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

Authors: Chen, Yu-si | Shu, Kai | Kang, Hui-cong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is becoming a prevalent disease in the elderly population. Past decades have witnessed the development of drug therapies with varying targets. However, all drugs with a single molecular target fail to reverse or ameliorate AD progression, which ultimately results in cortical and subcortical network dysregulation. Deep brain stimulation (DBS) has been proven effective for the treatment of Parkinson’s disease, essential tremor, and other neurological diseases. As such, DBS has also been gradually acknowledged as a potential therapy for AD. The current review focuses on DBS of the nucleus basalis of Meynert (NBM). As a critical component of …the cerebral cholinergic system and the Papez circuit in the basal ganglia, the NBM plays an indispensable role in the subcortical regulation of memory, attention, and arousal state, which makes the NBM a promising target for modulation of neural network dysfunction and AD treatment. We summarized the intricate projection relations and functionality of the NBM, current approaches for stereotactic localization and evaluation of the NBM, and the therapeutic effects of NBM-DBS both in patients and animal models. Furthermore, the current shortcomings of NBM-DBS, such as variations in cortical blood flow, increased temperature in the target area, and stimulation-related neural damage, were presented. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, functional neurosurgery, neuromodulation, nucleus basalis of Meynert, technical consideration

DOI: 10.3233/JAD-201141

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Prakash, Mithilesh | Abdelaziz, Mahmoud | Zhang, Linda | Strange, Bryan A. | Tohka, Jussi | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Quantitatively predicting the progression of Alzheimer’s disease (AD) in an individual on a continuous scale, such as the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores, is informative for a personalized approach as opposed to qualitatively classifying the individual into a broad disease category. Objective: To evaluate the hypothesis that the multi-modal data and predictive learning models can be employed for future predicting ADAS-cog scores. Methods: Unimodal and multi-modal regression models were trained on baseline data comprised of demographics, neuroimaging, and cerebrospinal fluid based markers, and genetic factors to predict future ADAS-cog scores for 12, 24, and …36 months. We subjected the prediction models to repeated cross-validation and assessed the resulting mean absolute error (MAE) and cross-validated correlation (ρ) of the model. Results: Prediction models trained on multi-modal data outperformed the models trained on single modal data in predicting future ADAS-cog scores (MAE12, 24 & 36 months = 4.1, 4.5, and 5.0, ρ 12, 24 & 36 months = 0.88, 0.82, and 0.75). Including baseline ADAS-cog scores to prediction models improved predictive performance (MAE12, 24 & 36 months = 3.5, 3.7, and 4.6, ρ 12, 24 & 36 months = 0.89, 0.87, and 0.80). Conclusion: Future ADAS-cog scores were predicted which could aid clinicians in identifying those at greater risk of decline and apply interventions at an earlier disease stage and inform likely future disease progression in individuals enrolled in AD clinical trials. Show more

Keywords: Alzheimer’s disease, machine learning, magnetic resonance imaging, multi-modal imaging, neuropsychology

DOI: 10.3233/JAD-200906

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Farugia, Taya L. | Cuni-Lopez, Carla | White, Anthony R.

Article Type: Research Article

Abstract: Australia often experiences natural disasters and extreme weather conditions such as: flooding, sandstorms, heatwaves, and bushfires (also known as wildfires or forest fires). The proportion of the Australian population aged 65 years and over is increasing, alongside the severity and frequency of extreme weather conditions and natural disasters. Extreme heat can affect the entire population but particularly at the extremes of life, and patients with morbidities. Frequently identified as a vulnerable demographic in natural disasters, there is limited research on older adults and their capacity to deal with extreme heat and bushfires. There is a considerable amount of literature that …suggests a significant association between mental disorders such as dementia, and increased vulnerability to extreme heat. The prevalence rate for dementia is estimated at 30% #x0025;by age 85 years, but there has been limited research on the effects extreme heat and bushfires have on individuals living with dementia. This review explores the differential diagnosis of dementia, the Australian climate, and the potential impact Australia’s extreme heat and bushfires have on individuals from vulnerable communities including low socioeconomic status Indigenous and Non-Indigenous populations living with dementia, in both metropolitan and rural communities. Furthermore, we investigate possible prevention strategies and provide suggestions for future research on the topic of Australian bushfires and heatwaves and their impact on people living with dementia. This paper includes recommendations to ensure rural communities have access to appropriate support services, medical treatment, awareness, and information surrounding dementia. Show more

Keywords: Bushfire, climate change, dementia, extreme heat, wildfire

DOI: 10.3233/JAD-201388

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Delic, Vedad | Ratliff, Whitney A. | Citron, Bruce A.

Article Type: Research Article

Abstract: An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million mericans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of …inadequate sleep have been shown to cause an increase in amyloidβ and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, post-traumatic stress disorder, sleep deprivation, tau

DOI: 10.3233/JAD-201378

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

Authors: Mai, Yingren | Yu, Qun | Zhu, Feiqi | Luo, Yishan | Liao, Wang | Zhao, Lei | Xu, Chunyan | Fang, Wenli | Ruan, Yuting | Cao, Zhiyu | Lei, Ming | Au, Lisa | Mok, Vincent C.T. | Shi, Lin | Liu, Jun

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) provides objective information about brain structural atrophy in patients with Alzheimer’s disease (AD). This multi-structural atrophic information, when integrated as a single differential index, has the potential to further elevate the accuracy of AD identification from normal control (NC) compared to the conventional structure volumetric index. Objective: We herein investigated the performance of such an MRI-derived AD index, AD-Resemblance Atrophy Index (AD-RAI), as a neuroimaging biomarker in clinical scenario. Method: Fifty AD patients (19 with the Amyloid, Tau, Neurodegeneration (ATN) results assessed in cerebrospinal fluid) and 50 age- and gender-matched NC …(19 with ATN results assessed using positron emission tomography) were recruited in this study. MRI-based imaging biomarkers, i.e., AD-RAI, were quantified using AccuBrain® . The accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of these MRI-based imaging biomarkers were evaluated with the diagnosis result according to clinical criteria for all subjects and ATN biological markers for the subgroup. Results: In the whole groups of AD and NC subjects, the accuracy of AD-RAI was 91%, sensitivity and specificity were 88% and 96%, respectively, and the AUC was 92%. In the subgroup of 19 AD and 19 NC with ATN results, AD-RAI results matched completely with ATN classification. AD-RAI outperforms the volume of any single brain structure measured. Conclusion: The finding supports the hypothesis that MRI-derived composite AD-RAI is a more accurate imaging biomarker than individual brain structure volumetry in the identification of AD from NC in the clinical scenario. Show more

Keywords: AD-Resemblance atrophy index, Alzheimer’s disease, ATN biological markers, automated brain volumetry, magnetic resonance imaging

DOI: 10.3233/JAD-201033

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

Authors: Underlien Kristensen, Rachel | Jensen-Dahm, Christina | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Studies have shown declining use of potentially inappropriate medication (PIM), medication where risks associated with use outweigh potential benefits in older people. However, the trend in people with dementia remains unknown. Objective: To test the hypothesis that the use of PIM has decreased in people with dementia in line with the declining use in the general older population. Methods: Repeated cross-sectional register-based study of the entire Danish population aged ≥65 years (2000: N = 802,106; 2015: N = 1,056,476). PIM was identified using the Danish “Red-yellow-green list”. Changes in the use of PIM were examined by calculating the annual …prevalence of filling prescriptions for at least one PIM in older people with and without dementia. Characteristics of the study population were examined annually including comorbidity. Results: From 2000 to 2015, the prevalence of PIM use decreased from 54.7%to 43.5%in people with dementia and from 39.5%to 28.8%in people without dementia; the decrease was significant across all age groups and remained so in a sensitivity analysis where antipsychotics were removed. During the same period, comorbidity scores increased in people with and without dementia. Conclusion: The declining use of PIM in people with dementia from 2000 to 2015 parallels the trend in the general older population. The use of PIM decreased despite increasing levels of comorbidity and was not solely attributable to the decreasing use of antipsychotics in people with dementia. However, PIM use remained more widespread in people with dementia who may be more vulnerable to the risks associated with PIM. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, potentially inappropriate medication, time trend

DOI: 10.3233/JAD-200627

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

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