Journal of Alzheimer's Disease - Volume 73, issue 3

Authors: Göthlin, Mattias | Eckerström, Marie | Lindwall, Magnus | Rolstad, Sindre | Eckerström, Carl | Jonsson, Michael | Kettunen, Petronella | Svensson, Johan | Wallin, Anders

Article Type: Research Article

Abstract: Background: It is unclear if latent cognitive profiles can distinguish between dementia with subcortical vascular lesions and Alzheimer’s disease (AD) at the incipient stage, and if they differ in performance from the Petersen subtypes. Objective: To identify latent cognitive profiles in a naturalistic population of patients from a memory clinic sample, and investigate the derived classes not only in terms of conversion to AD, but also in terms of conversion to dementia with subcortical vascular lesions. Another objective was to compare the derived classes to the Petersen subtypes. Methods: We performed a latent profile analysis (LPA) …on standardized neuropsychological test scores from 476 memory clinic patients (age 64±8) without dementia, and analyzed progression to dementia after 2 years. Results: The LPA resulted in two classes with impaired cognition (Amnestic and Slow/Dysexecutive) and two classes with normal cognition (Normal-Low and Normal-High cognition). Belonging to the Amnestic class predicted progression to all-cause dementia and to AD; belonging to the Slow/Dysexecutive class predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. Of the Petersen MCI subtypes, only amnestic multi-domain MCI predicted progression to all-cause dementia, AD, and dementia with subcortical vascular lesions. Conclusion: Latent cognitive profiles separated between AD and dementia with subcortical vascular lesions, while the Petersen subtypes did not. However, similar to the Petersen subtypes, LPA classes work better for ruling out progression to dementia than for case finding. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, mild neurocognitive disorder, observational study, subcortical vascular dementia

DOI: 10.3233/JAD-190515

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 955-966, 2020

Authors: Hoang, Minh Tuan | Kåreholt, Ingemar | von Euler, Mia | Jönsson, Linus | von Koch, Lena | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Stroke and dementia are frequent comorbidities. Dementia possibly increases total costs of stroke care, especially cost of institutionalization and informal medical care. However, stroke rehabilitation costs in dementia patients are understudied. Objective: To estimate inpatient stroke rehabilitation costs for Swedish dementia patients in comparison with non-dementia patients. Methods: A longitudinal cohort study with linked data from the Swedish Dementia Register and the Swedish Stroke Register was conducted. Patients diagnosed with dementia who suffered a first ischemic stroke between 2010 and 2014 (n  = 138) were compared with non-dementia patients (n  = 935). Cost analyses were conducted from …a Swedish health care perspective. The difference of rehabilitation costs between the two groups was examined via simple linear regression (before and after matching by propensity scores of dementia) and multiple linear regression. Results: Mean inpatient rehabilitation costs for dementia and non-dementia patients were SEK 103,693/$11,932 and SEK 130,057/$14,966, respectively (median SEK 92,183/$10,607 and SEK 106,365/$12,239) (p  = 0.001). Dementia patients suffered from more comorbidities and experienced lower functioning, compared to non-dementia patients. The inpatient rehabilitation cost for patients with known dementia was 0.84 times the cost in non-dementia individuals. Conclusion: Dementia diagnosis was significantly associated with lower inpatient stroke rehabilitation costs. This might be explained by physicians’ beliefs on the limited effectiveness of rehabilitation in dementia patients. Further research on cost-effectiveness of stroke rehabilitation and patients’ satisfaction with stroke rehabilitation is necessary. Show more

Keywords: Cost analysis, dementia, rehabilitation, register studies, stroke, Sweden

DOI: 10.3233/JAD-190749

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 967-979, 2020

Authors: Okano, Takayuki | Yamamoto, Yosuke | Kuzuya, Akira | Egawa, Naohiro | Kawakami, Koji | Furuta, Ichiro | Mizuno, Kayoko | Fujino, Kiyohiro | Kojima, Ken | Omori, Koichi

Article Type: Research Article

Abstract: Background: Early detection of cognitive decline allows timely intervention to delay progression of dementia. However, current cognitive evaluation tools often include items delivered via verbal forms of instruction, which can cause poor performance in patients with hearing loss. Objective: To develop and validate a cognitive screening battery, the Reading Cognitive Test Kyoto (ReaCT Kyoto), comprising test items given through non-verbal instruction. Methods: A cross-sectional and multi-center study was conducted in the three medical institutes. ReaCT Kyoto was designed to evaluate domains of “registration,” “repetition,” “delayed recall,” “visuospatial recognition,” “orientation in time and place,” and “executive function.” …The Japanese version of the Mini-Mental State Examination Test (MMSE-J) and ReaCT Kyoto were applied by experienced psychotherapists. Concurrent validity was evaluated between the ReaCT Kyoto Test and MMSE-J and between the ReaCT Kyoto Test and physician-diagnosed dementia. Results: ReaCT Kyoto was validated in a sample of 115 participants. The mean age of subjects was 81.0±6.4 years, and the sample comprised 53.0% females. The area under the receiver operating curves was 0.95 for detecting physician-diagnosed dementia. When classifying patients in accordance with presence or absence of hearing loss, the AUCs were 0.93 and 0.97 for those with and without hearing loss, respectively. With a cut-off score of < 29 points for suspected dementia, ReaCT Kyoto correctly classified 90.4% of the subjects as belonging to the group with or without physician-diagnosed dementia. Conclusion: ReaCT Kyoto provides an appropriate solution for detection of cognitive impairment in persons with or without hearing loss. Show more

Keywords: Age-related hearing loss, cognitive test, dementia, screening, validation

DOI: 10.3233/JAD-190982

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 981-990, 2020

Authors: Ma, Zhe | Jing, Bin | Li, Yuxia | Yan, Huagang | Li, Zhaoxia | Ma, Xiangyu | Zhuo, Zhizheng | Wei, Lijiang | Li, Haiyun | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) exhibits a high risk of progression to Alzheimer’s disease (AD), and it is commonly deemed as the precursor of AD. It is important to find effective and robust ways for the early diagnosis of MCI. In this paper, a random forest-based method combining multiple morphological metrics was proposed to identify MCI from normal controls (NC). Voxel-based morphometry, deformation-based morphometry, and surface-based morphometry were utilized to extract morphological metrics such as gray matter volume, Jacobian determinant value, cortical thickness, gyrification index, sulcus depth, and fractal dimension. An initial discovery dataset (56 MCI/55 NC) from the ADNI were …used to construct classification models and the performances were testified with 10-fold cross validation. To test the generalization of the proposed method, two extra validation datasets including longitudinal ADNI data (30 MCI/16 NC) and collected data from Xuanwu Hospital (27 MCI/32 NC) were employed respectively to evaluate the performance. No matter whether testing was done on the discovery dataset or the extra validation datasets, the accuracies were about 80% with the combined morphological metrics, which were significantly superior to single metric (accuracy: 45% ∼76%) and also displayed good generalization across datasets. Additionally, gyrification index and cortical thickness derived from surface-based morphometry outperformed other features in MCI identification, suggesting they were some key morphological biomarkers for early MCI diagnosis. Combining the multiple morphological metrics together resulted in a significantly better and reliable identification model, which may be helpful to assist in the clinical diagnosis of MCI. Show more

Keywords: Deformation-based morphometry, mild cognitive impairment, random forest, surface-based morphometry, voxel-based morphometry

DOI: 10.3233/JAD-190715

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 991-1002, 2020

Authors: Witter, Steffi | Samoson, Ago | Vilu, Raivo | Witter, Raiker

Article Type: Research Article

Abstract: Fluorescence spectroscopy for in vitro amyloid-β (Aβ) fibrillation diagnosis and spectral fluorescence signature for the identification of bioactive compounds were applied to study traditional Ayurvedic nutraceuticals – Brahmi, Ashwagandha, Shanka pushpi, and Gotu kola – as well as their plant extracts for possible treatment of Alzheimer’s disease. All samples manifest as inhibitors on three different variants of the Aβ peptide: methionine Aβ1–40 , Aβ1–40 , and Aβ1–42 . The main compounds within the nutraceuticals were identified. Since related medicals are known to have reduced negative post- and side-effects and even may introduce further positive health impacts by preventing pathogen …plaque formation and reducing free Aβ to a natural level, such treatment approaches could be of further interest. Show more

Keywords: Dietary supplements, fluorescence spectroscopy, phytotherapy, spectral fluorescence signature

DOI: 10.3233/JAD-190758

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1003-1012, 2020

Authors: Zupanic, Eva | Kramberger, Milica G. | von Euler, Mia | Norrving, Bo | Winblad, Bengt | Secnik, Juraj | Fastbom, Johan | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Recurrent ischemic stroke (IS) increases the risk of cognitive decline. To lower the risk of recurrent IS, secondary prevention is essential. Objective: Our aim was to compare post-discharge secondary IS prevention and its maintenance up to 3 years after first IS in patients with and without Alzheimer’s disease and other dementia disorders. Methods: Prospective open-cohort study 2007–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who experienced an IS (n  = 1410; 332 [23.5%] with Alzheimer’s disease) were compared with matched non-dementia IS patients (n  = 7150). We …analyzed antiplatelet, anticoagulant, blood pressure lowering, and statin treatment as planned medication initiation at discharge and actual dispensation of medications at first, second, and third year post-stroke. Results: At discharge, planned initiation of medication was higher in patients with dementia compared to non-dementia patients for antiplatelets (OR with 95% CI for fully adjusted models 1.23 [1.02–1.48]) and lower for blood pressure lowering medication (BPLM; 0.57 [0.49–0.67]), statins (0.57 [0.50–0.66]), and anticoagulants (in patients with atrial fibrillation – AF; 0.41 [0.32–0.53]). When analysis for antiplatelets was stratified according to the presence of AF, ORs for receiving antiplatelets remained significant only in the presence of AF (in the presence of AF 1.56 [1.21–2.01], in patients without AF 0.99 [0.75–1.33]). Similar trends were observed in 1st, 2nd, and 3rd year post-stroke. Conclusions: Dementia was a predictor of lower statin and BPLM use. Patients with dementia and AF were more likely to be prescribed antiplatelets and less likely to receive anticoagulants. Show more

Keywords: Alzheimer’s disease, anticoagulants, antihypertensive agents, cohort studies, dementia, hydroxymethylglutaryl-CoA reductase inhibitors, ischemic stroke, platelet aggregation inhibitors, secondary prevention

DOI: 10.3233/JAD-191011

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1013-1021, 2020

Authors: Surmak, Andrew J. | Wong, Koon-Pong | Cole, Graham B. | Hirata, Kenji | Aabedi, Alexander A. | Mirfendereski, Omid | Mirfendereski, Payam | Yu, Amy S. | Huang, Sung-Cheng | Ringman, John M. | Liebeskind, David S. | Barrio, Jorge R.

Article Type: Research Article

Abstract: Background: 2-(4’- [11 C]Methylaminophenyl)-6-hydroxybenzothiazole ([11 C]-PiB), purportedly a specific imaging agent for cerebral amyloid-β plaques, is a specific, high affinity substrate for estrogen sulfotransferase (SULT1E1), an enzyme that regulates estrogen homeostasis. Objective: In this work, we use positron emission tomography (PET) imaging with [11 C]-PiB to assess the functional activity of SULT1E1 in the brain of moyamoya disease patients. Methods: Ten moyamoya subjects and five control patients were evaluated with [11 C]-PiB PET and structural MRI scans. Additionally, a patient with relapsing-remitting multiple sclerosis (RRMS) received [11 C]-PiB PET scans before and after steroidal and immunomodulatory …therapy. Parametric PET images were established to assess SULT1E1 distribution in the inflamed brain tissue. Results: Increased [11 C]-PiB SRTM DVR in the thalamus, pons, corona radiata, and internal capsule of moyamoya cohort subjects was observed in comparison with controls (p  ≤ 0.01). This was observed in patients without treatment, with collateralization, and also after radiation. The post-treatment [11 C]-PiB PET scan in one RRMS patient also revealed substantially reduced subcortical brain inflammation. In validation studies, [11 C]-PiB autoradiography signal in the peri-infarct area of the rat middle cerebral arterial occlusion stroke model was shown to correlate with SULT1E1 immunohistochemistry. Conclusion: Strong [11 C]-PiB PET signal associated with intracranial inflammation in the moyamoya syndrome cohort and a single RRMS patient appears consistent with functional imaging of SULT1E1 activity in the human brain. This preliminary work offers substantial and direct evidence that significant [11 C]-PiB PET focal signals can be obtained from the living human brain with intracranial inflammation, signals not attributable to amyloid-β plaques. Show more

Keywords: Inflammation, moyamoya, PET, PIB, sulfotransferase

DOI: 10.3233/JAD-190559

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1023-1033, 2020

Authors: Cogliati, Sebastián | Clementi, Victoria | Francisco, Marcos | Crespo, Cira | Argañaraz, Federico | Grau, Roberto

Article Type: Research Article

Abstract: Multiple causes, apart from genetic inheritance, predispose to the production and aggregation of amyloid-β (Aβ) peptide and Alzheimer’s disease (AD) development in the older population. There is currently no therapy or medicine to prevent or delay AD progression. One novel strategy against AD might involve the use of psychobiotics, probiotic gut bacteria with specific mental health benefits. Here, we report the neuronal and behavioral protective effects of the probiotic bacterium Bacillus subtilis in a Caenorhabditis elegans AD model. Aging and neuronal deterioration constitute important risk factors for AD development, and we showed that B. subtilis significantly delayed …both detrimental processes in the wild-type C. elegans strain N2 compared with N2 worms colonized by the non-probiotic Escherichia coli OP50 strain. Importantly, B. subtilis alleviated the AD-related paralysis phenotype of the transgenic C. elegans strains CL2120 and GMC101 that express, in body wall muscle cells, the toxic peptides Aβ3-42 and Aβ1-42 , respectively. B. subtilis -colonized CL2355 worms were protected from the behavioral deficits (e.g., poor chemotactic response and decreased body bends) produced by pan-neuronal Aβ1-42 expression. Notably, B. subtilis restored the lifespan level of C. elegans strains that express Aβ to values similar to the life expectancy of the wild-type strain N2 fed on E. coli OP50 cells. The B. subtilis proficiencies in quorum-sensing peptide (i.e., the Competence Sporulation Factor, CSF) synthesis and gut-associated biofilm formation (related to the anti-aging effect of the probiotic) play a crucial role in the anti-AD effects of B. subtilis . These novel results are discussed in the context of how B. subtilis might exert its beneficial effects from the gut to the brain of people with or at risk of developing AD. Show more

Keywords: Aβ42 , Alzheimer’s disease, B. subtilis , healthy aging, neuroprotection, probiotics, psychobiotics

DOI: 10.3233/JAD-190837

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1035-1052, 2020

Authors: Kan, Cheuk Ni | Gyanwali, Bibek | Hilal, Saima | Ng, Kok Pin | Venketasubramanian, Narayanaswamy | Chen, Christopher Li-Hsian | Xu, Xin

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (SVD) and neuropsychiatric symptoms (NPS) independently increase the risk of cognitive decline. While their co-existence has been reported in the preclinical stage of dementia, longitudinal data establishing the prognosis of their associations, especially in an Asian context remains limited. Objective: This study investigated the role of SVD and NPS progressions on cognitive outcomes over 2 years in a dementia-free elderly cohort. Methods: 170 dementia-free elderly with baseline and 2-year neuropsychological assessments and MRI scans were included in this study. White matter hyperintensities (WMH), lacunes, and microbleeds (CMBs) were graded as markers …of SVD. The Neuropsychiatric Inventory (NPI) was used to measure NPS. Generalized estimating equations modelling evaluated the relationship between NPI change and SVD progression. Logistic regression evaluated the risk of incident cognitive decline with both SVD and NPS. All models were adjusted for demographics, baseline cerebrovascular diease, and medial temporal lobe atrophy. Results: Higher NPI scores were associated with higher SVD burden at baseline. Subjects with WMH progression had greater increase in total NPI (β[SE] = 0.46[0.19], p  = 0.016), driven by hyperactivity subsyndrome (β[SE] = 0.88[0.34], p  = 0.007). Subjects with incident CMBs had greater increase in psychosis subsyndrome (β[SE] = 0.89[0.30], p  < 0.001). Subjects with progressions in both SVD and NPS were more likely to develop cognitive decline over 2 years (OR[95% CI] = 4.17[1.06–16.40], p  < 0.05). Conclusion: Our findings support worsening of NPS as a clinical indicator of SVD progression and are associated with cognitive decline over 2 years. Early detection of NPS and targeted interventions on SVD burden may improve NPS outcomes. Show more

Keywords: Cerebral small vessel disease, cognitive impairment, dementia, lacune, microbleeds, neurobehavioral symptoms, Neuropsychiatric Inventory, white matter hyperintensities

DOI: 10.3233/JAD-190999

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1053-1062, 2020

Authors: Zammit, Andrea R. | Bennett, David A. | Hall, Charles B. | Lipton, Richard B. | Katz, Mindy J. | Muniz-Terrera, Graciela

Article Type: Research Article

Abstract: Background: Conceptualizing cognitive aging as a step-sequential process is useful in identifying particular stages of cognitive function and impairment. Objective: We applied latent transition analysis (LTA) to determine 1) whether the underlying structure of cognitive profiles found at every measurement occasion are uniform across three waves of assessment, 2) whether class-instability is predictive of distal outcomes, and 3) whether class-reversions from impaired to non-impaired using latent modelling is lower than when using clinical criteria of mild cognitive impairment (MCI). Methods: A mover-stayer LTA model with dementia as a distal outcome was specified to model transitions of …ten neuropsychological measures over three annual waves in the Rush Memory and Aging Project (n  = 1,661). The predictive validity of the mover-stayer status for incident Alzheimer’s disease (AD) was then assessed. Results: We identified a five-class model across the three time-points: Mixed-Domain Impairment, Memory-Specific Impairment, Frontal Impairment, Average, and Superior Cognition. None of the individuals in the Impairment classes reverted to the Average or Superior classes. Conventional MCI classification identified 26.4% and 14.1% at Times 1 and 2 as false-positive cases. “Movers” had 87% increased risk of developing dementia compared to those classified as “Stayers”. Conclusion: Our findings support the use of latent variable modelling that incorporates comprehensive neuropsychological assessment to identify and classify cognitive impairment. Show more

Keywords: Alzheimer’s disease, latent transition analysis, cognitive status, cognitive profiles, cognitive heterogeneity, individual differences, dementia, neuropsychological profiles

DOI: 10.3233/JAD-190778

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1063-1073, 2020