Journal of Alzheimer's Disease - Volume 79, issue 3

Authors: Clark, I.A. | Vissel, B.

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. 79, no. 3, pp. 931-948, 2021

Authors: Tham, Rachel | Schikowski, Tamara

Article Type: Review Article

Abstract: Traffic-related air pollution is ubiquitous and almost impossible to avoid. It is important to understand the role that traffic-related air pollution may play in neurodegenerative diseases, such as dementia, Alzheimer’s disease, and Parkinson’s disease, particularly among older populations and at-risk groups. There is a growing interest in this area among the environmental epidemiology literature and the body of evidence identifying this role is emerging and strengthening. This review focuses on the principal components of traffic-related air pollutants (particulate matter and nitrogen oxides) and the epidemiological evidence of their contribution to common neurodegenerative diseases. All studies reported are currently observational in …nature and there are mixed findings depending on the study design, assessment of traffic-related air pollutant levels, assessment of the neurodegenerative disease outcome, time period of assessment, and the role of confounding environmental factors and at-risk genetic characteristics. All current studies have been conducted in income-rich countries where traffic-related air pollution levels are relatively low. Additional longer-term studies are needed to confirm the levels of risk, consider other contributing environmental factors and to be conducted in settings where air pollution exposures are higher and at-risk populations reside and work. Better understanding of these relationships will help inform the development of preventive measures and reduce chronic cognitive and physical health burdens (cost, quality of life) at personal and societal levels. Show more

Keywords: Air pollution, Alzheimer’s disease, dementia, mild cognitive impairment, Parkinson’s disease

DOI: 10.3233/JAD-200813

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 949-959, 2021

Authors: Streit, Wolfgang J. | Khoshbouei, Habibeh | Bechmann, Ingo

Article Type: Review Article

Abstract: Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade …theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea. Show more

Keywords: Aging, dystrophy, late-onset Alzheimer’s disease, neurodegeneration, neuroinflammation, senescence

DOI: 10.3233/JAD-201248

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 961-968, 2021

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

Article Type: Review 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%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. 79, no. 3, pp. 969-978, 2021

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) and tau oligomers have been identified as neurotoxic agents responsible for causing Alzheimer’s disease (AD). Clinical trials using Aβ and tau as targets have failed, giving rise to calls for new research approaches to combat AD. This paper provides such an approach. Most basic AD research has involved quiescent Aβ and tau solutions. However, studies involving laminar and extensional flow of proteins have demonstrated that mechanical agitation of proteins induces or accelerates protein aggregation. Recent MRI brain studies have revealed high energy, chaotic motion of cerebrospinal fluid (CSF) in lower brain and brainstem regions. These and studies showing …CSF flow within the brain have shown that there are two energetic hot spots. These are within the third and fourth brain ventricles and in the neighborhood of the circle of Willis blood vessel region. These two regions are also the same locations as those of the earliest Aβ and tau AD pathology. In this paper, it is proposed that cardiac systolic pulse waves that emanate from the major brain arteries in the lower brain and brainstem regions and whose pulse waves drive CSF flows within the brain are responsible for initiating AD and possibly other amyloid diseases. It is further proposed that the triggering of these diseases comes about because of the strengthening of systolic pulses due to major artery hardening that generates intense CSF extensional flow stress. Such stress provides the activation energy needed to induce conformational changes of both Aβ and tau within the lower brain and brainstem region, producing unique neurotoxic oligomer molecule conformations that induce AD. Show more

Keywords: Amyloid-β, arteries, atherosclerosis, cerebrospinal fluid, extensional flow, fluid flow stress, heart failure, oligomer, shear, strain, systolic pulse, tau, ventricles

DOI: 10.3233/JAD-201025

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 979-1002, 2021

Authors: Futamura, Akinori | Hieda, Sotaro | Mori, Yukiko | Sugimoto, Azusa | Kasai, Hideyo | Kuroda, Takeshi | Yano, Satoshi | Kasuga, Kensaku | Murakami, Hidetomo | Ikeuchi, Takeshi | Ono, Kenjiro

Article Type: Short Communication

Abstract: We compared ‘CIScore’ determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer’s disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

Keywords: Alzheimer’s disease, amyloid β-protein 42, cingulate island sign, Lewy body disease, medial temporal atrophy, phosphorylated tau protein

DOI: 10.3233/JAD-201145

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1003-1008, 2021

Authors: Babulal, Ganesh M. | Johnson, Ann | Fagan, Anne M. | Morris, John C. | Roe, Catherine M.

Article Type: Short Communication

Abstract: We examined whether driving behavior can predict preclinical Alzheimer’s disease (AD). Data from 131 cognitively normal older adults with cerebrospinal fluid (CSF) and/or positron emission tomography (PET) biomarkers were examined with naturalistic driving behavior. Receiver operating characteristic curves were used to predict the highest 10%, 25%, and 50% of values for CSF tau/Aβ42 , ptau181 /Aβ42 , or amyloid PET. Six in vivo driving variables alone yielded area under the curves (AUC) from 0.64–0.82. Addition of age, Apolipoprotein ɛ 4, and neuropsychological measures to the models improved the AUC (0.81 to 0.90). Driving can be used as novel neurobehavioral …marker to identify presence of preclinical AD. Show more

Keywords: Aging drivers, Alzheimer’s disease, biomarkers, driving decline, preclinical

DOI: 10.3233/JAD-201294

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1009-1014, 2021

Authors: Soldevila-Domenech, Natalia | Forcano, Laura | Boronat, Anna | Lorenzo, Thais | Piera, Iris | Puig-Pijoan, Albert | Mateus, Julian | González de Echevarri Gómez, José María | Knezevic, Iva | Soteras, Anna | Fauria, Karine | Pizarro, Nieves | Molinuevo, Jose Luis | de la Torre, Rafael | PENSA Study Group. From IMIM: | From BBRC:

Collaborators: de la Torre, Rafael | Forcano, Laura | Pizarro, Neus | Puig-Pijoan, Albert | Soldevila-Domenech, Natalia | Boronat, Anna | Lorenzo, Thais | Cuenca, Aida | Mateus, Julian | Piera, Iris | Aldea, Ana | Diaz-Pellicer, Patricia | Dierssen, Mara | Gomis, Maria | Molinuevo, Jose Luis | Knezevic, Iva | Menezes-Cabral, Sofia | Soteras, Anna | González-de-Echávarri, José Maria | Sánchez-Benavides, Gonzalo | Gispert, Juan Domingo | Fauria, Karine | Minguillón, Carolina

Article Type: Short Communication

Abstract: We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60–80 years) diagnosed with subjective cognitive decline and APOE ɛ 3/ɛ 4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages …of Alzheimer’s disease should be further evaluated. Show more

Keywords: Alzheimer’s disease, confinement, COVID-19, mental health, subjective cognitive decline

DOI: 10.3233/JAD-201408

Citation: Journal of Alzheimer's Disease, vol. 79, no. 3, pp. 1015-1021, 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. 79, no. 3, pp. 1023-1032, 2021

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. 79, no. 3, pp. 1033-1040, 2021