Journal of Alzheimer's Disease - Volume 84, issue 1

Authors: Kuipers, Sanne | Biessels, Geert Jan | Greving, Jacoba P. | Amier, Raquel P. | de Bresser, Jeroen | Bron, Esther E. | van der Flier, Wiesje M. | van der Geest, Rob J. | Hooghiemstra, Astrid M. | van Oostenbrugge, Robert J. | van Osch, Matthias J.P. | Kappelle, L. Jaap | Exalto, Lieza G. | Heart-Brain Connection Consortium

Article Type: Research Article

Abstract: Background: Emerging evidence shows sex differences in manifestations of vascular brain injury in memory clinic patients. We hypothesize that this is explained by sex differences in cardiovascular function. Objective: To assess the relation between sex and manifestations of vascular brain injury in patients with cognitive complaints, in interaction with cardiovascular function. Methods: 160 outpatient clinic patients (68.8±8.5 years, 38% female) with cognitive complaints and vascular brain injury from the Heart-Brain Connection study underwent a standardized work-up, including heart-brain MRI. We calculated sex differences in vascular brain injury (lacunar infarcts, non-lacunar infarcts, white matter hyperintensities [WMHs], and …microbleeds) and cardiovascular function (arterial stiffness, cardiac index, left ventricular [LV] mass index, LV mass-to-volume ratio and cerebral blood flow). In separate regression models, we analyzed the interaction effect between sex and cardiovascular function markers on manifestations of vascular brain injury with interaction terms (sex*cardiovascular function marker). Results: Males had more infarcts, whereas females tended to have larger WMH-volumes. Males had higher LV mass indexes and LV mass-to-volume ratios and lower CBF values compared to females. Yet, we found no interaction effect between sex and individual cardiovascular function markers in relation to the different manifestations of vascular brain injury (p -values interaction terms > 0.05). Conclusion: Manifestations of vascular brain injury in patients with cognitive complaints differed by sex. There was no interaction between sex and cardiovascular function, warranting further studies to explain the observed sex differences in injury patterns. Show more

Keywords: Cardiovascular function, cerebrovascular disorders, cognitive dysfunction, female, male, sex, vascular brain injury

DOI: 10.3233/JAD-210360

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 261-271, 2021

Authors: Sato, Tomohiko | Hanyu, Haruo | Koyama, Yumi | Horita, Haruka | Aoki, Toshinori | Hirao, Kentaro | Kanetaka, Hidekazu | Shimizu, Soichiro

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD) patients, the severity of cognitive impairment is thought to correlate with the degree of brain imaging abnormalities. However, some patients show only mild cognitive deficit, despite severe brain atrophy on magnetic resonance imaging (MRI) or marked hypoperfusion in the cerebral cortices on single-photon emission computed tomography (SPECT). This suggests that cognitive reserve (CR) can compensate for the clinical manifestations of AD in patients with extensive brain pathology. Objective: We aimed to determine whether this discrepancy between cognitive and imaging findings is associated with CR. Methods: Factors associated with the discrepancy between …the degree of cognitive impairment and MRI (medial temporal lobe atrophy) and SPECT (posterior cerebral hypoperfusion) findings were analyzed in 135 patients with probable AD. Factors as proxies for CR included education, occupation, leisure activity, comorbidities, frailty, and other demographics. The discrepancy index (DI) was calculated as the difference between the degree of imaging abnormalities and the degree of cognitive dysfunction. Results: Multiple regression analysis showed that leisure activity and education were significantly associated with the discrepancy between cognitive and imaging findings. When the level of CR was determined based on leisure activity and education, the high-CR group showed a significantly larger DI than the moderate- and low-CR groups. Conclusion: The discrepancy between cognitive and imaging findings in patients with AD is associated with CR, measured using a combination of two indicators, i.e., leisure activity and education. Therefore, lifestyle interventions may delay the appearance of clinical symptoms resulting from underlying AD pathology, by increasing CR. Show more

Keywords: Alzheimer’s disease, brain imaging, cognition, cognitive reserve, education, leisure activity

DOI: 10.3233/JAD-210728

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 273-281, 2021

Authors: Sogorb-Esteve, Aitana | Colas, Romain A. | Dalli, Jesmond | Rohrer, Jonathan D.

Article Type: Research Article

Abstract: Background: The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective: We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods: 15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited …to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results: Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion: This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher). Show more

Keywords: C9orf72, frontotemporal dementia, lipid mediators, neuroinflammation, progranulin, tau.

DOI: 10.3233/JAD-210559

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 283-289, 2021

Authors: Abdulkadir, Teslim S. | Dawud, Fatima A. | Isa, Ahmed Sherif | Ayo, Joseph O.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease associated with deficiency in motor coordination, cognitive impairment, and excessive reactive oxygen species production in the brain. Objective: The study evaluated effects of taurine and camel milk (CM) on neurobehavior, amyloid-beta peptide 1–42 (Aβ) expression, acetylcholinesterase, and superoxide dismutase activities in aluminum chloride (AlCl3 ) model of Alzheimer’s disease in rats. Methods: Thirty-five female Wistar rats were divided into seven groups (n  = 5): Normal saline (0.2 mL/kg body weight); AlCl3 (100 mg/kg) (AD); CM (33 mL/kg); Taurine (50 mg/kg); AlCl3 (100 mg/kg) + CM (33 mL/kg); AlCl3 (100 mg/kg) + Taurine (50 mg/kg); …and AlCl3 (100 mg/kg) + CM (33 mL/kg) + Taurine (50 mg/kg). The administration lasted for eight weeks via oral gavage. After the eighth week, neurobehavior assessments were performed. Rats were sacrificed, and brain and blood samples collected for analysis. Results: There was a significant (p  < 0.0001) increase in the duration of motor endurance in AD + CM rats, compared to AD rats. Duration of forced swimming time was lowest (p  < 0.0001) in AlCl3 + Taurine rats, compared to that of AD rats. Concentration of Aβ peptide decreased (p  < 0.05) in AD rats, treated with CM and/or combination. In taurine-treated rats, superoxide dismutase activity was significantly (p  < 0.05) higher than in AD rats. Treatment with taurine + CM increased (p  < 0.05) acetylcholinesterase activity compared to controls. Conclusion: Taurine and CM enhanced cognition and sensorimotor activity by decreasing Aβ peptide concentration and increasing superoxide dismutase and acetylcholinesterase activities in AD rats. Show more

Keywords: Aluminum chloride, amyloid-beta peptide, camel milk, neurobehavior, oxidative stress, taurine

DOI: 10.3233/JAD-210130

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 291-302, 2021

Authors: Wei, Shan | Shang, Suhang | Dang, Liangjun | Gao, Fan | Gao, Yao | Gao, Ling | Chen, Chen | Huo, Kang | Wang, Jingyi | Wang, Jin | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Studies have found that blood lipids are associated with plasma amyloid-β (Aβ) levels, but the underlying mechanism is still unclear. Two Aβ transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aβ transport. Objective: The aim was to investigate the effects of lipids on the relationships between plasma Aβ and transporter levels. Methods: This study included 1,436 adults aged 40 to 88 years old. Blood Aβ, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze …the relationships between lipids and plasma Aβ, sLRP1, and sRAGE. Results: After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aβ42 and sRAGE (β= 6.158, p  = 0.049; β= 121.156, p  < 0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aβ40 , Aβ42 , and sRAGE (β= –48.389, p  = 0.017; β= –11.142, p  = 0.020; β= –147.937, p  = 0.003, respectively). Additionally, positive correlations were found between plasma Aβ and sRAGE in the normal TG (Aβ40 : β= 0.034, p  = 0.005; Aβ42 : β= 0.010, p  = 0.001) and HDL-c groups (Aβ40 : β= 0.023, p  = 0.033; Aβ42 : β= 0.008, p  = 0.002) but not in the high TG and low HDL-c groups. Conclusion: Abnormal levels of TG and HDL-c are associated with decreased Aβ and sRAGE levels. Positive correlations between plasma Aβ and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aβ levels might also be involved in peripheral Aβ clearance. Show more

Keywords: Alzheimer’s disease, amyloid-β, high-density lipoprotein, soluble low-density lipoprotein receptor-related protein-1, soluble receptor of advanced glycation end products, triglyceride

DOI: 10.3233/JAD-210405

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 303-314, 2021

Authors: Yamada, Yasunori | Shinkawa, Kaoru | Kobayashi, Masatomo | Caggiano, Vittorio | Nemoto, Miyuki | Nemoto, Kiyotaka | Arai, Tetsuaki

Article Type: Research Article

Abstract: Background: Gait, speech, and drawing behaviors have been shown to be sensitive to the diagnosis of Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, previous studies focused on only analyzing individual behavioral modalities, although these studies suggested that each of these modalities may capture different profiles of cognitive impairments associated with AD. Objective: We aimed to investigate if combining behavioral data of gait, speech, and drawing can improve classification performance compared with the use of individual modality and if each of these behavioral data can be associated with different cognitive and clinical measures for the diagnosis of …AD and MCI. Methods: Behavioral data of gait, speech, and drawing were acquired from 118 AD, MCI, and cognitively normal (CN) participants. Results: Combining all three behavioral modalities achieved 93.0% accuracy for classifying AD, MCI, and CN, and only 81.9% when using the best individual behavioral modality. Each of these behavioral modalities was statistically significantly associated with different cognitive and clinical measures for diagnosing AD and MCI. Conclusion: Our findings indicate that these behaviors provide different and complementary information about cognitive impairments such that classification of AD and MCI is superior to using either in isolation. Show more

Keywords: Drawing, gait analysis, handwriting, machine learning, speech, voice, walking

DOI: 10.3233/JAD-210684

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 315-327, 2021

Authors: Ferreira-Brito, Filipa | Ribeiro, Filipa | Aguiar de Sousa, Diana | Costa, João | Caneiras, Cátia | Carriço, Luís | Verdelho, Ana

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) and dementia are associated with increased age. MCI is a clinical entity described as a transitional state between normal cognition and dementia. Video games (VGs) can potentially promote cognition and functional capacity since multiple cognitive domains are recruited during gameplay. However, there is still a lack of consensus regarding the efficacy of VGs as therapeutic tools, particularly in neurodegenerative diseases. Objective: We aimed to analyze the impact of VGs on cognition and functional capacity outcomes in MCI/dementia patients. Methods: We conducted a systematic review and meta-analysis study (PROSPERO [CRD42021229445]). PubMed, Web …of Science, Epistemonikos, CENTRAL, and EBSCO electronic databases were searched for RCT (2000-2021) that analyzed the impact of VGs on cognitive and functional capacity outcomes in MCI/dementia patients. Results: Nine studies were included (n  = 409 participants), and Risk of Bias (RoB2) and quality of evidence (GRADE) were assessed. Data regarding attention, memory/learning, visual working memory, executive functions, general cognition, functional capacity, quality of life were identified, and pooled analyses were conducted. An effect favoring VGs interventions was observed on Mini-Mental State Examination (MMSE) score (MD  = 1.64, 95%CI 0.60 to 2.69). Conclusion: Although promising, the effects observed should be interpreted with caution since serious methodological shortcomings were identified in the studies included. Nonetheless, the effect observed is higher than the minimum clinically important difference (1.4 points) established to MMSE. Future studies on the current topic urge. Recommendations for the design and conduction of cognitive RCT studies are presented. Show more

Keywords: Cognition, dementia, independent living, mhealth, mild cognitive impairment, telerehabilitation, video games

DOI: 10.3233/JAD-210545

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 329-341, 2021

Authors: Mohr, Wiebke | Rädke, Anika | Afi, Adel | Edvardsson, David | Mühlichen, Franka | Platen, Moritz | Roes, Martina | Michalowsky, Bernhard | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Person-centered care (PCC) is an important concept in many countries’ national guidelines and dementia plans. Key intervention categories, i.e., a taxonomy of person-centered (PC)-interventions, to provide person-centered dementia care, are difficult to identify from literature. Objective: This systematic review aimed to identify and categorize published PC-interventions into key intervention categories to guide the provision of person-centered dementia care. Methods: Conduct of this systematic review followed Cochrane guidelines. A search of the dimensions ‘Dementia’, ‘Person-Centered Care’, and ‘Intervention’ combined was performed in PubMed, EMBASE, and Web of Science. Study selection was based on 2-stage screening against …eligibility criteria, limited to controlled study designs. Information about interventions and outcomes was extracted into an “Effects Table”. The identified PC-interventions were categorized in intervention categories to provide person-centered dementia care. Results: Searches identified 1,806 records. 19 studies were included. These covered a range of psychosocial interventions, oftentimes multi-component interventions, which followed heterogeneous approaches. Studies were conducted in long-term care/hospital settings. Nine key intervention categories were identified: social contact, physical activities, cognitive training, sensory enhancement, daily living assistance, life history oriented emotional support, training and support for professional caregivers, environmental adjustments, and care organization. Conclusion: Our findings provide a current overview of published PC-interventions in dementia, which followed heterogeneous approaches under the PCC-concept. The heterogeneity made it challenging to identify a well-defined concept of PCC and common key intervention categories. An effectiveness-evaluation of “PC” - including “relationship-centered”-interventions may be valuable, to assess whether an explicit focus on relationships around PCC-interventions yields an added benefit. PROSPERO-ID: CRD42021225084. Show more

Keywords: Alzheimer’s disease, dementia, patient-centered care, patient-focused care, patient preferences, person-centered care, person-centered dementia care, person-centered interventions, psychosocial intervention

DOI: 10.3233/JAD-210647

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 343-366, 2021

Authors: Wang, Quan | Su, Ning | Huang, Jin | Liang, Xinyu | Yuan, Jing | Yao, Ming | Zhou, Li-Xin | Jin, Zheng-Yu | Zhang, Shu-Yang | Cui, Li-Ying | Gong, Gaolang | Tian, Feng | Zhu, Yi-Cheng | Ni, Jun

Article Type: Research Article

Abstract: Background: Few studies have investigated the association between cognition and brain volume associated with cerebral small vessel disease (CSVD). Objective: We investigated the association between cognition and brain volume and neuroimaging markers of CSVD in a community-dwelling population. Methods: Participants (n  = 993, age≥35 years) from the community-based Shunyi Study were included to investigate the association between neuroimaging markers and cognition cross-sectionally. Magnetic resonance imaging markers included brain volume measurements of the total cerebrum, white matter, gray matter, and CSVD imaging markers. Cognitive performance was assessed using neuropsychological tests of the Mini-Mental State Examination (MMSE), Montreal Cognitive …Assessment (MoCA), Fuld Object Memory, digit span, Trail Making Test (TMT)-A, and TMT-B. Results: For brain volume measurement, subcortical white matter fraction was positively associated with MMSE score (β= 0.034, p  = 0.0062) and MoCA score (β= 0.034, p  = 0.0174), and negatively associated with TMT-A and TMT-B completion time (β= –2.319, p  = 0.0002; β= –2.827, p  = 0.0073, respectively). For evaluation of CSVD imaging markers, the presence of lacunes was positively associated with TMT-B completion time (β= 17.241, p  = 0.0028). Conclusion: In community-dwelling populations, reduced white matter volumes, as a consequence of aging and vascular damage, are associated with worse global cognition and executive function. Our findings provide potential insights into the correlation between cognition and CSVD-associated subcortical white matter injury. Show more

Keywords: Brain volume, cerebral small vessel disease, cognition, gray matter, magnetic resonance imaging, white matter

DOI: 10.3233/JAD-210367

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 367-375, 2021

Authors: Seo, Seung-Jun | Chang, Won-Seok | Jeon, Jae-Geun | Choi, Younshick | Kim, EunHo | Kim, Jong-Ki

Article Type: Research Article

Abstract: Background: The coexistence of magnetite within protein aggregates in the brain is a typical pathologic feature of Alzheimer’s disease (AD), and the formation of amyloid-β (Aβ) plaques induces critical impairment of cognitive function. Objective: This study aimed to investigate the therapeutic effect of proton stimulation (PS) targeting plaque magnetite in the transgenic AD mouse brain. Methods: A proton transmission beam was applied to the whole mouse brain at a single entrance dose of 2 or 4 Gy to test the effect of disruption of magnetite-containing Aβ plaques by electron emission from magnetite. The reduction in Aβ plaque …burden and the cognitive function of the PS-treated mouse group were assayed by histochemical analysis and memory tests, respectively. Aβ-magnetite and Aβ fibrils were treated with PS to investigate the breakdown of the amyloid protein matrix. Results: Single PS induced a 48–87%reduction in both the amyloid plaque burden and ferrous-containing magnetite level in the early-onset AD mouse brain while saving normal tissue. The overall Aβ plaque burden (68–82%) and (94–97%) hippocampal magnetite levels were reduced in late onset AD mice that showed improvements in cognitive function after PS compared with untreated AD mice (p  < 0.001). Analysis of amyloid fibrils after exposure to a single 2 or 4 Gy proton transmission beam demonstrated that the protein matrix was broken down only in magnetite-associated Aβ fibrils. Conclusion: Single PS targeting plaque magnetite effectively decreases the amyloid plaque burden and the ferrous-containing magnetite level, and this effect is useful for memory recovery. Show more

Keywords: Adult neurogenesis, Alzheimer’s disease, amyloid plaque magnetite, iron toxicity, memory recovery, proton-stimulated magnetite, proton transmission beam

DOI: 10.3233/JAD-210739

Citation: Journal of Alzheimer's Disease, vol. 84, no. 1, pp. 377-392, 2021