Journal of Alzheimer's Disease - Volume 83, issue 1

Authors: Gouras, Gunnar K.

Article Type: Obituary

DOI: 10.3233/JAD-210742

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 1-2, 2021

Authors: Robakis, Nikolaos K.

Article Type: Editorial

DOI: 10.3233/JAD-215138

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 3-4, 2021

Authors: Beardmore, Rebecca | Hou, Ruihua | Darekar, Angela | Holmes, Clive | Boche, Delphine

Article Type: Review Article

Abstract: The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer’s disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to …be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway. Show more

Keywords: Aging, Alzheimer’s disease, human, locus coeruleus, magnetic resonance imaging, neuromelanin

DOI: 10.3233/JAD-210191

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 5-22, 2021

Authors: Squitti, Rosanna | Faller, Peter | Hureau, Christelle | Granzotto, Alberto | White, Anthony R. | Kepp, Kasper P.

Article Type: Research Article

Abstract: The cause of Alzheimer’s disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as …a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, ATP7B, copper, dementia, meta-analysis, Wilson’s disease

DOI: 10.3233/JAD-201556

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 23-41, 2021

Authors: Remoli, Giulia | Canevelli, Marco | Robertazzo, Umberto Maria | Nuti, Filippo | Bacigalupo, Ilaria | Salvi, Emanuela | Valletta, Martina | Toccaceli Blasi, Marco | Cesari, Matteo | Vanacore, Nicola | Bruno, Giuseppe

Article Type: Short Communication

Abstract: We aimed to explore the awareness and preparedness of dementia caregivers and people with mild cognitive deficits on how to prevent COVID-19 infection and cope with the indirect consequences of the pandemic. A total of 139 patient-caregiver dyads received a telephone survey and 109 completed the survey. The majority of respondents reported having a moderate-to-good knowledge of the typical manifestations of COVID-19. Conversely, only few of them were informed of the atypical presentations and on how to recognize emergency warning signs. Filling the knowledge gaps on COVID-19 in the most vulnerable people may represent a significant resource to tackle the …pandemic. Show more

Keywords: Atypical manifestations, caregiving, cognitive disorders, COVID-19, dementia, education

DOI: 10.3233/JAD-210264

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 43-49, 2021

Authors: Tank, Rachana | Ward, Joey | Celis-Morales, Carlos | Smith, Daniel J. | Flegal, Kristin E. | Lyall, Donald M.

Article Type: Short Communication

Abstract: Recent research suggests genetic variation in the Klotho locus may modify the association between APOE ɛ4 and cognitive impairment. We tested for associations and interactions between these genotypes versus risk of dementia, cognitive abilities, and brain structure in older UK Biobank participants. Klotho status was indexed with rs9536314 heterozygosity (versus not), in unrelated people with versus without APOE ɛ4 genotype, corrected for various confounders. APOE ɛ4 associated with increased risk of dementia, worse cognitive abilities, and brain structure. Klotho was associated with better reasoning. There were no interactions; potentially suggesting an age- and pathology-dependent …Klotho effect. Show more

Keywords: APOE, brain, cognitive, dementia, Klotho

DOI: 10.3233/JAD-210181

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 51-55, 2021

Authors: Tadokoro, Koh | Yamashita, Toru | Kawano, Satoko | Sato, Junko | Omote, Yoshio | Takemoto, Mami | Morihara, Ryuta | Nishiura, Koichiro | Sagawa, Natsuki | Tani, Tomiko | Abe, Koji

Article Type: Research Article

Abstract: Background: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients. Objective: To evaluate the immediate effect of makeup therapy on dementia patients. Methods: Female nursing home residents with dementia received either only skin care treatment (control group, n  = 17) or skin care plus makeup therapy treatment (makeup therapy group, n  = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software. …Results: Makeup therapy significantly improved Abe’s behavioral and psychological symptoms of dementia (BPSD) score (ABS, * p  < 0.05). AI software judged that makeup therapy significantly made the apparent age younger (* p  < 0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy (* p  < 0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r  = 0.42, * p  < 0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy (* p  < 0.05). Conclusion: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance. Show more

Keywords: Artificial intelligence, behavioral and psychological symptoms of dementia, dementia, facial appearance, makeup therapy

DOI: 10.3233/JAD-210284

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 57-63, 2021

Authors: Sible, Isabel J. | Bangen, Katherine J. | Blanken, Anna E. | Ho, Jean K. | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Blood pressure variability is linked to Alzheimer’s disease (AD) risk and MRI-based markers of cerebrovascular disease. Less is known about the role of blood pressure variability in postmortem evaluation of cerebrovascular disease and AD. Objective: To determine whether antemortem blood pressure variability predicts cerebrovascular and AD pathology and follow-up cognitive change in autopsy-confirmed AD. Methods: National Alzheimer’s Coordinating Center participants (n = 513) underwent 3-4 approximately annual blood pressure measurements and were confirmed to have AD at postmortem evaluation. A subset (n = 493) underwent neuropsychological evaluation at follow-up. Regression models examined relationships …between blood pressure variability and cerebrovascular and AD pathological features and follow-up cognitive change. Results: Elevated blood pressure variability predicted increased postmortem cerebrovascular lesion burden (ß = 0.26 [0.10, 0.42]; p = 0.001; R 2 = 0.12). Increased blood pressure variability predicted specific cerebrovascular lesion severity, including atherosclerosis in the Circle of Willis (OR = 1.22 [1.03, 1.44]; p = 0.02) and cerebral arteriolosclerosis (OR = 1.32 [1.04, 1.69]; p = 0.03). No significant relationships were observed between blood pressure variability and AD pathological findings, including Braak & Braak stage, neuritic plaques or diffuse plaques, or cerebral amyloid angiopathy, or follow-up cognitive decline. Conclusion: Findings suggest that elevated blood pressure variability is related to postmortem cerebrovascular lesion burden in autopsy-confirmed AD, independent of average blood pressure and AD neuropathology. Blood pressure fluctuation may selectively promote atherosclerotic and arteriolosclerotic brain lesions with potential implications for cognitive impairment and dementia. Show more

Keywords: Alzheimer’s disease, autopsy, blood pressure, cerebrovascular disorders, cognitive dysfunction

DOI: 10.3233/JAD-210435

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 65-75, 2021

Authors: Michalowsky, Bernhard | Hoffmann, Wolfgang | Xie, Feng

Article Type: Research Article

Abstract: Background: Assessing health-related quality of life in dementia poses challenges due to patients’ cognitive impairment. It is unknown if the newly introduced EQ-5D five-level version (EQ-5D-5L) is superior to the 3-level version (EQ-5D-3L) in this cognitively impaired population group. Objective: To assess the psychometric properties of the EQ-5D-5L in comparison to the EQ-5D-3L in patients living with dementia (PwD). Methods: The EQ-5D-3L and EQ-5D-5L were assessed via interviews with n  = 78 PwD at baseline and three and six months after, resulting in 131 assessments. The EQ-5D-3L and EQ-5D-5L were evaluated in terms of acceptability, agreement, ceiling …effects, redistribution properties and inconsistency, informativity as well as convergent and discriminative validity. Results: Mean index scores were higher for the EQ-5D-5L than the EQ-5D-3L (0.70 versus 0.64). Missing values occurred more frequently in the EQ-5D-5L than the EQ-5D-3L (8%versus 3%). Agreement between both measures was acceptable but poor in PwD with moderate to severe cognitive impairment. The index value’s relative ceiling effect decreased from EQ-5D-3L to EQ-5D-5L by 17%. Inconsistency was moderate to high (13%). Absolute and relative informativity increased in the EQ-5D-5L compared to the 3L. The EQ-5D-5L demonstrated a lower discriminative ability and convergent validity, especially in PwD with moderate to severe cognitive deficits. Conclusion: The EQ-5D-5L was not superior as a self-rating instrument due to a lower acceptability and discriminative ability and a high inconsistency, especially in moderate to severe dementia. The EQ-5D-3L had slightly better psychometric properties and should preferably be used as a self-rating instrument in economic evaluations in dementia. Show more

Keywords: Alzheimer’s diseases, dementia, EQ-5D, patient-reported outcomes, preference-based measures, quality of life, validation

DOI: 10.3233/JAD-210421

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 77-87, 2021

Authors: Jones, Eddie | Aigbogun, Myrlene Sanon | Pike, James | Berry, Mia | Houle, Christy R. | Husbands, Joseph

Article Type: Research Article

Abstract: Background: At least 90%of patients with dementia experience behavioral or neuropsychiatric symptoms including agitation, psychotic symptoms, apathy, depression, and sleep disturbances. Agitation has been reported to be experienced by 60%of patients with mild cognitive impairment and 76%of patients with Alzheimer’s disease. Objective: We aimed to assess the impact of agitation in patients with dementia on healthcare resource utilization (HCRU) and healthcare costs. Methods: This was a retrospective analysis of physician-reported patient data from a point-in-time survey. Patients included were aged≥50 years, with early cognitive impairment or dementia. Agitated and non-agitated patients were compared. Regression analyses assessed …the relationship of agitation score (calculated from number/severity of agitation symptoms) with outcomes, with covariates including age and Mini-Mental State Examination score. Sensitivity analyses compared patients with 0 and≥2 agitation symptoms following propensity score matching on the base-case covariates. Results: Data were included for 1,349 patients (agitated, n  = 693; non-agitated, n  = 656). Based on regression analyses, agitation score was correlated with proportion of patients with professional caregivers (p  < 0.01), institutionalized (p  < 0.01), hospitalized in a psychiatric ward (p  < 0.05), and receiving an antipsychotic/antidepressant (both p  < 0.001); number of consultations with a healthcare professional (HCP), psychiatrist, or psycho-geriatrician; number and cost of hospitalizations (p  < 0.01); cost of HCP consultations (p  < 0.001); and total direct healthcare costs (p  < 0.001). Sensitivity analyses generally supported the base-case analysis. Conclusion: Agitation in dementia is associated with increased HCRU and healthcare costs. Effective therapies are needed to address agitation in dementia, with the potential to alleviate patient impact, HCRU, and healthcare costs. Show more

Keywords: Agitation, behavioral symptoms, cognitive dysfunction, cost of illness, cross-sectional studies, dementia, health care costs, institutionalization, real-world, referral and consultation, therapeutics

DOI: 10.3233/JAD-210105

Citation: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 89-101, 2021