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

Authors: de la Torre, Jack C.

Article Type: Research Article

Abstract: This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer’s disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting …the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor’s active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH. Show more

Keywords: Axonal transport, brain hypoperfusion, cognition, mammalian target of rapamycin, neurofibrillary tangles, tau, vascular hypothesis of Alzheimer’s

DOI: 10.3233/JAD-201165

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Baril, Andrée-Ann | Beiser, Alexa S. | Redline, Susan | McGrath, Emer R. | Gottlieb, Daniel J. | Aparicio, Hugo | Seshadri, Sudha | Himali, Jayandra J. | Pase, Matthew P.

Article Type: Short Communication

Abstract: Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer’s type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.

Keywords: Alzheimer’s disease, dementia, inflammation, interleukin-6, sleep apnea, sleep-disordered breathing, sleep disorders

DOI: 10.3233/JAD-200545

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Clark, Ian Albert | Vissel, Bryce

Article Type: Review Article

Abstract: Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post- traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia …chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this. Show more

Keywords: Alzheimer’s disease, cardiac arrest survival, locus coeruleus, neurological COVID-19, norepinephrine, parkinson’s disease, stroke, traumatic brain injury, tumor necrosis factor

DOI: 10.3233/JAD-201186

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

Authors: Schonfeld, Ethan | Schonfeld, Elan | Aman, Casey | Gill, Navroop | Kim, Dami | Rabin, Sydney | Shamshuddin, Bushraa | Sealey, Lloyd | Senno, Ricardo Gabriel

Article Type: Research Article

Abstract: Background: There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers. Objective: We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations. Methods: This IRB-approved study (N = 84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected. Results: Sensory and olfactory deficits …lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE <15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age ≥85, MMSE <15, and male. Lastly, clinical correlates of olfactory lateralization: age <85, number of medications >10, and male. Conclusion: These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas. Show more

Keywords: Alzheimer’s disease, clinical markers, functional laterality, motor skills, olfactory perception, sensory thresholds, therapeutics

DOI: 10.3233/JAD-201216

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

Authors: Castagna, Alberto | Fabbo, Andrea | Manzo, Ciro | Lacava, Roberto | Ruberto, Carmen | Ruotolo, Giovanni

Article Type: Research Article

Abstract: Background: Background: Citicoline has been proven to have beneficial effects in patients with cognitive impairment. In previous studies, combined treatment with memantine and acetylcholinesterase inhibitors (AChEIs) maintained cognitive function in patients with Alzheimer’s disease (AD) better than memantine or AChEIs alone. Objective: To evaluate the effectiveness and safety of a combination therapy of oral citicoline, memantine, and an AChEI in AD when compared with memantine and an AChEI without citicoline. Methods: This was a retrospective multi-centric case-control study, conducted in Italian Centers for Cognitive Impairment and Dementia. Overall, 170 patients were recruited (34.11%of men, mean …age 76,81±4.93 years): 48.8%treated with memantine and donepezil; 48.2%with memantine and rivastigmine; 2.9%with memantine and galantamine. 89 patients (control-group) were treated with memantine and an AChEI, whereas 81 patients (case-group) were treated with oral citicoline 1000 mg/day added to memantine and an AChEI given orally. Cognitive functions, activities of daily living, instrumental activities of daily living, comorbidities, mood and behavioral disturbances were assessed at baseline, month 6, and month 12. Results: In the case group, MMSE score had a statistically significant increasing trend between T0 and T2 (14.88±2.95 versus 15.09±3.00; p  = 0.040), whereas in the control group, MMSE score showed a statistically significant decrease trend (14.37±2.63 versus 14.03±2.92 p  = 0.024). Conclusion: In older patients with AD, a triple therapy with citicoline, memantine, and AChEI was more effective than memantine and AChEI without citicoline in maintaining the MMSE total score after 12 months. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, citicoline, combined treatment, memantine

DOI: 10.3233/JAD-201211

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Bohlken, Jens | Riedel-Heller, Steffi | Steininger, Gilles | Kostev, Karel | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: The number of patients with dementia is forecast to grow continuously. However, there are indications that the incidence and prevalence is falling in high-income countries. Objective: To examine whether any effects of declining incidence and prevalence rates of dementia and mild cognitive impairment (MCI) were evident in Germany between 2015 and 2019. Methods: The analysis was based on 797 general and 132 specialists (neurological/psychiatric) practices and included 10.1 million patients aged 18 years and older who visited between January 2014 and December 2019 one of the practitioners. The prevalence and incidence of dementia and MCI …were demonstrated descriptively. Results: Between 2015 and 2019, the prevalence (incidence) of dementia decreased from 2.18%(0.44%) in 2015 to 2.07%(0.35%) in 2019. A relatively large decrease in the prevalence (incidence) of dementia was observed in patients aged 80 and older, at –1.47%(–0.62%), compared to younger patients, at –0.40%(–0.18%). By contrast, the prevalence and incidence of MCI have remained constant over the years (0.19%to 0.22%and 0.06%, respectively). Overall, the number of patients diagnosed with dementia decreased slightly by 1%while the number of patients diagnosed with MCI increased by 17%, which is caused by continued demographic changes. Conclusion: Our results confirmed the reduction in the prevalence and incidence of dementia and revealed a decrease in the number of patients with dementia despite continued demographic changes. Future studies are warranted to determine whether the results are caused by changing risk and lifestyle factors or changes in medical diagnosis and treatment behavior of the practitioners. Show more

Keywords: Cognitive dysfunction, dementia, diagnosis, incidence, prevalence

DOI: 10.3233/JAD-201385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Peng, Zhouyuan | Nishimoto, Hiroyuki | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: With the rapid aging of the population, the issue of driving by dementia patients has been causing increasing concern worldwide. Objective: To investigate the driving difficulties faced by senior drivers with cognitive impairment and identify the specific neuropsychological test that can reflect specific domains of driving maneuvers. Methods: Senior drivers with cognitive impairment were investigated. Neuropsychological tests and a questionnaire on demographic and driving characteristics were administered. Driving simulator tests were used to quantify participants’ driving errors in various domains of driving. Results: Of the 47 participants, 23 current drivers, though they had …better cognitive functions than 24 retired drivers, were found to have impaired driving performance in the domains of Reaction, Starting and stopping, Signaling, and Overall (wayfinding and accidents). The parameters of Reaction were significantly related to the diagnosis, and the scores of MMSE, TMT-A, and TMT-B. As regards details of the driving errors, “Sudden braking” was associated with the scores of MMSE (ρ = –0.707, p  <  0.01), BDT (ρ = –0.560, p  <  0.05), and ADAS (ρ = 0.758, p  <  0.01), “Forgetting to use turn signals” with the TMT-B score (ρ = 0.608, p  <  0.05), “Centerline crossings” with the scores of MMSE (ρ = –0.582, p  <  0.05) and ADAS (ρ = 0.538, p  <  0.05), and “Going the wrong way” was correlated with the score of CDT (ρ = –0.624, p  <  0.01). Conclusion: Different neuropsychological factors serve as predictors of different specific driving maneuvers segmented from driving performance. Show more

Keywords: Automobile driving, cognitive impairment, computer simulation, dementia, neuropsychological tests

DOI: 10.3233/JAD-201323

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Darst, Burcu F. | Huo, Zhiguang | Jonaitis, Erin M. | Koscik, Rebecca L. | Clark, Lindsay R. | Lu, Qiongshi | Kremen, William S. | Franz, Carol E. | Rana, Brinda | Lyons, Michael J. | Hogan, Kirk J. | Zhao, Jinying | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Keywords: Alzheimer’s disease, amino acids, cognition, executive function, fatty acids, longitudinal analysis, metabolomics

DOI: 10.3233/JAD-200176

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

Authors: Russ, Tom C. | Cherrie, Mark P.C. | Dibben, Chris | Tomlinson, Sam | Reis, Stefan | Dragosits, Ulrike | Vieno, Massimo | Beck, Rachel | Carnell, Ed | Shortt, Niamh K. | Muniz-Terrera, Graciela | Redmond, Paul | Taylor, Adele M. | Clemens, Tom | van Tongeren, Martie | Agius, Raymond M. | Starr, John M. | Deary, Ian J. | Pearce, Jamie R.

Article Type: Research Article

Keywords: Aging, air pollution, Alzheimer’s disease, atmosphere, cognition, dementia, epidemiologic methods

DOI: 10.3233/JAD-200910

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

Authors: Jobin, Benoît | Zahal, Rayane | Bussières, Eve-Line | Frasnelli, Johannes | Boller, Benjamin

Article Type: Research Article

Keywords: Alzheimer’s disease, biomarker, meta-analysis, olfaction, olfactory identification, smell, subjective cognitive decline

DOI: 10.3233/JAD-201022

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021