing factor for AD development. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, microglia, myocardial infarction, reactive oxygen species, tau

DOI: 10.3233/JAD-191225

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Gardner, Raquel C. | Rivera, Ernesto | O’Grady, Megan | Doherty, Colin | Yaffe, Kristine | Corrigan, John | Bogner, Jennifer | Kramer, Joel | Wilson, Fiona

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) is an established risk factor for dementia but mechanisms are uncertain. Accurate TBI exposure classification is critical for cognitive aging research studies seeking to discover mechanisms and treatments of post-TBI dementia. Brief TBI screens, commonly used in epidemiological studies of cognitive aging, are insensitive, leading to exposure mis-classification. Comprehensive TBI interviews, while more sensitive, may be impractical. Objective: We aimed to develop and validate a scalable, self-administered, comprehensive, web-based, TBI exposure survey for use in international cognitive aging research. Methods: We adapted a gold-standard comprehensive TBI interview (the Ohio State University …TBI Identification Method; OSU TBI-ID) into a self-administered web-based survey for older adults (Older Adult modification of the OSU TBI-ID; OA OSU TBI-ID). We assessed reliability of our web-based survey versus the gold-standard interview among 97 older adults with normal cognition and mild cognitive impairment (MCI). In addition, we assessed sensitivity of the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) brief TBI screen versus the interview among 70 older adults with normal cognition. Results: Our OA OSU TBI-ID web-based survey had good to excellent reliability versus the interview (κ 0.66–0.73; ICCs 0.68–0.81) even among the sub-set with MCI (κ 0.74–0.88; ICCs 0.76–0.85), except for several age-at-injury variables. The NACC UDS brief TBI screen missed 50% of TBI exposures identified using the OSU TBI-ID interview. Conclusion: The OSU TBI-ID interview and web-based survey may facilitate more accurate TBI exposure classification in cognitive aging research thereby accelerating discovery of targetable mechanisms of post-TBI dementia. Show more

Keywords: Clinical research, cognitive aging, reliability, screening, traumatic brain injury, validation

DOI: 10.3233/JAD-191138

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Hou, Ting-ting | Han, Yun-Dan | Cong, Lin | Liu, Cui-cui | Liang, Xiao-Yan | Xue, Fu-zhong | Du, Yi-feng

Article Type: Research Article

Abstract: Hyperphosphorylated tau is one of the key characteristics of Alzheimer’s disease (AD), and tau pathology correlates with cognitive impairment in AD better than amyloid-β (Aβ) pathology. Thus, a complete understanding of the relevant factors involved in tau phosphorylation is important for AD treatment. APOE ɛ 4 , the strongest genetic risk factor for AD, was found to be involved in tau pathology in frontotemporal dementia. This result indicated that apolipoprotein E (ApoE) may also participate in tau phosphorylation in AD. In the present study, we injected Aβ oligomer (AβO) into the lateral ventricles of wild-type (WT) mice and apoE-/- …mice to test the process of tau phosphorylation in the acute phase. We found that the phosphorylated tau and phosphokinase levels were higher in WT mice than in apoE-/- mice. These phenomena were also confirmed in vitro . ApoE ɛ 4-treated apoE-/- neurons exhibited more phosphorylated tau than ApoE ɛ 2- and ApoE ɛ 3-treated neurons. We also found that AβO induced more serious inflammation in WT mice and in ApoE-positive cultured neurons. Anti-inflammatory treatment reduced the phosphorylated tau level induced by AβOs in ApoE-positive neurons. These results suggest that ApoE may facilitate the phosphorylation of tau induced by AβO via inflammation. Show more

Keywords: Alzheimer’s disease, amyloid-β apolipoprotein E, inflammation, oligomer, phosphorylated tau

DOI: 10.3233/JAD-190711

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: James, Hailey J. | Van Houtven, Courtney Harold | Lippmann, Steven | Burke, James R. | Shepherd-Banigan, Megan | Belanger, Emmanuelle | Wetle, Terrie Fox | Plassman, Brenda L.

Article Type: Research Article

Abstract: Background: Amyloid-β PET scans will likely become an integral part of the diagnostic evaluation for Alzheimer’s disease if Medicare approves reimbursement for the scans. However, little is known about patients’ and their care partners’ interpretation of scan results. Objective: This study seeks to understand how accurately patients with mild cognitive impairment (MCI) or dementia and their care partners report results of amyloid-β PET scans and factors related to correct reporting. Methods: A mixed-methods approach was used to analyze survey data from 1,845 patient-care partner dyads and responses to open-ended questions about interpretation of scan results from …a sub-sample of 200 dyads. Results: Eighty-three percent of patients and 85% of care partners correctly reported amyloid-β PET scan results. Patients’ higher cognitive function was associated with a small but significant decrease in the predicted probability of not only patients accurately reporting scan results (ME: –0.004, 95% CI: –0.007, –0.000), but also care partners accurately reporting scan results (ME: –0.006, 95% CI: –0.007, –0.001), as well as decreased concordance between patient and care partner reports (ME: –0.004, 95% CI: –0.007, –0.001). Content analysis of open-ended responses found that participants who reported the scan results incorrectly exhibited more confusion about diagnostic terminology than those who correctly reported the scan results. Conclusion: Overall, patients with MCI or dementia showed high rates of accurate reporting of amyloid-β PET scan results. However, responses to questions about the meaning of the scan results highlight the need for improved provider communication, including providing written explanations and better prognostic information. Show more

Keywords: Alzheimer’s disease, amyloid PET, caregivers, dementia, mild cognitive impairment

DOI: 10.3233/JAD-190922

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Miguel, Laetitia | Frebourg, Thierry | Campion, Dominique | Lecourtois, Magalie

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is neuropathologically defined by two key hallmarks: extracellular senile plaques composed primarily of amyloid-β (Aβ) peptide and intraneuronal neurofibrillary tangles, containing abnormally hyperphosphorylated tau protein. The tau protein is encoded by the MAPT gene. Recently, the H1 and H2 haplotypes of the MAPT gene were associated with AD risk. The minor MAPT H2 haplotype has been linked with a decreased risk of developing late-onset AD (LOAD). MAPT haplotypes show different levels of MAPT/Tau expression with H1 being ∼1.5-fold more expressed than H2, suggesting that MAPT expression level could be related to …LOAD risk. In this study, we investigated whether this moderate difference in MAPT/Tau expression could influence Aβ-induced toxicity in vivo. We show that modest overexpression of tau protein in Drosophila exacerbates neuronal phenotypes in AβPP/BACE1 flies. The exacerbation of neuronal defects correlates with the accumulation of insoluble dTau oligomers, suggesting that the moderate difference in level of tau expression observed between H1 and H2 haplotypes could influence Aβ toxicity through the production of oligomeric tau insoluble species. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, Drosophila , oligomers, tau

DOI: 10.3233/JAD-190906

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Liguori, Claudio | Spanetta, Matteo | Izzi, Francesca | Franchini, Flaminia | Nuccetelli, Marzia | Sancesario, Giulia Maria | Di Santo, Simona | Bernardini, Sergio | Mercuri, Nicola Biagio | Placidi, Fabio

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease. Objective: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations. Methods: Mild to moderate AD patients were …enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls. Results: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation. Conclusion: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients. Show more

Keywords: Alzheimer’s disease, cognition, orexin, sleep-wake cycle, tau proteins

DOI: 10.3233/JAD-191124

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Toniolo, Sofia | Serra, Laura | Olivito, Giusy | Caltagirone, Carlo | Mercuri, Nicola B. | Marra, Camillo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: The cognitive role of the cerebellum has recently gained much attention, and its pivotal role in Alzheimer’s disease (AD) has now been widely recognized. Diffusion tensor imaging (DTI) has been used to evaluate the disruption of the microstructural milieu in AD, and though several white matter (WM) tracts such as corpus callosum, inferior and superior longitudinal fasciculus, cingulum, fornix, and uncinate fasciculus have been evaluated in AD, data on cerebellar WM tracts are currently lacking. We performed a tractography-based DTI reconstruction of the middle cerebellar peduncle (MCP), and the left and right superior cerebellar peduncles separately (SCPL and SCPR) and …addressed the differences in fractional anisotropy (FA), axial diffusivity (Dax), radial diffusivity (RD), and mean diffusivity (MD) in the three tracts between 50 patients with AD and 25 healthy subjects. We found that AD patients showed a lower FA and a higher RD compared to healthy subjects in MCP, SCPL, and SCPR. Moreover, a higher MD was found in SCPR and SCPL and a higher Dax in SCPL. This result is important as it challenges the traditional view that WM bundles in the cerebellum are unaffected in AD and might identify new targets for therapeutic interventions. Show more

Keywords: Alzheimer’s disease, cerebellum, diffusion tensor imaging, probabilistic tractography, white matter

DOI: 10.3233/JAD-191125

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Hong, Yue | Alvarado, Rachel L. | Jog, Amod | Greve, Douglas N. | Salat, David H.

Article Type: Research Article

Abstract: Background: Studies have found that individuals with mild cognitive impairment (MCI) exhibit a range of deficits outside the realm of primary explicit memory, yet the role of response speed and implicit learning in older adults with MCI have not been established. Objective: The current study aims to explore and document response speed and implicit learning in older adults with neuropsychologically defined MCI using a simple serial reaction (SRT) task. In addition, the study aims to explore the feasibility of a novel utilization of the simple cognitive task using machine learning procedures as a proof of concept. …Method: Participants were 22 cognitively healthy older adults and 20 older adults with MCI confirmed through comprehensive neuropsychological evaluation. Two-sample t -test, multivariate regression, and mixed-effect models were used to investigate group difference in response speed and implicit learning on the SRT task. We also explored the potential utility of SRT feature analysis through random forest classification. Results: With demographic variables controlled, the MCI group showed overall slower reaction time and higher error rate compared to the cognitively healthy volunteers. Both groups showed significant simple motor learning and implicit learning. The learning patterns were not statistically different between the two groups. Random forest classification achieved overall accuracy of 80.9%. Conclusions: Individuals with MCI demonstrated slower reaction time and higher error rate compared to cognitively healthy volunteers but demonstrated largely preserved motor learning and implicit sequence learning. Preliminary results from random forest classification using features from SRT performance supported further research in this area. Show more

Keywords: Aging, implicit learning, mild cognitive impairment, response speed, supervised machine learning

DOI: 10.3233/JAD-191323

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Rädke, Anika | Michalowsky, Bernhard | Thyrian, Jochen René | Eichler, Tilly | Xie, Feng | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Dementia care management (DCM) aims to provide optimal treatment for people with dementia (PwD). Treatment and care needs are dependent on patients’ sociodemographic and clinical characteristics and thus, economic outcomes could depend on such characteristics. Objective: To detect important subgroups that benefit most from DCM and for which a significant effect on cost, QALY, and the individual cost-effectiveness could be achieved. Methods: The analysis was based on 444 participants of the DelpHi-trial. For each subgroup, the probability of DCM being cost-effective was calculated and visualized using cost-effectiveness acceptability curves. The impact of DCM on individual …costs and QALYs was assessed by using multivariate regression models with interaction terms. Results: The probability of DCM being cost-effective at a willingness-to-pay of 40,000€ /QALY was higher in females (96% versus 16% for males), in those living alone (96% versus 26% for those living not alone), in those being moderately to severely cognitively (100% versus 3% for patients without cognitive impairment) and functionally impaired (97% versus 16% for patients without functional impairment), and in PwD having a high comorbidity (96% versus 26% for patients with a low comorbidity). Multivariate analyses revealed that females (b = –10,873; SE = 4,775, p  = 0.023) who received the intervention had significantly lower healthcare cost. DCM significantly improved QALY for PwD with mild and moderate cognitive (b = +0.232, SE = 0.105) and functional deficits (b = +0.200, SE = 0.095). Conclusion: Patients characteristics significantly affect the cost-effectiveness. Females, patients living alone, and those being moderately cognitively and functionally impaired benefit most from DCM. For those subgroups, healthcare payers could gain the highest cost savings and the highest effects on QALYs when DCM will be implemented. Show more

Keywords: Alzheimer’s disease, cost-effectiveness acceptability curve, cost-effectiveness analysis, dementia, economic evaluation, health care costs, individual cost-effectiveness ratio, net benefit regression, net monetary benefit

DOI: 10.3233/JAD-190578

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Jung, Na-Yeon | Kim, Eun Soo | Kim, Hyang-Sook | Jeon, Sumin | Lee, Myung Jun | Pak, Kyoungjune | Lee, Jae-Hyeok | Lee, Young Min | Lee, Kangyoon | Shin, Jin-Hong | Ko, Jun Kyeung | Lee, Jae Meen | Yoon, Jin A | Hwang, Chungsu | Choi, Kyung-Un | Lee, Eun Chong | Seong, Joon-Kyung | Huh, Gi Yeong | Kim, Dae-Seong | Kim, Eun-Joo

Article Type: Research Article

Abstract:  The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between CSF Aβ1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer’s disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aβ1-42 , t-tau, and p-tau levels were analyzed in 203 individuals [27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases] consecutively recruited from two dementia clinics. We used both visual and standardized …uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aβ1-42 and t-tau/Aβ1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aβ1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aβ1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aβ1-42 .  However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aβ1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aβ1-42 and amyloid PET, baseline CSF Aβ1-42 better predicted AD conversion. Show more

Keywords: Alzheimer disease, amyloid, cerebrospinal fluid, mild cognitive impairment, positron emission tomography, tau

DOI: 10.3233/JAD-191109

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Koch, Manja | Costanzo, Simona | Fitzpatrick, Annette L. | Lopez, Oscar L. | DeKosky, Steven | Kuller, Lewis H. | Price, Julie | Mackey, Rachel H. | Jensen, Majken K. | Mukamal, Kenneth J.

Article Type: Research Article

Abstract: Background: Light to moderate alcohol consumption has been variably associated with lower or higher risk of dementia, but effects on Alzheimer’s disease pathology are less clear. Objective: We determined whether late-life alcohol consumption was associated with Alzheimer’s disease pathology among older adults. Methods: We assessed the associations of alcohol consumption self-reported in 2000–2002 with brain amyloid-β deposition on PET scans, and white matter lesion and hippocampal volume on MRIs measured 7–9 years later in 189 participants of the Ginkgo Evaluation of Memory Study (age 75–87 years at baseline) who were free of clinical dementia, using multivariable-adjusted …and inverse probability-weighted robust linear regression models. Results: Alcohol consumption was not statistically significantly associated with amyloid-β deposition (standardized uptake value ratio difference per drink: –0.013 [95% CI: –0.027, 0.002]). Both non-drinkers and participants consuming ≥1 drink(s)/week had higher white matter lesion volume (% intracranial volume) than did the reference group of those consuming <1 drink/week (differences: 0.25 % [95% CI: 0.01, 0.50]; 0.26 % [95% CI: 0.02, 0.50]). The association of alcohol consumption and hippocampal volume was modified by age (p  = 0.02). Among participants younger than 77 years, participants consuming 1–7 drinks/week had larger hippocampal volume compared with participants consuming <1 drink/week. Conclusions: Alcohol consumption was not statistically significantly associated with amyloid-β deposition 7–9 years later. Non-drinking and greater alcohol consumption were associated with higher white matter lesion volume compared with drinking <1 drink/week. Moderate drinking was associated with higher hippocampal volume in younger individuals. Given the selective nature of this population and adverse health effects of excessive alcohol consumption, these findings warrant further investigation, but cannot be translated into clinical recommendations. Show more

Keywords: Alcohol, brain amyloid-β , epidemiology, hippocampal volume, white matter lesions

DOI: 10.3233/JAD-190834

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: de Heus, Rianne A.A. | Reumers, Stacha F.I. | van der Have, Alba | Tumelaire, Maxime | Tully, Phillip J. | Claassen, Jurgen A.H.R.

Article Type: Research Article

Abstract: Background: High visit-to-visit blood pressure variability (BPV) has been associated with cognitive decline and cerebral small vessel disease (cSVD), in particular cerebrovascular lesions. Whether day-to-day BPV also relates to cSVD has not been investigated. Objective: To investigate the cross-sectional association between day-to-day BPV and total cSVD MRI burden in older memory clinic patients. Methods: We included outpatients referred to our memory clinic, who underwent cerebral MRI as part of their diagnostic assessment. We determined the validated total cSVD score (ranging from 0–4) by combining four markers of cSVD that were visually rated. Home blood pressure (BP) …measurements were performed for one week, twice a day, according to international guidelines. BPV was defined as the within-subject coefficient of variation (CV; standard deviation/mean BP*100). We used multivariable ordinal logistic regression analyses adjusted for age, sex, smoking, diabetes, antihypertensive medication, history of cardiovascular disease, and mean BP. Results: For 82 patients (aged 71.2±7.9 years), mean home BP was 140/79±15/9 mmHg. Dementia and mild cognitive impairment were diagnosed in 46% and 34%, respectively. 78% had one or more markers of cSVD. Systolic CV was associated with cSVD burden (adjusted odds ratio per point increase in CV = 1.29, 95% confidence interval = 1.04–1.60, p  = 0.022). There were no differences in diastolic CV and mean BP between the cSVD groups. When we differentiated between morning and evening BP, only evening BPV remained significantly associated with total cSVD burden. Conclusion: Day-to-day systolic BPV is associated with cSVD burden in memory clinic patients. Future research should indicate whether lowering BPV should be included in BP management in older people with memory complaints. Show more

Keywords: Blood pressure, blood pressure variability, cerebrovascular damage, cognition, dementia, home monitoring, small vessel disease

DOI: 10.3233/JAD-191134

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Fleiner, Tim | Dauth, Hannah | Zijlstra, Wiebren | Haussermann, Peter

Article Type: Short Communication

Abstract:  Physical exercise is an effective treatment approach for neuropsychiatric symptoms (NPS), but it is unknown whether the reduction of NPS has an impact on professional caregiver burden. A randomized controlled trial in acute dementia care with N  = 70 patients, n  = 35 per group, was conducted. The intervention group (IG) received an exercise program, the control group a social stimulation program. The RM-ANOVA showed a significant group x time interaction with time effects for the IG and decreased caregiver burden due to the exercise program at follow-up. Physical exercise programs may not only be beneficial for the patients but also for …their professional caregivers. Show more

Keywords: dementia, hospital care, neuropsychiatric symptoms, professional caregiver burden, structured exercise, DRKS00006740 (German Clinical Trial Register)

DOI: 10.3233/JAD-191102

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Bharadwaj, Prashant | Martins, Ralph N.

Article Type: Research Article

Abstract: Increased amyloid-β (Aβ) accumulation associated with abnormal autophagy-lysosomal activity and nutrient kinase dysregulation are common features in Alzheimer’s disease (AD) brain. Recent studies have identified PRKAG2 and TIPRL genes that control nutrient kinase regulated autophagy, and here we determined if their expression is altered in postmortem AD brains. Gene and protein expression of TIPRL were unchanged. However, gene expression of PRKAG2 was increased 3-fold and its protein levels positively correlated with Aβ accumulation in the AD brain. In summary, our findings suggest that increased PRKAG2 is an important contributing factor to Aβ accumulation in the AD brain.

Keywords: Alzheimer’s disease, amyloid-β , autophagy, PRKAG2, TIPRL

DOI: 10.3233/JAD-190948

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Uijen, Iris L. | Aaronson, Justine A. | Karssemeijer, Esther G.A. | Olde Rikkert, Marcel G.M. | Kessels, Roy P.C.

Article Type: Short Communication

Abstract: The aim of this study was to investigate whether the effect of physical activity on cognitive function in persons with dementia is moderated by patient characteristics as Apolipoprotein E and dementia type. We included 101 individuals with dementia and calculated the reliable change index to determine the change in global cognition, executive function, episodic memory, working memory, and processing speed before and after a 12-week exercise training. We found a higher treatment-related benefit in episodic memory in persons with non-Alzheimer’s disease compared to persons with Alzheimer’s disease, and in executive function in individuals with better baseline cognitive function.

Keywords: APOE ɛ4, cognitive function, dementia, physical activity, reliable change index

DOI: 10.3233/JAD-190606

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Triantafyllou, Areti | Ferreira, João Pedro | Kobayashi, Masatake | Micard, Emilien | Xie, Yu | Kearney-Schwartz, Anna | Hossu, Gabriela | Rossignol, Patrick | Bracard, Serge | Benetos, Athanase

Article Type: Research Article

Abstract: Background: Hippocampal atrophy is associated with cognitive decline. Determining the clinical features associated with hippocampal volume (HV)/atrophy may help in tailoring preventive strategies. Objective: This study was aimed to investigate the association between HV (at visit 2) and vascular status (both at visit 1 and visit 2) in a cohort of individuals aged 60+ with hypertension and without overt cognitive impairment at visit 1 (visit 1 and visit 2 were separated by approximately 8 years). Methods: Hippocampal volume was estimated in brain MRIs as HV both clinically with the Scheltens’ Medial Temporal Atrophy score, and automatically …with the Free Surfer Software application. A detailed medical history, somatometric measurements, cognitive tests, leukoaraiosis severity (Fazekas score), vascular parameters including pulse wave velocity, central blood pressure, and carotid artery plaques, as well as several biochemical parameters were also measured. Results: 113 hypertensive patients, 47% male, aged 75.1±5.6 years, participated in both visit 1 and visit 2 of the ADELAHYDE study. Age (β= –0.30) and hypertension duration (β= –0.20) at visit 1 were independently associated with smaller HV at visit 2 (p  < 0.05 for all). In addition to these variables, low body mass index (β= 0.18), high MRI Fazekas score (β= –0.20), and low Gröber-Buschke total recall (β= 0.27) were associated with smaller HV at visit 2 (p  < 0.05 for all). Conclusion: In a cohort of older individuals without cognitive impairment at baseline, we described several factors associated with lower HV, of which hypertension duration can potentially be modified. Show more

Keywords: Aortic stiffness, brain MRI, cognitive decline, dementia, hippocampus, hypertension, macrovascular, microvascular, white matter lesions

DOI: 10.3233/JAD-190842

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Goldwaser, Eric L. | Acharya, Nimish K. | Wu, Hao | Godsey, George A. | Sarkar, Abhirup | DeMarshall, Cassandra A. | Kosciuk, Mary C. | Nagele, Robert G.

Article Type: Research Article

Abstract: Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer’s disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro . Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42 ), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α 7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α 7nAChR as …well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aβ42 peptide and serum from AD and control subjects. The rate and extent of Aβ42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α 7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aβ42 . Initial co-localization of IgG, α 7nAChR, and Aβ42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aβ42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aβ42 deposition in AD. Show more

Keywords: Aβ1-42 , Alzheimer’s disease, autoantibodies, blood-brain barrier, brain-reactive autoantibodies, cerebrovasculature

DOI: 10.3233/JAD-190962

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Casaletto, Kaitlin B. | Rentería, Miguel Arce | Pa, Judy | Tom, Sarah E. | Harrati, Amal | Armstrong, Nicole M. | Rajan, K. Bharat | Mungas, Dan | Walters, Samantha | Kramer, Joel | Zahodne, Laura B.

Article Type: Research Article

Abstract: Background: Active lifestyles are related to better cognitive aging outcomes, yet the unique role of different types of activity are unknown. Objective: To examine the independent contributions of physical (PA) versus cognitive (CA) leisure activities to brain and cognitive aging. Methods: Independent samples of non-demented older adults from University of California, San Francisco Hillblom Aging Network (UCSF; n  = 344 typically aging) and University of California, Davis Diversity cohort (UCD; n  = 485 normal to MCI) completed: 1) self-reported engagement in current PA and CA (UCSF: Physical Activity Scale for the Elderly and Cognitive Activity Scale; UCD: Life …Experiences Assessment Form); 2) neuropsychological batteries; and 3) neuroimaging total gray matter volume, white matter hyperintensities, and/or global fractional anisotropy. PA and CA were simultaneously entered into multivariable linear regression models, adjusting for demographic characteristics and functional impairment severity. Results: Brain outcomes : In UCSF, only PA was positively associated with gray matter volume and attenuated the relationship between age and fractional anisotropy. In UCD, only CA was associated with less white matter hyperintensities and attenuated the relationship between age and gray matter volume. Cognitive outcomes : In both cohorts, greater CA, but not PA, related to better cognition, independent of age and brain structure. In UCSF, CA attenuated the relationship between fractional anisotropy and cognition. In UCD, PA attenuated the association between white matter hyperintensities and cognition. Conclusions: Although their specificity was not easily teased apart, both PA and CA are clearly related to better brain and cognitive resilience markers across cohorts with differing educational, racial, and disease statuses. PA and CA may independently contribute to converging neuroprotective pathways for brain and cognitive aging. Show more

Keywords: Brain aging, cognitive aging, exercise, mental stimulation, reserve

DOI: 10.3233/JAD-191114

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Sinha, Neha | Berg, Chelsie N. | Shaw, Ashlee | Gluck, Mark A.

Article Type: Research Article

Abstract: African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer’s disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7, a gene known to confer significantly greater AD risk in African …Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotypes. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype. Show more

Keywords: ABCA7, aerobic exercise, African American, Alzheimer’s disease

DOI: 10.3233/JAD-190723

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Talaei, Mohammad | Feng, Lei | Barrenetxea, Jon | Yuan, Jian-Min | Pan, An | Koh, Woon-Puay

Article Type: Research Article

Abstract: Background: Few prospective studies with long duration of follow-up have assessed the relations of body mass index (BMI) and weight change with cognitive function, especially in Asian populations. Objective: To investigate whether BMI and weight change in midlife are associated with cognitive impairment in old age. Methods: We used data from 14,691 participants in the Singapore Chinese Health Study and computed weight change as the difference between weight reported at baseline (1993–1998) at mean age of 53.0 years and follow-up 1 (1999–2004) at mean age of 58.6 years. Cognitive impairment was determined using education-specific cut-offs of …the Singapore Modified Mini-Mental State Examination at follow-up 3 (2014–2016) at mean age of 72.9 years. We used multivariable logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations. Results: Obesity (as defined BMI ≥27.5 kg/m2 ) was associated with a higher risk of cognitive impairment at baseline (OR 1.33, 95% CI 1.12–1.58) and follow-up 1 (OR 1.30, 95% CI 1.10–1.54) compared to BMI of 18.5–22.9 kg/m2 . Underweight (BMI <18.5 kg/m2 ) was not associated with a significant risk either at baseline (OR 0.91, 95% CI 0.73–1.13) or follow-up 1 (OR 1.05, 95% CI 0.85–1.28). Compared to participants with <5% weight change, the ORs (95% CIs) of cognitive impairment were 1.20 (1.03–1.41) for those with 5–9.9% weight loss, 1.53 (1.29–1.81) for ≥10% weight loss, 1.00 (0.85–1.17) for 5–9.9% weight gain, and 1.50 (1.28–1.75) for ≥10% weight gain. Conclusion: Obesity, weight loss, and excessive weight gain at midlife were associated with an increased risk of cognitive impairment at old age. Show more

Keywords: Body mass index, Chinese, cognitive impairment, cohort study, weight change

DOI: 10.3233/JAD-191052

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Tobey, Hope | Lucas, Tyler | Paul, Soumen | Berr, Stuart S. | Mehrkens, Brittney | Brolinson, Per Gunnar | Klein, Bradley G. | Costa, Blaise M.

Article Type: Short Communication

Abstract:  Current advancements in neurovascular biology relates a mechanoceutics treatment, known as cranial osteopathic manipulation (COM), with Alzheimer’s disease (AD). COM could be used as an evidence-based treatment strategy to improve the symptoms of AD if molecular mechanisms, which currently remain unclear, are elucidated. In the present pilot study, using transgenic rats, we have identified COM mediated changes in behavioral and biochemical parameters associated with AD phenotypes. We expect these changes may have functional implications and that might account for improved clinical outcomes of COM treatment. Further investigations on COM will be helpful to establish an adjunct treatment for AD.

Keywords: Alzheimer’s disease, cranial osteopathic manipulation, TgF344-AD, mechanical pressure, mechanoceutics

DOI: 10.3233/JAD-191071

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Whitwell, Jennifer L. | Tosakulwong, Nirubol | Weigand, Stephen D. | Graff-Radford, Jonathan | Duffy, Joseph R. | Clark, Heather M. | Machulda, Mary M. | Botha, Hugo | Utianski, Rene L. | Schwarz, Christopher G. | Senjem, Matthew L. | Strand, Edythe A. | Ertekin-Taner, Nilufer | Jack Jr , Clifford R. | Lowe, Val J. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Rates of amyloid-β (Aβ) accumulation have been characterized across the cognitively normal totypical Alzheimer’s dementia spectrum, but little is known about Aβ accumulation inatypical Alzheimer’s disease (AD)and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD). Objective: We aimed tocharacterize longitudinal Aβ accumulation anddetermine the influence of age, apolipoprotein E genotype, disease duration, and sexin atypical AD and FTLD. Methods: 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serialPiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated for every scan. Mixed …effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ. Results: Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOE ɛ 4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET≤4 years. Female sex was associated with faster rates of accumulation in atypical AD. Conclusion: Accumulation of Aβ is observed in atypical AD and FTLD, although different demographic factors influenceaccumulation in these diseases providing insight into different biological mechanisms of Aβ deposition. Show more

Keywords: Alzheimer’s disease, amyloid plaques, frontotemporal lobar degeneration, positron emission tomography

DOI: 10.3233/JAD-190699

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Benvenutto, Agnès | Guedj, Eric | Felician, Olivier | Eusebio, Alexandre | Azulay, Jean-Philippe | Ceccaldi, Mathieu | Koric, Lejla

Article Type: Research Article

Abstract: Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer’s disease (AD) pathology. We thus compared clinical, eye movement, and 18 FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A+ ) were compared with 16 CBS patients without amyloidosis (CBS-A- ). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A+ patients who displayed more posterior cortical abnormalities, CBS-A- patients demonstrated more anterior cortical and brain …stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on 18 FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination. Show more

Keywords: Alzheimer’s disease, corticobasal syndrome, DaTSCAN© , eye movements, 18FDG-PET, video-oculography

DOI: 10.3233/JAD-190961

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Ceyzériat, Kelly | Tournier, Benjamin B. | Millet, Philippe | Frisoni, Giovanni B. | Garibotto, Valentina | Zilli, Thomas

Article Type: Review Article

Abstract:  Alzheimer’s disease (AD) is a neurodegenerative disease characterized by extracellular amyloid-β (Aβ ) peptide aggregates, forming amyloid plaques, and intracellular deposits of phosphorylated tau. Neuroinflammation is now considered as the third hallmark of AD. The majority of clinical trials tested pharmacological strategies targeting amyloid, tau, and neuroinflammation, with disappointing results overall. In parallel, innovative strategies exploring other pathways and approaches are being tested. In this article, we focus on the rationale and preliminary preclinical evidence for a novel application to AD of a widely used therapeutic strategy for oncological and benign conditions: low-dose radiation therapy (LD-RT). LD-RT has shown …to be effective against systemic amyloid deposits, as well as against chronic inflammatory diseases, and could thus be able to modulate amyloid load and neuroinflammation in AD. The anti-amyloid effect could be possibly mediated by the LD-RT action on the β -sheet structure of amyloid fibrils, by breaking H-bonds, and depolymerize glucoaminoglycans which are highly radiation-sensitive molecules associated with amyloid fibrils. The anti-inflammatory effect could be linked to the decrease of leukocytes-endothelial cells interactions and to the stimulation of the release of anti-inflammatory molecules. One preclinical study has observed a dramatic reduction of amyloid plaques 4 weeks post-RT, more important with fractionated protocols at low doses than hypofractionated single dose treatments, associated with modulation of inflammatory and anti-inflammatory cytokines and cognitive improvement. Ongoing Phase I clinical trials will test the ability of LD-RT to hold these promises. Show more

Keywords: Alzheimer’s disease, amyloid, inflammation, radiotherapy, therapy

DOI: 10.3233/JAD-190984

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Li, Xiaoran | Liu, Chunyan | Wang, Rong

Article Type: Review Article

Abstract:  Light modulation plays an important role in understanding the pathology of brain disorders and improving brain function. Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise control, and have recently become a method for quick manipulation of genetically identified types of neurons. Photobiomodulation (PBM) is light therapy that utilizes non-ionizing light sources, including lasers, light emitting diodes, or broadband light. It provides a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice. This manuscript reviews 1) how optogenetic approaches have been used …to dissect neural circuits in animal models of Alzheimer’s disease, Parkinson’s disease, and depression, and 2) how low level transcranial lasers and LED stimulation in humans improves brain activity patterns in these diseases. State-of-the-art brain machine interfaces that can record neural activity and stimulate neurons with light have good prospects in the future. Show more

Keywords: Alzheimer’s disease, brain-machine interfaces, depression, optogenetics, Parkinson’s disease, photobiomodulation, transcranial near-infrared stimulation

DOI: 10.3233/JAD-191240

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Martins, Tânia Soares | Magalhães, Sandra | Rosa, Ilka Martins | Vogelgsang, Jonathan | Wiltfang, Jens | Delgadillo, Ivonne | Catita, José | da Cruz e Silva, Odete A.B. | Nunes, Alexandra | Henriques, Ana Gabriela

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) diagnosis is based on psychological and imaging tests but can also include monitoring cerebrospinal fluid (CSF) biomarkers. However, CSF based-neurochemical approaches are expensive and invasive, limiting their use to well-equipped settings. In contrast, blood-based biomarkers are minimally invasive, cost-effective, and a widely accessible alternative. Blood-derived exosomes have recently emerged as a reliable AD biomarker source, carrying disease-specific cargo. Fourier-transformed infrared (FTIR) spectroscopy meets the criteria for an ideal diagnostic methodology since it is rapid, easy to implement, and has high reproducibility. This metabolome-based technique is useful for diagnosing a broad range of diseases, although to our knowledge, …no reports for FTIR spectroscopy applied to exosomes in AD exist. In this ground-breaking pilot study, FTIR spectra of serum and serum-derived exosomes from two independent cohorts were acquired and analyzed using multivariate analysis. The regional UA-cohort includes 9 individuals, clinically diagnosed with AD, mean age of 78.7 years old; and the UMG-cohort comprises 12 individuals, clinically diagnosed with AD (based on molecular and/or imaging data), mean age of 73.2 years old. Unsupervised principal component analysis of FTIR spectra of serum-derived exosomes revealed higher discriminatory value for AD cases when compared to serum as a whole. Consistently, the partial least-squares analysis revealed that serum-derived exosomes present higher correlations than serum. In addition, the second derivative peak area calculation also revealed significant differences among Controls and AD cases. The results obtained suggest that this methodology can discriminate cases from Controls and thus be potential useful to assist in AD clinical diagnosis. Show more

Keywords: Alzheimer’s disease, biomarker, blood, diagnosis, exosomes, serum, spectroscopy

DOI: 10.3233/JAD-191034

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Gezen-Ak, Duygu | Alaylıoğlu, Merve | Genç, Gençer | Şengül, Büşra | Keskin, Ebru | Sordu, Pelin | Güleç, Zeynep Ece Kaya | Apaydın, Hülya | Bayram-Gürel, Çiğdem | Ulutin, Turgut | Yılmazer, Selma | Ertan, Sibel | Dursun, Erdinç

Article Type: Research Article

Abstract: Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer’s disease (AD) or Parkinson’s disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded …gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral mononuclear blood cells of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset <50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA copy number was not a confounder. Intracellular ATP levels of PD case subgroups were significantly higher than those of healthy subjects. We suggest that a systemic dysregulation of transcription of mtDNA or mitochondrial quality control genes might result in the development of a sporadic form of the disease. Additionally, ATP elevation might be an independent compensatory and response mechanism. Hyperactive cells in AD and PD require further investigation. Show more

Keywords: Alzheimer’s disease, ATP, mitochondrial DNA, OXPHOS, PARKIN, Parkinson’s disease, PINK1

DOI: 10.3233/JAD-191164

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2020

Authors: Yang, Heyun | Wang, Wei | Jia, Longfei | Qin, Wei | Hou, Tingting | Wu, Qiaoqi | Li, Haitao | Tian, Yuanruhua | Jia, Jianping

Article Type: Research Article

Abstract: The blood-brain barrier (BBB) can restrict the therapeutic effects of Alzheimer’s disease (AD) medications. While a large number of AD drug treatment trials targeting BBB dynamics have emerged, most have failed due to insufficient permeability. Furthermore, a subset of AD cases, which also feature chronic hypoperfusion are complicated by BBB deficits. We used a mouse model of AD with chronic hypoperfusion—transgenic mice (PS1V97L) with right common carotid artery ligation. In this model, we assessed how chronic cerebral hypoperfusion changed the pathophysiological processes that increase BBB permeability. Compared with control mice, AD mice with chronic hypoperfusion revealed significantly upregulated expression of …the receptor for advanced glycation end products (RAGE) on the BBB. Upregulated RAGE caused increased accumulation of amyloid-β (Aβ) in the brain in these mice. Upregulation of RAGE (or binding to Aβ) can promote activation of the NF-κ B pathway and enhance oxidative stress and increase the release of pro-inflammatory factors. These factors promoted the reduction of tight junction proteins between the endothelial cells in the BBB and increased its permeability. These findings suggest that the transporter RAGE dysregulation on the BBB initiates a series of pathophysiological processes which lead to increased BBB permeability. Taken together, we have shown that chronic hypoperfusion can serve to enhance and aggravate the BBB impairment in AD. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, chronic cerebral hypoperfusion, NF-κB pathway, permeability, transgenic mice

DOI: 10.3233/JAD-191045

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Zhang, Yaxin | Li, Yun | Wang, Rong | Sha, Guiming | Jin, He | Ma, Lina

Article Type: Research Article

Abstract: Background: Hypertension, a common chronic disease, is associated with cognitive impairment. Cognitive impairment, especially Alzheimer’s disease (AD), seriously affects older adults’ quality of life and aggravates the burden of disease on society and families. Elevated Alzheimer-associated neuronal thread protein (AD7c-NTP) has been observed in the urine of patients with AD and mild cognitive impairment; however, it is not clear whether this protein can be used as a biomarker for cognitive impairment in older hypertensive patients. Objective: To explore the value of urinary AD7c-NTP, and the association of urinary AD7c-NTP with cognitive function in older hypertensive patients. …Methods: This was a cross-sectional study. In total, 134 hypertensive patients aged ≥60 years were divided into two groups: Lower Cognitive Function group (LCF group, n  = 89) and a Normal Control group (NC group, n  = 45) based on the Montreal Cognitive Assessment (MoCA). Urinary AD7c-NTP, blood glucose, serum insulin, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. Results: Urinary AD7c-NTP level was significantly higher in the LCF group than in the NC group [0.48 (0.21–1.00) versus 0.25 (0.04–0.44) ng/ml, p  < 0.001]. SOD level [(43.07±23.74) versus (53.12±25.80) U/ml, p  = 0.026] and higher homeostasis model assessment of insulin resistance (HOMA-IR) [7.17 (3.74–13.94) versus 6.01 (3.78–7.43), p = 0.033] was lower in the older hypertensive patients than in the NC group. Urinary AD7c-NTP level was associated with MoCA score and HOMA-IR but not with SOD, MDA, blood glucose, and insulin. Conclusion: The level of urinary AD7c-NTP is elevated in older hypertensive patients with lower cognitive function, and insulin resistance may be involved in the process. Show more

Keywords: AD7c-NTP, cognitive function, hypertension, urine

DOI: 10.3233/JAD-190944

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Jääskeläinen, Olli | Hall, Anette | Tiainen, Mika | van Gils, Mark | Lötjönen, Jyrki | Kangas, Antti J. | Helisalmi, Seppo | Pikkarainen, Maria | Hallikainen, Merja | Koivisto, Anne | Hartikainen, Päivi | Hiltunen, Mikko | Ala-Korpela, Mika | Soininen, Pasi | Soininen, Hilkka | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), …mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, machine learning, metabolomics

DOI: 10.3233/JAD-191226

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Lai, Michelle M.Y. | Sharman, Matthew J. | Ames, David J. | Ellis, Kathryn A. | Cox, Kay L. | Hepworth, Graham | Desmond, Patricia | Cyarto, Elizabeth V. | Martins, Ralph N. | Masters, Colin L. | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Background: There is a paucity of information on the role of microvascular and inflammatory biomarkers in cognitive dysfunction. Objective: This study sought to evaluate the relationships between established and a number of peripheral biomarkers on cognitive patterns in 108 older adults with memory complaints. Methods: Participants in the AIBL Active study aged 60 years and older with at least one vascular risk factor and memory complaints completed a neuropsychological test battery and provided cross-sectional health data. Linear regression models adjusted for covariates examined associations between cognitive performance and a panel of vascular risk factors (Framingham cardiovascular …scores, hs-CRP, homocysteine, fasting glucose, LDL-cholesterol) and peripheral biomarkers (TNF-α , BDNF, VCAM-1, ICAM-1, PAI-1, CD40L). Results: Higher fasting glucose and homocysteine levels were independent factors associated with poorer performance in Trail Making Test (TMT) B (adjusted β= 0.40±0.10 and 0.43±0.09, respectively). Increasing homocysteine levels were weakly associated with poorer global cognition and delayed recall (adjusted β= 0.23±0.10 and –0.20±0.10 respectively). Increasing Framingham cardiovascular scores were related to poorer performance in TMT B (β  = 0.42±0.19). There was early evidence of associations between increasing plasma TNF-α and poorer TMT B (adjusted β  = 0.21±0.10) and between increasing BDNF and better global cognition (β= –0.20±0.09). Conclusion: This study provides evidence to support the associations between vascular risk factors (Framingham scores, fasting glucose, and homocysteine) and poorer cognitive functions. Additionally, we measured several peripheral biomarkers to further investigate their associations with cognition. The relationship between TNF-α , BDNF, and cognitive performance in various domains may offer new insights into potential mechanisms in vascular cognitive impairment. Show more

Keywords: BDNF, biomarkers, cardiovascular disease, cognitive impairment, homocysteine, TNF-α, vascular risk factors, Trial Registration: Australia New Zealand Clinical Trials Registry ACTRN126110006129

DOI: 10.3233/JAD-190953

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Mendes, Fúlvio R. | Leclerc, Jenna L. | Liu, Lei | Kamat, Pradip K. | Naziripour, Arash | Hernandez, Damian | Li, Chris | Ahmad, Abdullah S. | Doré, Sylvain

Article Type: Research Article

Abstract: Background: Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer’s disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2 -EP1 receptor pathway. Objective: Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. Methods: Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. …Results: pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p  = 0.0373) and percent tissue loss (p  = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 group (p  = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p  = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p  = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented with characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. Conclusion: In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits in anatomical outcomes after stroke, mainly in APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, amyloid-β, EP1 receptor, ischemia, permanent middle cerebral artery occlusion, prostaglandin E2, transgenic mice

DOI: 10.3233/JAD-191069

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Abdelhamid, Mona | Jung, Cha-Gyun | Zhou, Chunyu | Abdullah, Mohammad | Nakano, Manabu | Wakabayashi, Hiroyuki | Abe, Fumiaki | Michikawa, Makoto

Article Type: Research Article

Abstract: Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients and amyloid-β protein precursor transgenic (AβPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AβPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated …memory impairment in J20 mice and decreased brain Aβ40 and Aβ42 levels through the inhibition of amyloidogenic processing of AβPP, as it decreased β-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aβ in primary astrocyte cultures. These findings indicate that the reduction in Aβ levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aβ in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD. Show more

Keywords: ABCA1, Alzheimer’s disease, amyloid-β, apolipoprotein E, BACE1, ERK1/2 MAPK, lactoferrin

DOI: 10.3233/JAD-191181

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

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

Article Type: Research Article

Abstract: The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. 141 [72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer’s disease (AD)] cases consisting of Braak stages 0-II and III from the Rush Religious Order Study cohort were used. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOE ɛ 4 status, and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathological diagnosis. Individuals with CAA …were more likely to be classified as Braak stage III relative to those without CAA [OR = 2.33, 95% CI (1.06, 5.14), p  = 0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (β = –0.58, SE = 0.25, p  = 0.02). Episodic memory also showed a significant association between Braak stage and CAA (β = –0.75, SE = 0.35, p  = 0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum. These findings show that CAA plays a key role in the early stages of tau pathology and cognitive decline in AD. Show more

Keywords: Alzheimer’s disease, Braak stage, cerebral amyloid angiopathy, cognition, cognitive aging, mild cognitive impairment, neurofibrillary tangles

DOI: 10.3233/JAD-191151

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Westwood, Sarah | Baird, Alison L. | Anand, Sneha N. | Nevado-Holgado, Alejo J. | Kormilitzin, Andrey | Shi, Liu | Hye, Abdul | Ashton, Nicholas J. | Morgan, Angharad R. | Bos, Isabelle | Vos, Stephanie J.B. | Baker, Susan | Buckley, Noel J. | Ten Kate, Mara | Scheltens, Philip | Teunissen, Charlotte E. | Vandenberghe, Rik | Gabel, Silvy | Meersmans, Karen | Engelborghs, Sebastiaan | De Roeck, Ellen E. | Sleegers, Kristel | Frisoni, Giovanni B. | Blin, Olivier | Richardson, Jill C. | Bordet, Régis | Molinuevo, José L. | Rami, Lorena | Wallin, Anders | Kettunen, Petronella | Tsolaki, Magda | Verhey, Frans | Lléo, Alberto | Sala, Isabel | Popp, Julius | Peyratout, Gwendoline | Martinez-Lage, Pablo | Tainta, Mikel | Johannsen, Peter | Freund-Levi, Yvonne | Frölich, Lutz | Dobricic, Valerija | Legido-Quigley, Cristina | Bertram, Lars | Barkhof, Frederik | Zetterberg, Henrik | Morgan, B. Paul | Streffer, Johannes | Visser, Pieter Jelle | Lovestone, Simon

Article Type: Research Article

Abstract: We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer’s disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery …assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ 4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, plasma, proteomics

DOI: 10.3233/JAD-190434

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Jia, Jianping | Wei, Cuibai | Chen, Wei | Jia, Longfei | Zhou, Aihong | Wang, Fen | Tang, Yi | Xu, Luoyi

Article Type: Research Article

Abstract: Background: Efficacy and dose-effect relationship of donepezil for treating patients with Alzheimer’s disease (AD) have been proven. However, few studies focused on the safety of donepezil, particularly in Chinese patients. Objective: To assess the safety of donepezil 10 mg/day in Chinese patients with mild-to-moderate AD. Methods: In this single-arm, prospective, multicenter trial, 241 patients with mild to moderate AD who had been treated with donepezil 5 mg/day for at least 4 weeks were enrolled. All patients received donepezil 10 mg/day for 20 weeks. Primary outcome was the incidence of adverse events (AEs). Safety profile was evaluated by physical examinations …including vital signs and weight, clinical laboratory tests and electrocardiograms, and also correlation analysis between AEs and APOE genotypes. Results: 241 patients were enrolled. Of which, 38.59% patients experienced at least one AE and 17.43% discontinued due to AEs. Most AEs were mild to moderate, with diarrhea, vomiting, and nausea the most frequently reported. Risk of AEs was significantly increased by concomitant use of drugs for cardiovascular and cerebrovascular diseases. Mean changes in heart rate and corrected QT relative to baseline were –1.08±6.02 beat/min (p  = 0.009) and –3.91±18.68 ms (p  = 0.0062) at week 4 and –1.48 beat/min±7.18 (p  = 0.0028) and –0.66 ms±19.66 (p  = 0.6561) at week 20, respectively. There were no significant changes in other vital sign parameters. Patients’ MMSE scores improved significantly after treatment (p  = 0.0038), especially for non-APOE ɛ 4 allele carriers and patients ≤75 years. Conclusion: Donepezil 10 mg/day can be tolerated and is effective in Chinese patients with mild-to-moderate AD. Show more

Keywords: Alzheimer’s disease, Chinese, clinical trial, donepezil, safety

DOI: 10.3233/JAD-190940

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Chen, Shi-Dong | Li, Hong-Qi | Shen, Xue-Ning | Li, Jie-Qiong | Xu, Wei | Huang, Yu-Yuan | Tan, Lan | Dong, Qiang | Yu, Jin-Tai | on behalf of Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: As cognitive function declines with age, identifying factors affecting the trajectory of cognitive decline is an indispensable step toward developing intervention strategies to improve the quality of the elderly life. Objective: We performed a genome-wide association study (GWAS) focusing on memory function to explore single nucleotide polymorphisms (SNPs) associated with the rate of memory decline. Methods: Seven hundred and nine eligible non-Hispanic Caucasians from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included for analysis after quality control. GWAS was performed with linear regression. We subsequently tested whether the associations remained significant in subgroup analysis and …also examined the impact of SNPs on the longitudinal changes in other neuropsychological measures and amyloid pathology. Results: We identified rs13374761-A in SLAMF1 gene associated with less memory decline (MAF = 0.071, β = 0.0103, p  = 4.14×10–8 ). Subgroup analysis showed stability of results across groups with different diagnosis at baseline. Rs13374761-A also had protective effects on global cognition (p  = 0.024), episodic memory (p  = 0.024), and semantic memory (p  = 0.042), and exerts protection against a decrease in CSF Aβ 42 concentration (p  = 0.0463) and an increase in Aβ loading in cerebral cortex (p  = 0.00666) among minor allele carriers. Conclusion: A novel variant in gene SLAMF1 affects the rate of memory decline in the aged population. Given the protective effect of this variant, SLAMF1 should be further investigated as a potential preventive and therapeutic target for monitoring cognition trajectories. Show more

Keywords: Alzheimer’s disease, amyloid, cognitive decline, genome-wide association study, memory, SLAMF1, SNP

DOI: 10.3233/JAD-191214

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

Authors: Beyer, Leonie | Brendel, Matthias | Scheiwein, Franziska | Sauerbeck, Julia | Hosakawa, Chisa | Alberts, Ian | Shi, Kuangyu | Bartenstein, Peter | Ishii, Kazunari | Seibyl, John | Cumming, Paul | Rominger, Axel | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) accumulation in brain of patients with suspected Alzheimer’s disease (AD) can be assessed by positron emission tomography (PET) in vivo. While visual classification prevails in the clinical routine, semiquantitative PET analyses may enable more reliable evaluation of cases with a visually uncertain, borderline Aβ accumulation. Objective: We evaluated different analysis approaches (visual/semiquantitative) to find the most accurate and sensitive interpretation of Aβ-PET for predicting risk of progression from mild cognitive impairment (MCI) to AD. Methods: Based on standard uptake value (SUV) ratios of a cortical-composite volume of interest of 18 F-AV45-PET from MCI …subjects (n = 396, ADNI database), we compared three different reference region (cerebellar grey matter, CBL; brainstem, BST; white matter, WM) normalizations and the visual read by receiver operator characteristics for calculating a hazard ratio (HR) for progression to Alzheimer’s disease dementia (ADD). Results: During a mean follow-up time of 45.6±13.0 months, 28% of the MCI cases (110/396) converted to ADD. Among the tested methods, the WM reference showed best discriminatory power and progression-risk stratification (HRWM of 4.4 [2.6–7.6]), but the combined results of the visual and semiquantitative analysis with all three reference regions showed an even higher discriminatory power. Conclusion: A multi-analytical composite of visual and semiquantitative reference tissue analyses of 18F-AV45-PET gave improved risk stratification for progression from MCI to ADD relative to performance of single read-outs. This optimized approach is of special interest for prospective treatment trials, which demand a high accuracy. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, dementia, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-190818

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

Authors: Ademowo, Opeyemi S. | Dias, Irundika H.K. | Diaz-Sanchez, Lorena | Sanchez-Aranguren, Lissette | Stahl, Wilhelm | Griffiths, Helen R.

Article Type: Research Article

Abstract: Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5’-oxo-valeroyl)-sn -glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer’s disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal …cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1–20μ M) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20μ M POVPC. Following delivery of lutein (0.1-1μ M) and zeaxanthin (0.5-5μ M) over 24 hours in vitro , oxocarotenoid recovery from dSH-SY5Y cells was >  50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1μ M but not 20μ M POVPC, whereas the increase in ROS production induced by 20μ M POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20μ M but not 1μ M POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20μ M POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids. Show more

Keywords: Bioenergetics, carotenoids, lutein, mitochondria, oxidative stress, oxidized phospholipids, POVPC, viability, zeaxanthin

DOI: 10.3233/JAD-190923

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

Authors: Heser, Kathrin | Kleineidam, Luca | Pabst, Alexander | Wiese, Birgitt | Roehr, Susanne | Löbner, Margrit | Hajek, André | van der Leeden, Carolin | Angermeyer, Matthias C. | Scherer, Martin | König, Hans-Helmut | Maier, Wolfgang | Riedel-Heller, Steffi G. | Wagner, Michael

Article Type: Research Article

Abstract: Background: An association between depression and an increased risk for subsequent dementia is well-established. Sexspecific associations are understudied yet. Objective: We aimed to investigate sex-specific associations between depressive symptoms and dementia risk. Methods: Longitudinal analyses were conducted in a pooled data set (n = 4,255, mean age = 80 years) of two prospective cohort studies (LEILA 75+, AgeCoDe). Depressive symptoms were harmonized by dichotomized scores of two different depression screening scales using established cutoffs. Transition to dementia was used as outcome in Cox proportional hazards models. Results: Depressive symptoms at baseline were associated …with an increased risk for subsequent dementia, and this association was more pronounced in males (interaction of depressive symptoms × sex: HR = 1.64, 95% CI: 1.02–2.64, p = 0.042) in a model adjusted for study, age, and education. After additional adjustment for subjective and objective cognition, depressive symptoms and their interaction with sex (HR = 1.38, 95% CI: 0.85–2.23, p = 0.188) were no longer significantly associated with the risk for subsequent dementia. Sex-stratified analyses showed stronger and significant associations between depressive symptoms and subsequent dementia in men (e.g., HR= 2.10, 95% CI: 1.36–3.23, p = 0.001, compared to HR= 1.28, 95% CI: 1.04–1.58, p = 0.020, in women). Conclusions: Overall, we provide evidence for a stronger association between depression and dementia in men compared to women. Depressive symptoms should be diagnosed, monitored, and treated, not only due to depression, but also with respect to the risk for subsequent dementia, especially in elderly men. Show more

Keywords: Dementia, depression, depressive symptoms, gender, sex

DOI: 10.3233/JAD-190770

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

Authors: Dorey, Jean-Michel | Rouch, Isabelle | Padovan, Catherine | Boublay, Nawèle | Pongan, Elodie | Laurent, Bernard | PACO Group | von Gunten, Armin | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Neuroticism is recognized as the personality domain that is most strongly associated with behavioral and psychological symptoms (BPS) of Alzheimer’s disease (AD). Two sub-components of neuroticism have been recently isolated. Neuroticism-withdrawal (N-withdrawal) refers to the tendency to internalize negative emotion, whereas neuroticism-volatility (N-volatility) reflect the predisposition to externalize negative emotions. Objective: The objective of the current study was to investigate the specific influence of these two sub-components of neuroticism on BPS. Methods: One hundred eighty-seven patients with prodromal or mild AD were drawn from the PACO study (Personalité Alzheimer COmportement). Neuroticism and its facets were …assessed at baseline using the NEO-PI-R inventory. N-withdrawal and N-volatility were isolated using a principal component analysis led on the six facets composing neuroticism. BPS were measured with the short version of Neuropsychiatric Inventory (NPI-Q) and collected at baseline, then every 6 months over an 18-month follow-up. Linear mixed-effect analyses were conducted to investigate the association between N-withdrawal, N-volatility, and the severity of BPS over the follow-up. Results: Mean age of the participant was 79.2±6.5; 59% were female; mean MMSE was 24.5±2.5. Both N-volatility and N-withdrawal were related with the NPI-Q (p  <  0.001; p  = 0,004). N-withdrawal was positively associated with anxiety (p  = 0.001) and depression (p  = 0.002), while N-volatility was positively related to delusions (p  = 0.004), agitation/aggression (p  <  0.001), irritability/volatility (p  = 0.037), and apathy (p  = 0.021). Conclusion: The present study demonstrates that N-volatility and N-withdrawal influence the risk of developing BPS in a different way. These results highlight the relevance of considering sub-components of neuroticism when studying links between personality and BPS. Show more

Keywords: Alzheimer’s disease, behavior, dementia, neuroticism, personality

DOI: 10.3233/JAD-190884

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

Authors: Ezzati, Ali | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The ideal participants for Alzheimer’s disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e., placebo arm) and also would be responsive to the therapeutic intervention being studied (i.e., drug arm). One strategy to boost the power of trials is to enroll individuals who are more likely to progress targeted using data-driven predictive models. Objective: To investigate if machine learning (ML) models can effectively predict clinical disease progression (cognitive decline) in mild-to-moderate AD patients during the timeframe of a phase III clinical trial. Methods: Data from 202 participants with a diagnosis …of AD at baseline from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to train ML classifiers that can differentiate between individuals who had declining cognitive function (DC) and individuals with stable cognitive function (SC). DC was defined as any downward change in the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) score over 12 months of follow-up. SC was defined by the absence of decline in ADAS-cog. Trained models were applied to data from 77 participants from the placebo arm of the phase III trial of Semagacestat (LFAN study) to identify subgroups of SC versus DC. Results: Only 74.8% of ADNI participants and 63.6% of LFAN participants had cognitive decline after one year of follow up. K-nearest neighbors (kNN) classifier had an accuracy of 68.3%, sensitivity of 80.1%, and specificity of 33.3% for identifying decliners in ADNI (training sample). In LFAN (validation sample), the model showed an overall accuracy of 61.3%, sensitivity of 65.5%, and specificity of 47.0% in identifying decliners at the 12 months of follow-up. The model had a positive predictive value of 80.8%, which was 17.2% more than the base prevalence of decliners. Conclusions: Machine learning predictive models can be effectively used to boost the power of clinical trials by reducing the sample size. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive decline, machine learning, predictive analytics

DOI: 10.3233/JAD-190822

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Nakanishi, Miharu | Igarashi, Ataru | Ueda, Kaname | Brnabic, Alan J.M. | Treuer, Tamas | Sato, Masayo | Kahle-Wrobleski, Kristin | Meguro, Kenichi | Yamada, Masahito | Mimura, Masaru | Arai, Heii

Article Type: Research Article

Abstract: Background: As the Japanese population ages, caring for people with Alzheimer’s disease (AD) dementia is becoming a major socioeconomic issue. Objective: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia. Methods: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products …(patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods. Results: Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs. Conclusion: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden. Show more

Keywords: Alzheimer’s disease, cost and cost analysis, Japan, observational study

DOI: 10.3233/JAD-190811

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

Authors: Fernando, W.M.A.D. Binosha | Martins, Ian J. | Morici, Michael | Bharadwaj, Prashant | Rainey-Smith, Stephanie R. | Lim, Wei Ling Florence | Martins, Ralph N.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological features, including abnormal deposition of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles, and neuronal death. Identifying therapeutics which can reduce memory deficits at an early stage of the disease has the advantage of slowing or even reversing disease progression before irreversible brain damage has occurred. Consequently, in this study, we investigated the ability of the histone deacetylase inhibitor sodium butyrate (NaB) to attenuate memory deficits in the 5xFAD mouse model of AD following a 12-week feeding regimen. 5xFAD mice demonstrate a unique time course of Aβ pathology, …developing Aβ plaques as early as 2 months. Male mice were assigned to either a control diet or a NaB-supplemented diet which was administered at either 5 mg/kg/day, or 15 mg/kg/day for 12 weeks (each group, N = 15). Supplementation commenced at an early disease stage (8–10 weeks of age). Behavioral testing (contextual and cued fear conditioning) was undertaken, and brain Aβ levels measured, at the end of the 12-week intervention. NaB had profound effects on Aβ levels and on associative learning and cognitive functioning. A 40% reduction in brain Aβ levels and a 25% increase in fear response in both the cued and contextual testing was observed in the NaB-treated animals compared to the control group. These findings suggest that NaB warrants further investigation as a potential therapeutic agent in the treatment of cognitive deficits associated with early stages of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , fear conditioning, sodium butyrate

DOI: 10.3233/JAD-190120

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Article Type: Correction

DOI: 10.3233/JAD-199670

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