Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease in South Korea

Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P<0.001 for all), and between the ADD and OND groups (P<0.001 for all). The areas under the curve in differentiation of ADD from control subjects were 0.97 for Aβ42, 0.93 for total tau (tTau), 0.86 for pTau, and 0.99 for both tTau/Aβ42 and pTau/Aβ42 ratios. Our revised cutoff value for Aβ42 was higher than our previous one, whereas the values for the Tau proteins were similar. The tTau/Aβ42 ratio had the highest accuracy, 97%. Our findings highlight the usefulness of CSF AD biomarkers in South Korea, and the necessity of continually testing the reliability of cutoff values.ope

Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

Background: Renin-angiotensin system (RAS) inhibitors have been suggested as protective agents in Parkinson’s disease (PD). However, epidemiological evidence on the association between RAS inhibitors and the development of PD is inconsistent. Objectives: To investigate the effect of RAS inhibitors on PD risk in patients with ischemic heart disease (IHD) by type and cumulative duration of RAS inhibitors and their degree of blood-brain barrier (BBB) penetration ability. Methods: This was a propensity score-matched retrospective cohort study using 2008–2019 healthcare claims data from the Korean Health Insurance Review and Assessment database. The association between RAS inhibitor use and PD in patients with IHD was evaluated using multivariate Cox proportional hazard regression analysis. The risks are presented as adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Results: Over a 10-year follow-up, 1,086 of 62,228 IHD patients developed PD. The Cox regression model showed that the use of RAS inhibitors was significantly associated with a lower risk of PD (aHR = 0.75; 95% CI 0.66–0.85) than the non-use of RAS inhibitors. Specifically, this reduced risk of PD only remained with the use of BBB-crossing angiotensin II receptor blockers (ARBs) (aHR = 0.62; 95% CI = 0.53–0.74), and this association was more definite with an increasing cumulative duration. A significantly reduced risk of PD was not observed with the use of BBB-crossing angiotensin-converting enzyme inhibitors. Conclusions: The use of ARBs with BBB-penetrating properties and a high cumulative duration significantly reduces the risk of PD in IHD patients. This protective effect could provide insight into disease-modifying drug candidates for PD.ope

Anatomical heterogeneity of Alzheimer disease: based on cortical thickness on MRIs.

OBJECTIVE: Because the signs associated with dementia due to Alzheimer disease (AD) can be heterogeneous, the goal of this study was to use 3-dimensional MRI to examine the various patterns of cortical atrophy that can be associated with dementia of AD type, and to investigate whether AD dementia can be categorized into anatomical subtypes. METHODS: High-resolution T1-weighted volumetric MRIs were taken of 152 patients in their earlier stages of AD dementia. The images were processed to measure cortical thickness, and hierarchical agglomerative cluster analysis was performed using Ward's clustering linkage. The identified clusters of patients were compared with an age- and sex-matched control group using a general linear model. RESULTS: There were several distinct patterns of cortical atrophy and the number of patterns varied according to the level of cluster analyses. At the 3-cluster level, patients were divided into (1) bilateral medial temporal-dominant atrophy subtype (n = 52, ∼ 34.2%), (2) parietal-dominant subtype (n = 28, ∼ 18.4%) in which the bilateral parietal lobes, the precuneus, along with bilateral dorsolateral frontal lobes, were atrophic, and (3) diffuse atrophy subtype (n = 72, ∼ 47.4%) in which nearly all association cortices revealed atrophy. These 3 subtypes also differed in their demographic and clinical features. CONCLUSIONS: This cluster analysis of cortical thickness of the entire brain showed that AD dementia in the earlier stages can be categorized into various anatomical subtypes, with distinct clinical features.ope

Cerebellar Connectivity in Parkinson's Disease With Levodopa-Induced Dyskinesia

Objective: The precise pathogenesis or neural correlates underlying levodopa-induced dyskinesia (LID) remains poorly understood. There is growing evidence of the involvement of the cerebellum in Parkinson's disease (PD). The present study evaluated the role of motor cerebellar connectivity in determining vulnerability to LID. Methods: We enrolled 25 de novo patients with PD who developed LID within 5 years of levodopa treatment, 26 propensity score-matched PD patients who had not developed LID, and 24 age- and sex-matched healthy controls. We performed a comparative analysis of resting-state functional connectivity (FC) between the motor cerebellum and whole brain between the groups. Results: The patients with PD had increased FC bewteen the motor cerebellum and posterior cortical and cerebellar regions, while no gray matter regions had decreased FC with the motor cerebellum compared to the control participant. The patients with PD who were vulnerable to the development of LID had a significantly higher FC between the motor cerebellum lobule VIIIb and the left inferior frontal gyrus than those who were resistant to LID development. The connectivity of the motor cerebellum and left inferior frontal gyrus was negatively correlated with the latency from PD onset to the occurrence of LID. Interpretation: Increased FC between the motor cerebellum and left inferior frontal gyrus in de novo patients with PD could be an important determinant of vulnerability to LID.ope

Association of nonalcoholic fatty liver disease with incident dementia later in life among elderly adults

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Structural brain changes after traditional and robot-assisted multi-domain cognitive training in community-dwelling healthy elderly

The purpose of this study was to investigate if multi-domain cognitive training, especially robot-assisted training, alters cortical thickness in the brains of elderly participants. A controlled trial was conducted with 85 volunteers without cognitive impairment who were 60 years old or older. Participants were first randomized into two groups. One group consisted of 48 participants who would receive cognitive training and 37 who would not receive training. The cognitive training group was randomly divided into two groups, 24 who received traditional cognitive training and 24 who received robot-assisted cognitive training. The training for both groups consisted of daily 90-min-session, five days a week for a total of 12 weeks. The primary outcome was the changes in cortical thickness. When compared to the control group, both groups who underwent cognitive training demonstrated attenuation of age related cortical thinning in the frontotemporal association cortices. When the robot and the traditional interventions were directly compared, the robot group showed less cortical thinning in the anterior cingulate cortices. Our results suggest that cognitive training can mitigate age-associated structural brain changes in the elderly.ope

White matter hyperintensities and risk of levodopa-induced dyskinesia in Parkinson's disease

OBJECTIVE: To investigate whether the burden of white matter hyperintensities (WMHs) is associated with the risk of developing levodopa-induced dyskinesia (LID) in Parkinson's disease (PD). METHODS: According to the Clinical Research Center for Dementia of South Korea WMH visual rating scale, 336 patients with drug-naïve early stage PD (follow-up >3 years) were divided into two groups of PD with minimal WMHs (PD-WMH-; n = 227) and moderate-to-severe WMHs (PD-WMH+; n = 109). The Cox regression model was used to estimate the hazard ratio for the development of LID in the PD-WMH + group compared with the PD-WMH- group, while adjusting for age at PD onset, sex, striatal dopamine depletion, and PD medication dose. Additionally, we assessed the effects of WMH burden rated by the Scheltens scale and regional WMH distribution on the development of LID. RESULTS: Patients in the PD-WMH + group were older and had more severe parkinsonian motor signs despite comparable striatal dopamine transporter availability than those in the PD-WMH- group. Patients in the PD-WMH + group had a higher risk of developing LID (hazard ratio, 2.66; P < 0.001) than those in the PD-WMH- group after adjustment for other confounding factors. A greater WMH burden was associated with earlier occurrence of LID (hazard ratio, 1.04; P = 0.001), although the effects of WMHs on LID development did not exhibit region-specific patterns. INTERPRETATION: The present study demonstrates that the burden of WMHs is associated with occurrence of LID in patients with PD, suggesting comorbid WMHs as a risk factor for LID.ope

Higher Physical Activity Is Associated with Increased Attentional Network Connectivity in the Healthy Elderly

The purpose of this study was to demonstrate the potential alterations in structural network properties related to physical activity (PA) in healthy elderly. We recruited 76 elderly individuals with normal cognition from Samsung Medical Center in Seoul, Korea. All participants underwent the Cambridge Neuropsychological Test Automated Battery and 3.0T brain magnetic resonance imaging (MRI). Participants were subdivided into quartiles according to the International Physical Activity Questionnaire scores, which represents the amount of PA. Through graph theory based analyses, we compared global and local network topologies according to PA quartile. The higher PA group demonstrated better performance in speed processing compared to the lower PA group. Regional nodal strength also significantly increased in the higher PA group, which involved the bilateral middle frontal, bilateral inferior parietal, right medial orbitofrontal, right superior, and middle temporal gyri. These results were further replicated when the highest and the lowest quartile groups were compared in terms of regional nodal strengths and local efficiency. Our findings that the regional nodal strengths associated with the attentional network were increased in the higher PA group suggest the preventive effects of PA on age-related cognitive decline, especially in attention.ope

Deep learning-based amyloid PET positivity classification model in the Alzheimer's disease continuum by using 2-[ 18 F]FDG PET

Background: Considering the limited accessibility of amyloid position emission tomography (PET) in patients with dementia, we proposed a deep learning (DL)-based amyloid PET positivity classification model from PET images with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (2-[18F]FDG). Methods: We used 2-[18F]FDG PET datasets from the Alzheimer's Disease Neuroimaging Initiative and Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer's disease for model development. Moreover, we used an independent dataset from another hospital. A 2.5-D deep learning architecture was constructed using 291 submodules and three axes images as the input. We conducted the voxel-wise analysis to assess the regions with substantial differences in glucose metabolism between the amyloid PET-positive and PET-negative participants. This facilitated an understanding of the deep model classification. In addition, we compared these regions with the classification probability from the submodules. Results: There were 686 out of 1433 (47.9%) and 50 out of 100 (50%) amyloid PET-positive participants in the training and internal validation datasets and the external validation datasets, respectively. With 50 times iterations of model training and validation, the model achieved an AUC of 0.811 (95% confidence interval (CI) of 0.803-0.819) and 0.798 (95% CI, 0.789-0.807) on the internal and external validation datasets, respectively. The area under the curve (AUC) was 0.860 when tested with the model with the highest value (0.864) on the external validation dataset. Moreover, it had 75.0% accuracy, 76.0% sensitivity, 74.0% specificity, and 75.0% F1-score. We found an overlap between the regions within the default mode network, thus generating high classification values. Conclusion: The proposed model based on the 2-[18F]FDG PET imaging data and a DL framework might successfully classify amyloid PET positivity in clinical practice, without performing amyloid PET, which have limited accessibility.ope

Effects of amyloid and vascular markers on cognitive decline in subcortical vascular dementia

OBJECTIVE: To determine the independent and synergistic effects of amyloid and small vessel disease (SVD) burden on longitudinal cognitive decline in patients with subcortical vascular dementia (SVaD). METHODS: A longitudinal cohort study was conducted involving patients from outpatient clinics of 2 tertiary referral centers. Sixty-one patients with SVaD were prospectively recruited and underwent MRI, 11C-Pittsburgh compound B (PiB) PET at baseline, and a 3-year annual neuropsychological follow-up. Effects of PiB positivity and SVD markers (white matter hyperintensities [WMH], lacunes, and microbleeds) on longitudinal cognitive decline were evaluated using generalized estimation equation after controlling for age, sex, education, APOE4 allele, and follow-up interval. RESULTS: When individual neuropsychological tests were used as outcome measures, PiB positivity was associated with faster cognitive decline in attention, visuospatial, visual memory, and global cognition function. Higher WMH burden was associated with faster cognitive decline in attention, visuospatial, visual recognition memory, and semantic/phonemic fluency function, whereas lacunes and microbleeds had no significant effects. When global dementia rating (Clinical Dementia Rating sum of boxes) was considered as an outcome measure, however, only PiB positivity was associated with faster cognitive decline. Significant interactions between PiB positivity and higher SVD burden were found to affect cognitive decline in semantic word fluency (from WMH burden) and global dementia rating (from microbleed burden). CONCLUSIONS: In SVaD patients, amyloid burden, independently or interactively with SVD, contributed to longitudinal cognitive decline. Amyloid deposition was the strongest poor prognostic factor.ope