Journal of Alzheimer's Disease - Volume 80, issue 2

Authors: Lee, Seunghyun | Choi, Joon Yul | Lee, Wanhyung

Article Type: Research Article

Abstract: Background: Recent studies have shown that long working hours can have adverse consequences on health and possibly trigger biological processes that mediate the relationship between long working hours and cognitive decline. Objective: To investigate whether long working hours and the overall duration such exposure is associated with a decline in cognitive function. Methods: Data obtained during the Korean Longitudinal Study on Aging (n  = 2,518) during the period 2006–2018 were used to explore the relationship between long working hours and cognitive decline. Korean version of the Mini-Mental State Examination (K-MMSE) scores were used to evaluate cognitive function. …Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), which were used to evaluate declines in K-MMSE scores over the 12-year study period. Results: Overall HR (95% CI) for a decline in cognitive function in long working hours group was 1.13 (0.73–1.17). When categorized by sex, women with long working hours had an HR (95% CI) of 1.50 (1.05–2.22), K-MMSE scores decreased significantly after working long hours for 5 years (p  < 0.01). Conclusion: The study furthers understanding of the effects of long working hours on cognitive decline among female workers. Further research is required to determine the effects of long working hours on cognitive functions. Show more

Keywords: Alzheimer’s disease, cognitive screening test, cohort study, dementia, epidemiology, KLoSA, long working hours, workers

DOI: 10.3233/JAD-201404

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 727-734, 2021

Authors: Sood, Ajay | Pavlik, Valory | Darby, Eveleen | Chan, Wenyaw | Doody, Rachelle

Article Type: Research Article

Abstract: Background: Cognitive profiles characterized by primarily language or visuospatial deficits have been documented in individuals meeting diagnostic criteria for probable Alzheimer’s disease (AD), but their association with progression rate or overall survival is not well described. Objective: To compare time from diagnosis to severe disease stage and death in probable AD patients classified into three groups based on neuropsychological test performance: marked verbal impairment (Verb-PI) with relatively preserved visuospatial function, marked visuospatial impairment with preserved verbal function (Vis-PI), and balanced verbal and visuospatial impairments (Bal-PI). Methods: This prospective cohort study included 540 probable AD patients attending …an academic memory clinic who were enrolled from 1995–2013 and followed annually. Eligible individuals had a Mini-Mental State Exam (MMSE) score ≥10 at baseline, and at least one annual follow up visit. We used Cox proportional hazards modeling to analyze the association of cognitive profiles with time to decline in MMSE and CDR Global Score. Results: Sixty-one (11.3%) individuals had a Verb-PI profile, 86 (16%) had a Vis-PI profile, and 393 (72.8%) a Bal-PI profile. MMSE decline to <10 was faster in Verb-PI than Vis-PI (HR 2.004, 95%CI, 1.062–3.780; p  = 0.032). Progression to CDR-GS = 3 was faster in Verb-PI individuals compared to Bal-PI (HR 1.604, 95%CI, 1.022–2.515; p  = 0.040) or Vis-PI (HR 2.388, 95%CI, 1.330–4.288; p  = 0.004) individuals. Baseline cognitive profile did not affect mortality. Conclusion: A recognition of different AD profiles may help to personalize care by providing a better understanding of pathogenesis and expected progression. Show more

Keywords: Alzheimer’s disease variants, cognitive subtypes, disease progression, survival

DOI: 10.3233/JAD-201124

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 735-747, 2021

Authors: Lladó, Albert | Froelich, Lutz | Khandker, Rezaul K. | Roset, Montserrat | Black, Christopher M. | Lara, Nuria | Chekani, Farid | Ambegaonkar, Baishali M.

Article Type: Research Article

Abstract: Background: There exists considerable variation in disease progression rates among patients with Alzheimer’s disease (AD). Objective: The primary objective of this observational study is to assess the progression of AD by characterizing cognitive, functional, and behavioral changes during the follow-up period between 6 and 24 months. Methods: A longitudinal prospective study with community-dwelling patients with an established clinical diagnosis of AD of mild to moderate severity was conducted in Germany, Spain and the UK. A sample of 616 patients from 69 sites was included. Results: Patients had a mean of 1.9 years (SD = 1.9) since …AD diagnosis at study inclusion. Cognitive symptoms were reported to have first occurred a mean of 1.1 years (SD = 1.7) prior to AD diagnosis and 1.4 (SD = 1.8) years prior to AD treatment. Patients initially diagnosed with mild and moderate AD spent a median (95%CI) of 3.7 (2.8; 4.4) and 11.1 (6.1, ‘not reached’) years until progression to moderate and severe AD, respectively, according to the Mini-Mental State Examination (MMSE) scores. A mixed model developed for cognitive, functional, and neuropsychiatric scores, obtained from study patients at baseline and during follow-up period, showed progressive deterioration of AD patients over time. Conclusion: The study showed a deterioration of cognitive, functional, and neuropsychiatric functions during the follow-up period. Cognitive deterioration was slightly faster in patients with moderate AD compared to mild AD. The duration of moderate AD can be overestimated due to the use of retrospective data, lack of availability of MMSE scores in clinical charts and exclusion of patients at time of institutionalization. Show more

Keywords: Alzheimer’s disease, dementia, disease progression, real-world

DOI: 10.3233/JAD-201172

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 749-759, 2021

Authors: Sahu, Bijayani | Mackos, Amy R. | Floden, Angela M. | Wold, Loren E. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques, neuroinflammation, and neuronal death. There are several well-established genetic and environmental factors hypothesized to contribute to AD progression including air pollution. However, the molecular mechanisms by which air pollution exacerbates AD are unclear. Objective: This study explored the effects of particulate matter exposure on AD-related brain changes using the APP/PS1 transgenic model of disease. Methods: Male C57BL/6;C3H wild type and APP/PS1 mice were exposed to either filtered air (FA) or particulate matter sized under 2.5μm (PM2.5 ) for 6 h/day, …5 days/week for 3 months and brains were collected. Immunohistochemistry for Aβ, GFAP, Iba1, and CD68 and western blot analysis for PS1, BACE, APP, GFAP, and Iba1 were performed. Aβ ELISAs and cytokine arrays were performed on frozen hippocampal and cortical lysates, respectively. Results: The Aβ plaque load was significantly increased in the hippocampus of PM2.5 -exposed APP/PS1 mice compared to their respective FA controls. Additionally, in the PM2.5 -exposed APP/PS1 group, increased astrocytosis and microgliosis were observed as indicated by elevated GFAP, Iba1, and CD68 immunoreactivities. PM2.5 exposure also led to an elevation in the levels of PS1 and BACE in APP/PS1 mice. The cytokines TNF-α, IL-6, IL-1β, IFN-γ , and MIP-3α were also elevated in the cortices of PM2.5 -exposed APP/PS1 mice compared to FA controls. Conclusion: Our data suggest that chronic particulate matter exposure exacerbates AD by increasing Aβ plaque load, gliosis, and the brain inflammatory status. Show more

Keywords: Alzheimer’s disease, amyloid-β plaques, neuroinflammation, particulate matter

DOI: 10.3233/JAD-200919

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 761-774, 2021

Authors: Shoup, Timothy M. | Griciuc, Ana | Normandin, Marc D. | Quinti, Luisa | Walsh, Lindsay V. | Dhaynaut, Maeva | Moon, Sung-Hyun | Guehl, Nicolas J. | Brugarolas, Pedro | Elmaleh, David R. | Fakhri, Georges El | Tanzi, Rudolph E.

Article Type: Research Article

Abstract: Background: Cromolyn is an anti-neuroinflammatory modulator with a multifactorial mechanism of action that has been shown to inhibit amyloid-β (Aβ) aggregation and enhance microglial uptake and clearance of Aβ. Objective: We report the effects of fluoro-cromolyn derivatives on microglial cell toxicity and microglial clearance of Aβ42 . Methods: Microglial cell toxicity for cromolyn derivatives were determined in naive BV2 microglial cells. Microglial clearance assays were performed with Aβ42 in naive BV2 microglial cell line and single cell clone BV2 line expressing CD33WT . PET imaging was performed for three F-18 analogs in a rhesus …macaque. Results: All compounds but derivative 8 exhibited low microglial cell toxicity. Cromolyn 1 and derivatives 2 , 4 , and 7 displayed an increased uptake on Aβ42 in naïve BV2 microglial cells. Derivative 4 increased Aβ42 uptake in a dose-dependent manner and at 75μM resulted in a one-fold increase in Aβ42 uptake in BV2-CD33WT . PET imaging for three [18 F]cromolyn analogs revealed the order of brain tracer penetration to be 4a > 10 > 2a . Tracer 4a exhibited enhanced uptake in areas of high perfusion (putamen, grey matter, and cerebellum) and lower signal in areas of lower perfusion (caudate, thalamus, and white matter). Conclusion: Substantial uptake of Aβ42 in both naïve BV2 and BV2-CD33WT cells observed with 4 indicate conversion of microglial cells from a pro-inflammatory to an activation state favoring Aβ phagocytosis/clearance. These findings suggest that a fluoro-cromolyn analog could reduce fibril-prone Aβ42 in vivo and thereby serve as a therapeutic for the treatment and prevention of AD. Show more

Keywords: Aβ phagocytosis, Alzheimer’s disease therapy, amyloid, microglial, PET imaging

DOI: 10.3233/JAD-201419

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 775-786, 2021

Authors: Wang, Yi-Zhen | Meng, Lei | Zhuang, Qi-Shuai | Shen, Liang

Article Type: Research Article

Abstract: Background: In recent years, the efficacy of type 2 diabetes mellitus (T2DM) drugs in the treatment of Alzheimer’s disease (AD) has attracted extensive interest owing to the close associations between the two diseases. Objective: Here, we screened traditional Chinese medicine (TCM) and multi-target ingredients that may have potential therapeutic effects on both T2DM and AD from T2DM prescriptions. Methods: Network pharmacology and molecular docking were used. Results: Firstly, the top 10 frequently used herbs and corresponding 275 active ingredients were identified from 263 T2DM-related TCM prescriptions. Secondly, through the comparative analysis of 208 potential …targets of ingredients, 1,740 T2DM-related targets, and 2,060 AD-related targets, 61 common targets were identified to be shared. Thirdly, by constructing pharmacological network, 26 key targets and 154 representative ingredients were identified. Further enrichment analysis showed that common targets were involved in regulating multiple pathways related to T2DM and AD, while network analysis also found that the combination of Danshen (Radix Salviae )-Gancao (Licorice )-Shanyao (Rhizoma Dioscoreae ) contained the vast majority of the representative ingredients and might be potential for the cotreatment of the two diseases. Fourthly, MAPK1, PPARG, GSK3B, BACE1, and NR3C1 were selected as potential targets for virtual screening of multi-target ingredients. Further docking studies showed that multiple natural compounds, including salvianolic acid J, gancaonin H, gadelaidic acid, icos-5-enoic acid, and sigmoidin-B, exhibited high binding affinities with the five targets. Conclusion: To summarize, the present study provides a potential TCM combination that might possess the potential advantage of cotreatment of AD and T2DM. Show more

Keywords: Alzheimer’s disease, network pharmacology, traditional Chinese medicines, type 2 diabetes mellitus

DOI: 10.3233/JAD-201336

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 787-797, 2021

Authors: Di Lorito, Claudio | Bosco, Alessandro | Godfrey, Maureen | Dunlop, Marianne | Lock, Juliette | Pollock, Kristian | Harwood, Rowan H. | van der Wardt, Veronika

Article Type: Research Article

Abstract: Background: Caring for someone with dementia is associated with negative and positive experiences. There is little evidence based on large datasets. Objective: To present data around the experience of caring for someone with dementia, to identify support (emotional and practical) needs, and inform future service provision. Methods: A mixed-methods study embedded in the Promoting Activity, Independence and Stability in Early Dementia (PrAISED) Randomized Controlled Trial. We administered questionnaires on strain, quality of life (QoL), and perceived health to 301 caregivers and assessment of cognitive performance, depression, anxiety, and disability in activities of daily living to 301 …participants with dementia. Data were analyzed through descriptive and modelling statistics. A subsample of 20 patient-caregiver dyads were qualitatively interviewed. Data around caregivers’ experience of providing care were extrapolated and analyzed through inductive thematic analysis. Results: There were significant negative associations between caregiver strain and QoL (p  < 0.01) and between caregiver age and QoL (p  < 0.01), and significant positive associations between caregiver strain and disability (p  < 0.01), cognitive impairment (p  < 0.01), depression (p  < 0.05), and anxiety of the person with dementia (p  < 0.05). Older caregivers reported a lack of support, reinforced by their reluctance to seek help. All caregivers reported contradictory emotions associated with caring and accumulation of strain over time. Conclusion: While there is recognition that it is essential to support caregivers, dedicated intervention programs, and support strategies to respond to the needs of older caregivers are still needed. Show more

Keywords: Caregiver, caregiver exhaustion, dementia, quality of life, randomized controlled trial

DOI: 10.3233/JAD-201257

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 799-811, 2021

Authors: Quint, Wim Hendricus | Matečko-Burmann, Irena | Schilcher, Irene | Löffler, Tina | Schöll, Michael | Burmann, Björn Marcus | Vogels, Thomas

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson’s disease and Lewy body dementia also frequently occur together with tau pathology. Objective: Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes …it desirable to simultaneously target more than one disease pathway. Methods: Herein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q. Results: Affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway. Conclusion: Bispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders. Show more

Keywords: Alpha-synuclein, Alzheimer’s disease, C1q, immunotherapy, synucleinopathies, tau, tauopathies

DOI: 10.3233/JAD-201334

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 813-829, 2021

Authors: Golriz Khatami, Sepehr | Domingo-Fernández, Daniel | Mubeen, Sarah | Hoyt, Charles Tapley | Robinson, Christine | Karki, Reagon | Iyappan, Anandhi | Kodamullil, Alpha Tom | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Background: Neuroimaging markers provide quantitative insight into brain structure and function in neurodegenerative diseases, such as Alzheimer’s disease, where we lack mechanistic insights to explain pathophysiology. These mechanisms are often mediated by genes and genetic variations and are often studied through the lens of genome-wide association studies. Linking these two disparate layers (i.e., imaging and genetic variation) through causal relationships between biological entities involved in the disease’s etiology would pave the way to large-scale mechanistic reasoning and interpretation. Objective: We explore how genetic variants may lead to functional alterations of intermediate molecular traits, which can further impact neuroimaging …hallmarks over a series of biological processes across multiple scales. Methods: We present an approach in which knowledge pertaining to single nucleotide polymorphisms and imaging readouts is extracted from the literature, encoded in Biological Expression Language, and used in a novel workflow to assist in the functional interpretation of SNPs in a clinical context. Results: We demonstrate our approach in a case scenario which proposes KANSL1 as a candidate gene that accounts for the clinically reported correlation between the incidence of the genetic variants and hippocampal atrophy. We find that the workflow prioritizes multiple mechanisms reported in the literature through which KANSL1 may have an impact on hippocampal atrophy such as through the dysregulation of cell proliferation, synaptic plasticity, and metabolic processes. Conclusion: We have presented an approach that enables pinpointing relevant genetic variants as well as investigating their functional role in biological processes spanning across several, diverse biological scales. Show more

Keywords: Alzheimer’s disease, genetic variants, knowledge graph, neuroimaging, systems biology

DOI: 10.3233/JAD-201397

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 831-840, 2021

Authors: Tomoto, Tsubasa | Liu, Jie | Tseng, Benjamin Y. | Pasha, Evan P. | Cardim, Danilo | Tarumi, Takashi | Hynan, Linda S. | Munro Cullum, C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer’s disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion. Objective: To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD. Methods: This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid β-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total …CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak ). Results: Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. AET improved VO2peak , decreased carotid β-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r = 0.388, p  = 0.034) and negatively with carotid β-stiffness index (r = –0.418, p  = 0.007) and CBF pulsatility (r = –0.400, p  = 0.014). Decreases in carotid β-stiffness were associated with increases in cerebral perfusion (r = –0.494, p  = 0.003). AET effects on cognitive performance were minimal compared with SAT. Conclusion: AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI. Show more

Keywords: Aerobic exercise, arterial stiffness, carotid artery, cerebral blood flow, cognitive function, mild cognitive impairment

DOI: 10.3233/JAD-201456

Citation: Journal of Alzheimer's Disease, vol. 80, no. 2, pp. 841-853, 2021