Journal of Alzheimer's Disease - Volume 87, issue 3

Authors: Marinelli, Lucio | Trompetto, Carlo | Puce, Luca | Monacelli, Fiammetta | Mori, Laura | Serrati, Carlo | Fattapposta, Francesco | Ghilardi, Maria Felice | Currà, Antonio

Article Type: Research Article

Abstract: Background: Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia. Objective: To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects. Methods: We examined 18 patients with Alzheimer’s disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the “Paratonia Scale”. EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) …and discontinuous (linear) movements were applied at 2 different velocities (fast and slow). Results: In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles. Conclusion: Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles. Show more

Keywords: Alzheimer’s disease, cognitive impairment, dementia, frontal lobe, mild cognitive impairment, muscle tone, rigidity

DOI: 10.3233/JAD-215526

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1065-1077, 2022

Authors: Wang, Hongwei | Wang, Ge | Billings, Rebecca | Li, Daniel | Haase, Shakaye R. | Wheeler, Pariya F. | Vance, David E. | Li, Wei

Article Type: Research Article

Abstract: Background: Lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) are collectively called macular pigment. MZ can be converted from L in the macula. In the recent decade, many studies have been performed to investigate the effects for taking carotenoids, especially L and Z or L, Z, and MZ, as diet supplements on human health. Objective: We examined if diet supplements of L  + Z or L  + Z + MZ have effects on cognitive function in adults. Methods: A systemic literature search was performed in March 2021 with the following keywords: lutein, zeaxanthin, meso-zeaxanthin, cognition, cognitive, and macular pigment. The searched …databases included Medline EBSCOhost, Scopus, Elsevier, Cochrane Library, ProQuest, and ClinicalTrials.gov. Findings from eight clinical trials were presented as the strongest evidence on the studied topic. Results: Most studies have found that macular pigments (L  + Z) in blood or macula are positively correlated with cognitive performance. As an index of the amount of macular pigments in the brain, macular pigment optical density is related to cognitive performance in adults. In addition, there is an inverse relationship between a higher amount of macular pigment in the blood and lower risk of mild cognitive impairments or Alzheimer’s disease. Based on the findings from the clinical trials, diet supplements of L  + Z or L  + Z + MZ are associated with improved cognition in adults. Conclusion: The diet supplements of L  + Z or L  + Z+MZ are associated with better cognitive functioning, which may be via their beneficial effects on the vision. Show more

Keywords: Cognition, cognitive, lutein, macular pigment, meso-zeaxanthin, zeaxanthin

DOI: 10.3233/JAD-215736

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1079-1087, 2022

Authors: Hutten, Danique R. | Bos, Jens H.J. | de Vos, Stijn | Hak, Eelko

Article Type: Research Article

Abstract: Background: Animal studies suggested that β2-Adrenergic receptors (β2AR) may be a potential target for the treatment of Alzheimer’s disease (AD). Objective: This retrospective inception cohort study aimed to assess the association between antagonists and agonists of the β2AR and the risk of starting treatment for AD in older adults. Methods: A retrospective inception cohort study was conducted among older adults who initiated either non-selective βAR antagonists or selective β2AR agonists using the University Groningen IADB.nl prescription database (study period 1994–2019). For each exposed cohort, two reference cohorts (A and B) were matched on age at index …date. The main outcome was defined as at least two prescriptions for cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and/or memantine. Cox proportional hazard regression models were used to estimate hazard ratios (HR). Results: The risk of developing AD was elevated among patients exposed to non-selective βAR antagonists (A: aHR 3.303, 95% CI 1.230–8.869, B: aHR 1.569, 95% CI 0.560–4.394) and reduced among patients exposed to selective β2AR agonists (A: aHR 0.049, 95% CI 0.003–0.795, B: aHR 0.834, 95% CI 0.075–9.273) compared to reference patients. Conclusion: These findings suggest that exposure to non-selective βAR antagonists is associated with an increased risk for developing AD whereas there may be a decreased risk for developing AD after exposure to selective β2AR agonists. Show more

Keywords: Adrenergic beta agonist, adrenergic beta blockers, adrenergic beta receptors, Alzheimer’s disease, neurodegenerative diseases

DOI: 10.3233/JAD-215057

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1089-1101, 2022

Authors: Kumar, Dilip | Yatawara, Chathuri | Wang, Brian | Wong, Benjamin | Tan, Yi Jayne | Zailan, Fatin Zahra | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) are a known risk factor for cognitive decline. While the ɛ4 allele of apolipoprotein E gene (APOE4 ) is another risk factor for cognitive decline, it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. Objective: To determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. Methods: Two-hundred-sixteen participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain wise), cardiovascular risk factor assessments, and APOE genotyping. Visual ratings for WMH …as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain-specific cognitive measures. The role of confluent and non-confluent WMH on cognition was additionally studied using logistic regression. Results: APOE4 carriers (n  = 49) had poorer memory and higher global WMH (10.01 mL versus 6.23 mL, p  = 0.04), temporal WMH (1.17 mL versus 0.58 mL, p  = 0.01), and occipital WMH (0.38mL versus 0.22 mL, p  = 0.02) compared to APOE4 non-carriers (n  = 167). Moderation analysis revealed that APOE4 positivity strengthened the relationship between higher global as well as lobar WMH burden and poorer episodic memory. Furthermore, APOE4 carriers with confluent WMH were 4.81 times more likely to have impaired episodic memory compared to non-confluent WMH and non-APOE carriers. Conclusion: The impact of WMH on memory may be strongest among APOE4 carriers. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions. Show more

Keywords: APOE4 , cognition, episodic memory, prodromal dementia, white matter hyperintensities

DOI: 10.3233/JAD-215556

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1103-1114, 2022

Authors: Jeong, Sohyun | Huang, Li-Kai | Tsai, Ming-Ju | Liao, Yi-Tyng | Lin, Yow-Sien | Hu, Chaur-Jong | Hsu, Yi-Hsiang

Article Type: Research Article

Abstract: Background: Differential abundance of gut microbiota has found to be associated with Alzheimer’s disease (AD). However, the relative abundance of gut microbiota between dementia and mild cognitive impairment (MCI) in AD is not well studied. Objective: We attempted to identify differentially enriched gut microbes and their metabolic pathways in AD patients with dementia comparing to AD patients with MCI. Methods: Fecal samples were collected at Shuang Ho Hospital, Taipei Medical University, Taiwan and analyzed by whole metagenomic sequencing technique. For normal controls without AD (NC), 16S rRNA sequencing was obtained from the Taiwan Microbiome Database. A …total of 48 AD (38 dementia and 10 MCI defined by cognitive function scores) and 50 NC were included. Microbiome alpha and beta diversities were estimated. Differentially enriched microbes were identified with HAllA, MaAsLin, DESeq2, and LEfSe statistical modeling approaches. Results: We found significantly increased abundance of Firmicutes but decreased abundance of Bacteroidetes at phylum level in AD compared to NC. In AD patients, cognitive function scores were negatively associated with abundance of Blautia hydrogenotrophica (Firmicutes ), Anaerotruncus colihominis (Firmicutes ), and Gordonibacter pamelaeae (Actinobacteria ). In addition, microbial abundance in the sucrose and S-Adenosyl-L-methionine (SAMe) metabolic pathways was more enriched in AD with MCI than AD with dementia and significantly associated with higher cognitive function scores. Conclusion: Gut microbe community diversity was similar in AD patients regardless of MCI or dementia status. However, differential analyses probed in lower-level taxa and metabolic pathways suggested that specific gut microbes in Firmicutes and Actinobacteria might involve in cognitive decline. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, S-Adenosyl-L-Methionine (SAMe) metabolic pathway, sucrose metabolic pathway, whole metagenome sequencing

DOI: 10.3233/JAD-215090

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1115-1130, 2022

Authors: Hone-Blanchet, Antoine | Bohsali, Anastasia | Krishnamurthy, Lisa C. | Shahid, Salman S. | Lin, Qixiang | Zhao, Liping | Bisht, Aditya S. | John, Samantha E. | Loring, David | Goldstein, Felicia | Levey, Allan | Lah, James | Qiu, Deqiang | Crosson, Bruce

Article Type: Research Article

Abstract: Background: Women account for two thirds of the prevalence and incidence of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aβ1–42 ) and tau, for which early detection is crucial in prevention of the disease. Objective: We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aβ1–42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. Methods: 3T single-voxel MRS was performed on the medial frontal …cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50–85). CSF samples of Aβ1–42 and tau and scores of general cognition were also obtained. Results: Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. Conclusion: This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aβ1–42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample. Show more

Keywords: Aging, cerebrospinal fluid biomarkers, frontal cortex, general cognition, magnetic resonance spectroscopy, mild cognitive impairment, women’s health

DOI: 10.3233/JAD-215431

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1131-1141, 2022

Authors: Cukierman-Yaffe, Tali | Lee, Shun-Fu | Pare, Guillaume | McQueen, Matthew | Hess, Sibylle | Gerstein, Hertzel C.

Article Type: Research Article

Abstract: Background: Diabetes and cardiovascular disease increase the risk of incident cognitive dysfunction. Identification of novel biochemical markers for cognitive dysfunction may identify people at the highest risk while yielding insights regarding the pathophysiology of cognitive dysfunction. Objective: To identify cardiovascular biomarkers in serum that are independent predictors of cognitive dysfunction in individuals with dysglycemia. Methods: This analysis was conducted in 8,365 participants in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial whose stored serum was analyzed for 238 cardio-metabolic biomarkers and completed a baseline Mini-Mental State Examination (MMSE). Fine and Gray sub distribution hazard …models accounting for the competing risk of death accounting for clinical risk factors and the baseline MMSE were used to identify biomarkers that predicted incident cognitive dysfunction (MMSE < 24 or dementia) using forward selection with an inclusion p -value < 0.0002 to account for multiplicity. Results: During a median follow-up period of 6.2 years, 939 individuals developed cognitive dysfunction. After accounting for 17 clinical risk factors, glargine allocation, and the baseline MMSE, three biomarkers (α-2 Macroglobulin, HR 1.19; 95% CI 1.12, 1.27; Macrophage Inflammatory Protein 1α, HR 1.11; 95% CI 1.06, 1.16; and Growth Hormone, HR 0.91; 95% CI 0.87, 0.96) independently predicted incident cognitive dysfunction (p  < 0.0002). Addition of these biomarkers to a model that included clinical risk factors, however, did not improve the ability to predict cognitive dysfunction. Conclusion: Addition of independent biomarkers to clinical risk factors for cognitive dysfunction in people with dysglycemia did not predict incident cognitive dysfunction better than clinical risk factors alone. Show more

Keywords: Biomarkers, cardiovascular disease, cognition, cognitive dysfunction, diabetes, dysglycemia

DOI: 10.3233/JAD-215195

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1143-1150, 2022

Authors: Shimosaka, Momoyo | Nishimoto, Hiroyuki | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: Time disorientation is one of the main symptoms observed in patients with dementia; however, their clock-reading ability has not been fully reported. Objective: This study aimed to investigate the clock-reading ability of both digital and analog clocks in patients with dementia. We newly devised the clock-reading test (CRT) and the number-reading test (NRT) to assess cognitive factors that may affect clock-reading ability. Furthermore, the discriminating power of the CRT was calculated. Methods: 104 participants were categorized based on their Mini-Mental State Examination (MMSE) scores as follows: subjective cognitive decline ∼ mild cognitive impairment (SCD∼MCI, N … = 43), early Alzheimer’s disease (AD) (N  = 26), and middle-to-late AD (N  = 35). Their cognitive abilities were evaluated using the clock-drawing test (CDT), CRT, and NRT. Results: Cognitive decline leads to impairment of clock-reading ability which is more pronounced in the analog clocks than digital ones. This deficit in clock-reading is attributed to a loss of semantic memory regarding clocks at all stages. Additionally, visuospatial dysfunction and reduced ability of number recognition may lead to deficit in clock-reading in the advanced stage of AD. The discriminating power of the CRT (analog) (AUC = 0.853) was high enough to detect cognitive decline. Conclusion: Digital clocks are more readable by patients with dementia. Since reading clocks is closely associated with daily life, the CRT has proved to be a useful tool. A decline of analog clock-reading may be an early detector for the onset of dementia in elderly patients. Show more

Keywords: Alzheimer’s disease, clock test, cognitive impairments, dementia, neuropsychological tests

DOI: 10.3233/JAD-215471

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1151-1165, 2022

Authors: Ketchum, Fred B. | Erickson, Claire M. | Chin, Nathaniel A. | Gleason, Carey E. | Lambrou, Nickolas H. | Benton, Susan Flowers | Clark, Lindsay R.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) begins with an asymptomatic “preclinical” phase, in which abnormal biomarkers indicate risk for developing cognitive impairment. Research is increasingly focused on validating biomarkers to improve reliable diagnosis and timely clinical treatment of AD. Most preclinical biomarker research lacks adequate representation of Black/African American and other racially and ethnically minoritized individuals, limiting the applicability of data to these groups. This may exacerbate existing disparities by hindering diagnosis and treatment among racially and ethnically minoritized individuals. Objective: Understand the factors influencing willingness of Blacks/African Americans to participate in AD biomarker research and identify opportunities to improve …enrollment. Methods: We enrolled Blacks/African Americans (N  = 145) between 46–85 years of age who had previously participated in AD research. Participants gave open-ended responses to a vignette describing a hypothetical biomarker research study. Using qualitative content analysis, we identified themes that motivated and discouraged enrollment in AD biomarker research. Results: Participant responses were categorized into several themes. Themes motivating participation included a desire to know their biomarker results and to support research. Major themes discouraging participation included concerns about potential negative psychological outcomes to learning one’s increased risk for AD, doubt about the usefulness of testing, and worry about the potential physical harms of testing. Conclusion: Understanding themes motivating and discouraging AD preclinical biomarker research participation may inform research material development, approach to community engagement, and/or trial design to increase enrollment of Blacks/African Americans. Show more

Keywords: African Americans, Alzheimer’s disease, biomarkers, qualitative research

DOI: 10.3233/JAD-215521

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1167-1179, 2022

Authors: Han, Seung-Hyup | Noh, Dong-Hee | Jo, Eun-Ju | Kam, Kyung-Yoon

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) gene is the most potent genetic risk factor for dementia. However, there are few studies on how the APOE gene affects cognitive domain functions. Objective: This study aimed to investigate the effects of risk factors for dementia on cognitive function in patients with mild cognitive impairment and Alzheimer’s disease (AD). Methods: This study included subjects whose Clinical Dementia Rating scores ranged from 0.5 to 2 and who were older than 65 years. Risk factors for dementia included the APOE ɛ4 allele, age, education period, employment period, body mass …index, and exercise. APOE genotyping was performed by polymerase chain reaction, and other factors were identified using medical charts or structured checklists. Cognitive function was measured using the Seoul Neuropsychological Screening Battery II. Results: General cognitive function did not show a significant difference according to APOE ɛ4 status. However, the score for delayed verbal memory was lower in the APOE ɛ4-carrier group than in the non-carrier group (p  < 0.05). In addition, age, education period, employment period, and exercise were correlated with different cognitive function domains in the non-carrier group (p  < 0.05); however, the carrier group was showed a significant correlation between age, body mass index, and cognitive domains. Conclusion: Our findings suggest that APOE ɛ4 significantly decreases verbal memory in patients with AD. Moreover, the effects of risk factors on cognitive function were significantly different according to the APOE ɛ4 status. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cognition, risk factors

DOI: 10.3233/JAD-215075

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1181-1188, 2022