fNIRS Assessment during Cognitive Tasks in Elderly Patients with Depressive Symptoms.

This study aimed to investigate differences in prefrontal cortex activation between older adults with and without depressive symptoms during cognitive tasks using functional near-infrared spectroscopy (fNIRS). We examined 204 older participants without psychiatric or neurological disorders who completed the Geriatric Depression Scale, digit span, Verbal Fluency Test, and Stroop test. At the same time, prefrontal cortex activation was recorded using fNIRS. During the Stroop test, significantly reduced hemodynamics were observed in the depressive-symptom group. The mean accΔHbO2 of all channel averages was 0.14 µM in the control group and -0.75 µM in the depressive-symptom group (p = 0.03). The right hemisphere average was 0.13 µM and -0.96 µM, respectively (p = 0.02), and the left hemisphere average was 0.14 µM and -0.54 µM, respectively (p = 0.12). There was no significant difference in hemodynamic response (mean accΔHbO2) between the two groups during the digit span backward and VFT. In conclusion, reduced hemodynamics in the frontal cortex of the depressive-symptom group has been observed. The frontal fNIRS signal and the Stroop task may be used to measure depressive symptoms sensitively in the elderly.

Double Mutations in a Patient with Early-Onset Alzheimer's Disease in Korea: An APP Val551Met and a PSEN2 His169Asn.

The etiology of early-onset Alzheimer's disease (EOAD) is associated with alterations in the production of amyloid beta (Aß) species caused by mutations in the APP, PSEN1, and PSEN2 genes. Mutations affect intra- or inter-molecular interactions and processes between the γ-secretase complex and amyloid precursor protein (APP), leading to the aberrant sequential cleavage of Aß species. A 64-year-old woman presented with progressive memory decline, mild right hippocampal atrophy, and a family history of Alzheimer's dementia (AD). Whole exome sequencing was performed to evaluate AD-related gene mutations, which were verified by Sanger sequencing. A mutation-caused structural alteration of APP was predicted using in silico prediction programs. Two AD-related mutations, in APP (rs761339914; c.G1651A; p.V551M) and PSEN2 (rs533813519; c.C505A; p.H169N), were identified. The APP Val551Met mutation in the E2 domain may influence APP homodimerization through changes in intramolecular interactions between adjacent amino acids, altering Aß production. The second mutation was PSEN2 His169Asn mutation, which was previously reported in five EOAD patients from Korea and China, with a relatively high frequency in the East Asian population. According to a previous report, the presenilin 2 protein was predicted to result in a major helical torsion by PSEN2 His169Asn mutation. Notably, the co-existence of APP Val551Met and PSEN2 His169Asn may induce a synergistic effect by both mutations. Future functional studies are needed to clarify the pathological effects of these double mutations.

Cognitive decline according to amyloid uptake in patients with poststroke cognitive impairment.

BACKGROUND AND PURPOSE: Poststroke cognitive impairment (PSCI) is common, but the impact of ß-amyloid (Aß) on PSCI is uncertain. The proposed study will investigate amyloid pathology in participants with PSCI and how differently their cognition progress according to the amyloid pathology. METHODS: This multicenter study was designed to be prospective and observational based on a projected cohort size of 196 participants with either newly developed cognitive impairment, or rapidly aggravated CI, within 3 months after acute cerebral infarction. They will undergo 18F-flutemetamol positron emission tomography at baseline and will be categorized as either amyloid-positive (A+) or amyloid-negative (A-) by visual rating. The primary outcome measures will be based on Korean Mini-Mental State Examination changes (baseline to 12 months) between the A+ and A- groups. The secondary outcome measures will be the dementia-conversion rate and changes in the Korean version of the Montreal Cognitive Assessment (baseline to 12 months) between the A+ and A- groups. CONCLUSIONS: This study will provide a broadened perspective on the impact of Aß on the cause and outcomes of PSCI in clinical practice. Identifying amyloid pathology in patients with PSCI will help select patients who need more focused treatments such as acetylcholinesterase inhibitors. TRIAL REGISTRATION: Clinical Research Information Service identifier: KCT0005086.

Double-Blind, Randomized, Placebo-Controlled Trial of DA-9701 in Parkinson's Disease: PASS-GI Study.

OBJECTIVES: This study aimed to assess the efficacy of DA-9701 on gastrointestinal symptom-related quality of life in patients with Parkinson's disease on stable dopaminergic medications. METHODS: This multicenter, double-blind, placebo-controlled, phase 4 trial included a total of 144 patients with Parkinson's disease with gastrointestinal dysfunctions based on predefined criteria. Participants were randomized to take either DA-9701 or placebo for 4 weeks, and then both groups were administered DA-9701 for an additional 8 weeks while antiparkinsonian medications were unchanged. The primary outcome measure was gastrointestinal symptoms and related quality-of-life changes assessed on the Korean Nepean dyspepsia index after 4 and 12 weeks of therapy. We also evaluated the impact of DA-9701 therapy on parkinsonian motor symptoms at each time point. RESULTS: The gastrointestinal symptom-related quality-of-life score significantly improved in the DA-9701-treated group compared with the placebo-treated group after 4weeks (adjusted P = 0.012 by linear mixed effect model analysis). The overall gastrointestinal symptom and dyspepsia sum scores improved at 12 weeks after intervention in the DA-9701-first treated group (adjusted P = 0.002 and 0.014, respectively) and also in the placebo-first treated group (adjusted P = 0.019 and 0.039) compared with the baseline. Parkinsonian motor severity was not significantly affected by DA-9701 treatment in both groups at 4 and 12 weeks after intervention. There were no drug-related serious adverse events throughout the trial. CONCLUSIONS: DA-9701 therapy improved gastrointestinal symptom-related quality of life, and 12 weeks of daily administration can relieve the overall severity of gastrointestinal symptoms in patients with Parkinson's disease without affecting motor symptoms. (Clinical trial identifier: NCT02775591.) © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Genetic analyses of early-onset Alzheimer's disease using next generation sequencing.

Alzheimer's disease (AD) is the most common type of neurodegenerative dementia, but the cause of AD remained poorly understood. Many mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases. In this study, we screened familiar/de novo EOAD (n = 67) samples by next-generation sequencing (NGS) of a 50-gene panel, which included causative and possible pathogenic variants linked to neurodegenerative disorders. Remarkably, three missense mutations in PSEN1 (T119I, G209A, and G417A) and one known variant in PSEN2 (H169N) were discovered in 6% of the cases. Additionally, 67 missense mutations in susceptibility genes for late-onset AD were identified, which may be involved in cholesterol transport, inflammatory response, and ß-amyloid modulation. We identified 70 additional novel and missense variants in other genes, such as MAPT, GRN, CSF1R, and PRNP, related to neurodegenerative diseases, which may represent overlapping clinical and neuropathological features with AD. Extensive genetic screening of Korean patients with EOAD identified multiple rare variants with potential roles in AD pathogenesis. This study suggests that individuals diagnosed with AD should be screened for other neurodegenerative disease-associated genes. Our findings expand the classic set of genes involved in neurodegenerative pathogenesis, which should be screened for in clinical trials. Main limitation of this study was the absence of functional assessment for possibly and probably pathogenic variants. Additional issues were that we could not perform studies on copy number variants, and we could not verify the segregation of mutations.

Dynamic changes of oligomeric amyloid ß levels in plasma induced by spiked synthetic Aß42.

BACKGROUND: A reliable blood-based assay is required to properly diagnose and monitor Alzheimer's disease (AD). Many attempts have been made to develop such a diagnostic tool by measuring amyloid-ß oligomers (AßOs) in the blood, but none have been successful in terms of method reliability. We present a multimer detection system (MDS), initially developed for the detection of prion oligomers in the blood, to detect AßOs. METHODS: To characterize Aß in the blood, plasma was spiked with synthetic amyloid-ß (Aß) and incubated over time. Then, the MDS was used to monitor the dynamic changes of AßO levels in the plasma. RESULTS: Increasing concentrations of AßOs were observed in the plasma of patients with AD but not in the plasma of normal control subjects. The plasma from patients with AD (n = 27) was differentiated from that of the age-matched normal control subjects (n = 144) with a sensitivity of 83.3% and a specificity of 90.0%. CONCLUSIONS: Synthetic Aß spiked into the blood plasma of patients with AD, but that of not elderly normal control subjects, induced dynamic changes in the formation of AßOs over time. AßOs were detected by the MDS, which is a useful blood-based assay with high sensitivity and specificity for AD diagnosis.

Differences in the clinical manifestations and short-term prognosis of acute cerebral infarction after exposure to Agent Orange.

BACKGROUND: Agent Orange (AO) is the code name for one of the herbicides and defoliants used in the Vietnam War. Studies conducted thus far show a significant correlation between AO and the occurrence of cardiovascular diseases. But there is little data on the association between AO and stroke, and limited studies have targeted patient groups exposed to AO. METHOD: Bohun medical center Institutional Review Board (IRB) approved the study. (ID: 341) We studied patients with acute ischemic stroke within 7 days of onset in VHS medical center and 4 other general hospitals. Among them, 91 consecutive patients with previous exposure to AO were evaluated. For controlled group, 288 patients with no history of AO exposure were chosen. RESULT: There were 49 (44.0 %) DM patient with a higher frequency in the exposure group (93 (32.3 %) in control P = 0.045). There were 6 (6.6 %) hyperlipidemia in exposure group and 69 (24.0 %) in control. (P < 0.002). Small vessel occlusion was the most common subtype (36, 39.6 %) in exposure group but in control group, the large artery atherosclesosis was (120, 41.7 %) (P = 0.014). The NIHSS of the exposure group on admission showed lower scores (median values, 2 and 4, respectively; P = 0.003). The median mRS was 1 for the exposure group and 2 for the control group, at discharge and after 3 months. After 3 months of discharge, 55 (60.4 %) in the exposure group and 171 (59.4 %) in the control group showed below mRS 1 (P = 0.001). CONCLUSION: This study targeted patients who are Vietnam veteran. There is some difference in vascular risk factors and clinical manifestations suggest AO exposure has contributed to a certain extent to the stroke.

Differences in Regional Glucose Metabolism of the Brain Measured with F-18-FDG-PET in Patients with Essential Tremor According to Their Response to Beta-Blockers.

OBJECTIVE: In this study, there was an investigation as to whether there is a functional difference in essential tremor (ET), according to responses to beta-blockers, by evaluating regional changes in cerebral glucose metabolism. MATERIALS AND METHODS: Seventeen male patients with ET were recruited and categorized into two groups: 8 that responded to medical therapy (group A); and 9 that did not respond to medical therapy (group B). Eleven age-sex matched healthy control male subjects were also included in this study. All subjects underwent F-18 fluorodeoxyglucose (FDG)-PET, and evaluated for their severity of tremor symptoms, which were measured as a score on the Fahn-Tolosa-Marin tremor rating scale (FTM). The FDG-PET images were analyzed using a statistical parametric mapping program. RESULTS: The mean FTM score 6 months after the initiation of propranolol therapy was significantly lower in group A (18.13 > 8.13), compared with group B (14.67 = 14.67). The glucose metabolism in group A in the left basal ganglia was seen to be decreased, compared with group B. The ET showed a more significantly decreased glucose metabolism in both the fronto-temporo-occipital lobes, precuneus of right parietal lobe, and both cerebellums compared with the healthy controls. CONCLUSION: Essential tremor is caused by electrophysiological disturbances within the cortical-cerebellar networks and degenerative process of the cerebellum. Furthermore, ET may have different pathophysiologies in terms of the origin of disease according to the response to first-line therapy.

Changes in regional brain glucose metabolism measured with F-18-FDG-PET in essential tremor.

BACKGROUND: There is growing evidence that essential tremor (ET) is a multiple-system disorder. Previous PET studies in ET typically have measured brain oxygen consumption and cerebral blood flow. PURPOSE: To compare ET patients with control subjects to investigate any regional change in cerebral glucose metabolism through statistical parametric mapping (SPM) analysis of F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET). MATERIAL AND METHODS: We studied 17 patients with ET (17 men; mean age, 67.3 ± 4.8 years) and age-sex matched normal subjects. All subjects underwent FDG-PET imaging, and evaluated severity of tremor symptoms was measured as score on the Fahn-Tolosa-Marin rating scale (FTM). We also evaluated detailed the medical history and neurological examinations in all patients. RESULTS: The mean age of tremor onset was 57.6 ± 12.9 years and the mean FTM score was 15.1 ± 4.9. Brain FDG-PET analysis demonstrated hypometabolism in the medial frontal lobe, medial temporal lobe, and the precuneus of parietal lobe. However, there was no significant difference of glucose metabolism in the cerebellum. CONCLUSION: We propose that motor symptom of ET are caused by electrophysiological disturbances within cortical-cerebellar networks, rather than degenerative process of cerebellum, because the metabolism of the cerebellum was normal at rest. Furthermore, the abnormal glucose metabolism in the cerebral regions that do not mainly participate in motor function suggest that these regions may play a role as early markers of non-motor manifestations.