Difference in trajectories according to early amyloid accumulation in cognitively unimpaired elderly.

BACKGROUND AND PURPOSE: Amyloid ß (Aß), a major biomarker of Alzheimer's disease, leads to tau accumulation, neurodegeneration and cognitive decline. Modelling the trajectory of Aß accumulation in cognitively unimpaired (CU) individuals is crucial, as treatments targeting Aß are anticipated. The evolution of Aß levels was investigated to determine whether it could lead to classification into different groups by studying longitudinal Aß changes in older CU individuals, and differences between the groups were compared. METHODS: A total of 297 CU participants were included from the Alzheimer's Disease Neuroimaging Initiative database, and these participants underwent apolipoprotein E (APOE) genotyping, neuropsychological testing, brain magnetic resonance imaging, and an average of 3.03 follow-up 18F-florbetapir positron emission tomography scans. Distinct Aß trajectory patterns were classified using latent class growth analysis, and longitudinal cognitive performances across these patterns were assessed with a linear mixed effects model. RESULTS: The optimal model consisted of three classes, with a high entropy value of 0.947. The classes were designated as follows: class 1, non-accumulation group (n = 197); class 2, late accumulation group (n = 70); and class 3, early accumulation group (n = 30). The late accumulation and early accumulation groups had more APOE ε4 carriers than the non-accumulation group. The longitudinal analysis of cognitive performance revealed that the early accumulation group showed the steepest decline (modified Preclinical Alzheimer's Cognitive Composite with digit symbol substitution [mPACCdigit], p < 0.001; modified Preclinical Alzheimer's Cognitive Composite with trails B [mPACCtrailsB], p < 0.001) and the late accumulation group showed a steeper decline (mPACCdigit, p = 0.014; mPACCtrailsB, p = 0.007) compared to the non-accumulation group. CONCLUSIONS: Our study showed the heterogeneity of Aß accumulation trajectories in CU older individuals. The prognoses for cognitive decline differ according to the Aß trajectory patterns.

Different associations between body mass index and Alzheimer's markers depending on metabolic health.

BACKGROUND: Increasing evidence supports the association between body mass index (BMI), Alzheimer's disease, and vascular markers. Recently, metabolically unhealthy conditions have been reported to affect the expression of these markers. We aimed to investigate the effects of BMI status on Alzheimer's and vascular markers in relation to metabolic health status. METHODS: We recruited 1,736 Asians without dementia (71.6 ± 8.0 years). Participants were categorized into underweight, normal weight, or obese groups based on their BMI. Each group was further divided into metabolically healthy (MH) and unhealthy (MU) groups based on the International Diabetes Foundation definition of metabolic syndrome. The main outcome was Aß positivity, defined as a Centiloid value of 20.0 or above and the presence of vascular markers, defined as severe white matter hyperintensities (WMH). Logistic regression analyses were performed for Aß positivity and severe WMH with BMI status or interaction terms between BMI and metabolic health status as predictors. Mediation analyses were performed with hippocampal volume (HV) and baseline Mini-Mental State Examination (MMSE) scores as the outcomes, and linear mixed models were performed for longitudinal change in MMSE scores. RESULTS: Being underweight increased the risk of Aß positivity (odds ratio [OR] = 2.37, 95% confidence interval [CI] 1.13-4.98), whereas obesity decreased Aß positivity risk (OR = 0.63, 95% CI 0.50-0.80). Especially, obesity decreased the risk of Aß positivity (OR = 0.38, 95% CI 0.26-0.56) in the MH group, but not in the MU group. Obesity increased the risk of severe WMH (OR = 1.69, 1.16-2.47). Decreased Aß positivity mediate the relationship between obesity and higher HV and MMSE scores, particularly in the MH group. Obesity demonstrated a slower decline in MMSE (ß = 1.423, p = 0.037) compared to being normal weight, especially in the MH group. CONCLUSIONS: Our findings provide new evidence that metabolic health has a significant effect on the relationship between obesity and Alzheimer's markers, which, in turn, lead to better clinical outcomes.

Prediction of Amyloid Positivity in Patients with Subcortical Vascular Cognitive Impairment.

Background: Amyloid-ß (Aß) commonly coexists and impacts prognosis in subcortical vascular cognitive impairment (SVCI). Objective: This study aimed to examine the differences in clinical and neuroimaging variables between Aß-positive and Aß-negative SVCI and to propose a prediction model for Aß positivity in clinically diagnosed SVCI patients. Methods: A total of 130 patients with SVCI were included in model development, and a separate cohort of 70 SVCI patients was used in external validation. The variables for the prediction model were selected by comparing the characteristics of the Aß-negative and Aß-positive SVCI groups. The final model was determined using a stepwise method. The model performance was evaluated using the receiver operating characteristic (ROC) curve and a calibration curve. A nomogram was used for visualization. Results: Among 130 SVCI patients, 70 (53.8%) were Aß-positive. The Aß-positive SVCI group was characterized by older age, tendency to be in the dementia stage, a higher prevalence of APOEɛ4, a lower prevalence of lacune, and more severe medial temporal atrophy (MTA). The final prediction model, which excluded MTA grade following the stepwise method for variable selection, demonstrated good accuracy in distinguishing between Aß-positive and Aß-negative SVCI, with an area under the curve (AUC) of 0.80. The external validation demonstrated an AUC of 0.71. Conclusions: The findings suggest that older age, dementia stage, APOEɛ4 carrier, and absence of lacunes may be predictive of Aß positivity in clinically diagnosed SVCI patients.

Effects of risk factors on the development and mortality of early- and late-onset dementia: an 11-year longitudinal nationwide population-based cohort study in South Korea.

BACKGROUND: Early-onset dementia (EOD, onset age < 65) and late-onset dementia (LOD, onset age ≥ 65) exhibit distinct features. Understanding the risk factors for dementia development and mortality in EOD and LOD respectively is crucial for personalized care. While risk factors are known for LOD development and mortality, their impact on EOD remains unclear. We aimed to investigate how hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and osteoporosis influence the development and mortality of EOD and LOD, respectively. METHODS: Using the Korean National Health Insurance Service (NHIS) database, we collected 546,709 dementia-free individuals and followed up for 11 years. In the two study groups, the Younger group (< 65 years old) and the Older group (≥ 65 years old), we applied Cox proportional hazard models to assess risk factors for development of EOD and LOD, respectively. Then, we assessed risk factors for mortality among EOD and LOD. RESULTS: Diabetes mellitus and osteoporosis increased the risk of EOD and LOD development. Hypertension increased the risk of EOD, while atrial fibrillation increased the risk of LOD. Conversely, hyperlipidemia exhibited a protective effect against LOD development. Additionally, diabetes mellitus increased mortality in EOD and LOD. Hypertension and atrial fibrillation increased mortality in LOD, while hyperlipidemia decreased mortality in EOD and LOD. CONCLUSIONS: Risk factors influencing dementia development and mortality differed in EOD and LOD. Targeted public health interventions addressing age-related risk factors may reduce dementia incidence and mortality.

Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens.

OBJECTIVES: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. METHODS: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. RESULTS: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. CONCLUSION: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.

Cortical neuroanatomical changes related to specific language impairments in primary progressive aphasia.

Objective: Language function test-specific neural substrates in Korean patients with primary progressive aphasia (PPA) might differ from those in other causes of dementia and English-speaking PPA patients. We investigated the correlation between language performance tests and cortical thickness to determine neural substrates in Korean patients with PPA. Materials and methods: Ninety-six patients with PPA were recruited from the memory clinic. To acquire neural substrates, we performed linear regression using the scores of each language test as a predictor, cortical thickness as an outcome and age, sex, years of education, and intracranial volume as confounders. Results: Poor performance in each language function test was associated with lower cortical thickness in specific cortical regions: (1) object naming and the bilateral anterior to mid-portion of the lateral temporal and basal temporal regions; (2) semantic generative naming and the bilateral anterior to mid-portion of the lateral temporal and basal temporal regions; (3) phonemic generative naming and the left prefrontal and inferior parietal regions; and (4) comprehension and the left posterior portion of the superior and middle temporal regions. In particular, the neural substrates of the semantic generative naming test in PPA patients, left anterior to mid-portion of the lateral and basal temporal regions, quite differed from those in patients with other causes of dementia. Conclusion: Our findings provide a better understanding of the different pathomechanisms for language impairments among PPA patients from those with other causes of dementia.

Optimization of a lumbar interspinous fixation device for the lumbar spine with degenerative disc disease.

Interspinous spacer devices used in interspinous fixation surgery remove soft tissues in the lumbar spine, such as ligaments and muscles and may cause degenerative diseases in adjacent segments its stiffness is higher than that of the lumbar spine. Therefore, this study aimed to structurally and kinematically optimize a lumbar interspinous fixation device (LIFD) using a full lumbar finite element model that allows for minimally invasive surgery, after which the normal behavior of the lumbar spine is not affected. The proposed healthy and degenerative lumbar spine models reflect the physiological characteristics of the lumbar spine in the human body. The optimum number of spring turns and spring wire diameter in the LIFD were selected as 3 mm and 2 turns, respectively-from a dynamic range of motion (ROM) perspective rather than a structural maximum stress perspective-by applying a 7.5 N∙m extension moment and 500 N follower load to the LIFD-inserted lumbar spine model. As the spring wire diameter in the LIFD increased, the maximum stress generated in the LIFD increased, and the ROM decreased. Further, as the number of spring turns decreased, both the maximum stress and ROM of the LIFD increased. When the optimized LIFD was inserted into a degenerative lumbar spine model with a degenerative disc, the facet joint force of the L3-L4 lumbar segment was reduced by 56%-98% in extension, lateral bending, and axial rotation. These results suggest that the optimized device can strengthen the stability of the lumbar spine that has undergone interspinous fixation surgery and reduce the risk of degenerative diseases at the adjacent lumbar segments.

Randomized controlled trial assessing the effectiveness of midazolam premedication as an anxiolytic, analgesic, sedative, and hemodynamic stabilizer.

BACKGROUND: Midazolam premedication is widely used before general anesthesia, but lacks clinical evidence of effectiveness. The present study aimed to evaluate the effectiveness of midazolam premedication following 4 aspects: anxiety reduction, sedation, hemodynamic stabilization, and analgesia. METHODS: In a randomized, single-blind, prospective study, a total of 128 women were allocated to the midazolam premedication group (Group P, n = 64) or the control group (Group N, n = 64). The patients were asked to complete the Beck anxiety inventory (BAI) 2 times: on the day before surgery (BS) and 30 minutes after midazolam premedication (T0). Depth of anesthesia using state entropy (SE), conventional hemodynamic data using heart rate (HR) and mean blood pressure (MBP), and analgesic profiles using surgical pleth index (SPI) were acquired at the following 4 points: T1-pre-induction, T2-prior to intubation, T3-intubation, and T4-20 minutes after intubation. RESULTS: No change in BAI score was observed between BS and T0 in both groups P and N (median and interquartile range [IQR], Group P: BS-4.5 [2.0-7.0], T0-4.0 [1.0-9.0], P = .603; Group N: BS-4.0 [1.0-8.5], T0-3.5 [1.0-6.0], P = .066). Midazolam premedication reduced SE at T2-4 (mean difference with 95% confidence interval [95% CI], T2-7.1 [1.6-12.6], P = .012; T3-10.4 [6.5-14.4], P < .001; T4-9.2 [5.0-13.4], P < .001). Midazolam premedication also reduced HR (mean differences [95% CI], T1-7.3 [2.5-12.1], P = .003; T3-6.6 [1.1-12.2], P = .020) and MBP at T1 and T3 (mean differences [95% CI], T1-7.3 [2.5-12.1], P = .003; T3-8.6 [1.3-15.9], P = .021), and lowered SPI at T1-3 (mean differences [95% CI]: T1-12.7 [6.1-19.4], P < .001; T2-6.0 [0.5-11.5], P = .033; T3-7.9 [1.7-14.1], P = .012). CONCLUSION: Midazolam premedication did not reduce the level of anxiety. However, midazolam premedication reduced the entropy values, stabilized hemodynamics, and provided analgesia during the induction of anesthesia. The purpose of midazolam premedication needs to be reconsidered.

Abrupt hemodynamic changes accompanying intrapleural hyperthermic chemotherapy: Case series.

RATIONALE: Intrapleural hyperthermic chemotherapy (IPHC) is the preferred method to locally treat lung cancer with pleural seeding. Anesthetic management during IPHC is a very challenging task for the anesthesiologist because of the hemodynamic instability associated with the procedure; however, there is no report on anesthetic considerations during the IPHC procedure. PATIENT CONCERNS: Three patients who diagnosed lung cancer with pleural invasion scheduled for IPHC were reported in this case series. DIAGNOSIS: Case 1, a 48-year-old woman, suffered from lung cancer (adenocarcinoma, T2NxM1a) with diffuse pleural seeding. Case 2, a 58-year-old female, diagnosed with lung cancer (adenocarcinoma, T3N0M1a) with pleural dissemination. Case 3, a 47-year-old male, diagnosed as sarcoma on the left lung with right pericardial invasion and right hemidiaphragm invasion (stage, T3N0M1a). INTERVENTION: All three patients underwent IPHC with cisplatin diluted in normal saline (2000 ml) at a rate of 600 ml/min. Inflow temperature of 42°C was using a heart-lung machine over 90 minutes. Hemodynamic changes were monitored through the procedure. OUTCOMES: The patient did not require supplemental oxygenation anymore after he recovered from lung transplantation. LESSONS: There was sudden drop in the cardiac output and an increase in the pulmonary vascular resistance, which were caused by the volume and temperature of the hyperthermic chemotherapeutic drugs in the pleura during the early stage of IPHC; these changes can be a major problem during the procedure, and supportive hemodynamic management may be needed.