Clinical Significance of Physical Frailty in Subjects With Subjective Cognitive Decline: A Prospective Study With Amyloid PET Data

Background@#and Purpose Physical frailty is known to be closely associated with cognitive impairment and to be an early sign of Alzheimer’s disease. We aimed to understand the characteristics of physical frailty and define factors associated with physical frailty in subjects with subjective cognitive decline (SCD) by analyzing amyloid data. @*Methods@#We prospectively enrolled subjects with SCD from a cohort study to identify predictors for the clinical progression to mild cognitive impairment or dementia from SCD (CoSCo). All of the subjects underwent brain magnetic resonance imaging, and brain amyloid positron-emission tomography (PET) to detect amyloid beta plaques. Self-reported exhaustion, handgrip strength, and gait speed were used to measure physical frailty. @*Results@#Of 120 subjects with SCD, 26 (21.7%) were amyloid-positive in PET. Female (odds ratio [OR]=3.79, p=0.002) and amyloid-PET-positive (OR=3.80, p=0.008) subjects with SCD were at high risks of self-reported exhaustion. Amyloid PET positivity (OR=3.22, p=0.047) and high burden from periventricular white-matter hyperintensity (OR=3.34, 95% confidence interval=1.18–9.46, p=0.023) were significantly associated with a weaker handgrip. The subjects with SCD with self-reported exhaustion and weaker handgrip presented with lower cognitive performance in neuropsychological tests, especially for information processing speed and executive function. Subjects with a slower gait performed worse in visual memory function tests. @*Conclusions@#Amyloid PET positivity was associated with a higher risk of self-reported exhaustion and weaker handgrip in subjects with SCD. The subjects with SCD and physical frailty also performed worse in neuropsychological tests.

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer’s Disease

Background@#and Purpose Oral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimer’s disease (AD). @*Methods@#This prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose; patients in each stratum were randomized to the test and control groups at a 1:1 ratio. @*Results@#The difference between the control group and the IPI-301 group, quantified as the Hodges–Lehmann estimate of location shift, was 0.00 (95% confidence interval: -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimer’s Disease Cooperative Study– Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups (p=0.02). However, the changes in the full-itemized ADCS-ADL scores at week 24 did not differ significantly between the two groups. There were no differences between the two groups regarding the scores for the Clinician Interview-Based Impression of Change (f0.9097), Mini-Mental State Examination (p=0.7018), Neuropsychiatric Inventory (p=0.7656), or Clinical Dementia Rating (p=0.9990). Adverse events, vital signs, and laboratory test results were comparable between the two groups. @*Conclusions@#IPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

Coping with Dementia in the Middle of the COVID-19 Pandemic

Multiple neurological complications have been associated with the coronavirus disease-19 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2. This is a narrative review to gather information on all aspects of COVID-19 in elderly patients with cognitive impairment. First, the following three mechanisms have been proposed to underlie the neurological complications associated with COVID-19: 1) direct invasion, 2) immune and inflammatory reaction, and 3) hypoxic brain damage by COVID-19. Next, because the elderly dementia patient population is particularly vulnerable to COVID-19, we discussed risk factors and difficulties associated with cognitive disorders in this vulnerable population. We also reviewed the effects of the patient living environment in COVID-19 cases that required intensive care unit (ICU) care. Furthermore, we analyzed the impact of stringent social restrictions and COVID-19 pandemic-mediated policies on dementia patients and care providers. Finally, we provided the following strategies for working with elderly dementia patients: general preventive methods; dementia care at home and nursing facilities according to the activities of daily living and dementia characteristics; ICU care after COVID-19 infection; and public health care system and government response. We propose that longitudinal follow-up studies are needed to fully examine COVID-19 associated neurological complications, such as dementia, and the efficacy of telemedicine/telehealth care programs.

Coexistence of Cerebral Microbleeds and Amyloid Pathology in Patients with Cognitive Complaints

Reliability and Validity of a Short Form of the Korean Dementia Screening Questionnaire-Cognition

Different Cortical Thinning Patterns Depending on Their Prognosis in Individuals with Subjective Cognitive Decline

BACKGROUND AND PURPOSE: Subjective cognitive decline (SCD) may be the first stage corresponding to subtle cognitive changes in patients with Alzheimer's disease (AD) spectrum disorders. We evaluated the differences in cortical thinning patterns among patients with SCD who progressed to mild cognitive impairment or dementia (pSCD), those who remained stable (sSCD), and healthy normal controls (NCs).METHODS: We retrospectively recruited SCD subjects (14 pSCD and 21 sSCD cases) and 29 NCs. Structural 3-dimensional-T1-weighted magnetic resonance imaging was performed using a single 1.5 Tesla scanner. Freesurfer software was used to map cortical thickness for group comparisons.RESULTS: Compared with NC group, the sSCD group showed diffuse cortical atrophy associated with bilateral fronto-parieto-temporal area. The pSCD group showed further characteristic cortical atrophy in AD-vulnerable regions including the inferior parieto-temporal and middle temporal areas. Cortical thinning in the bilateral medial frontal areas was observed in patients with sSCD and involved the right inferior temporal and left precentral areas in those with pSCD.CONCLUSIONS: Our study showed that SCD subjects exhibit different cortical thinning patterns depending on their prognosis.

A Comparative Evaluation of the KDSQ-C, AD8, and SMCQ as a Cognitive Screening Test to Be Used in National Medical Check-ups in Korea

BACKGROUND: Korea has a periodic general health check-up program that uses the Korean Dementia Screening Questionnaire-Cognition (KDSQ-C) as a cognitive dysfunction screening tool. The Alzheimer Disease 8 (AD8) and Subjective Memory Complaints Questionnaire (SMCQ) are also used in clinical practice. We compared the diagnostic ability of these screening questionnaires for cognitive impairment when completed by participants and their caregivers. Hence, we aimed to evaluate whether the SMCQ or AD8 is superior to the KDSQ-C and can be used as its replacement. METHODS: A total of 420 participants over 65 years and their informants were recruited from 11 hospitals for this study. The patients were grouped into normal cognition, mild cognitive impairment, and dementia subgroups. The KDSQ-C, AD8, and SMCQ were completed separately by participants and their informants. RESULTS: A receiver operating characteristic analysis of questionnaire scores completed by participants showed that the areas under the curve (AUCs) for the KDSQ-C, AD8, and SMCQ for diagnosing dementia were 0.75, 0.8, and 0.73, respectively. Regarding informant-completed questionnaires, the AD8 (AUC of 0.93), KDSQ-C (AUC of 0.92), and SMCQ (AUC of 0.92) showed good discriminability for dementia, with no differences in discriminability between the questionnaires. CONCLUSION: When an informant-report is possible, we recommend that the KDSQ-C continues to be used in national medical check-ups as its discriminability for dementia is not different from that of the AD8 or SMCQ. Moreover, consistent data collection using the same questionnaire is important. When an informant is not available, either the KDSQ-C or AD8 may be used. However, in the cases of patient-reports, discriminability is lower than that for informant-completed questionnaires.

Safety and Efficacy of Anti-dementia Agents in the Extremely Elderly Patients with Dementia

BACKGROUND: There are debates on representation and generalizability of previous randomized controlled trials about anti-dementia agents in the oldest old population. In this context, we aimed to investigate the efficacy and safety of anti-dementia agents in the very elderly patients with dementia. METHODS: We conducted a retrospective study of patients with dementia 1) who were 85 years or older, 2) got started anti-dementia agents, and 3) went through follow-up evaluation about one year thereafter. As a control, patients with dementia who were less than 85 years old with similar inclusion criteria were randomly selected during the same period. The adverse drug effects and discontinuation rates were investigated with self-reported complaint after starting or increasing anti-dementia drugs. For efficacy outcome, we also analyzed the change in neuropsychological results during follow-up period. RESULTS: A total of 77 dementia patients who were at least 85 years were enrolled. As a control group, 78 patients with dementia who were younger than 85 was analyzed. The adverse drug effects were observed in 26 (33.3%) patients in the younger old and in 26 (33.8%) in the oldest old (P = 0.095). Twenty-one patients (26.9%) in the younger old group and 13 patients (16.9%) in the oldest old group discontinued their medication (P = 0.131). There were no differences between the two groups about changes of Mini-Mental State Examination and Instrumental Activity of Daily Living scores over time. CONCLUSION: The use of anti-dementia agents in the oldest old dementia patients may be safe and effective as the younger old dementia patients.

Clinical Predictors for Mild Cognitive Impairment Progression in a Korean Cohort

BACKGROUND AND PURPOSE: Patients with mild cognitive impairment (MCI) and their caregivers are concerned with the likelihood and time course of progression to dementia. This study was performed to identify the clinical predictors of the MCI progression in a Korean registry, and investigated the effects of medications without evidence, frequently prescribed in clinical practice. METHODS: Using a Korean cohort that included older adults with MCI who completed at least one follow-up visit, clinical characteristics and total medical expenses including prescribed medications were compared between two groups: progressed to dementia or not. Cox proportional hazards regression analysis was conducted. RESULTS: During the mean 1.42±0.72 years, 215 (27.63%) of 778 participants progressed to dementia. The best predictors were age [hazard ratio (HR), 1.036; 95% confidence interval (CI), 1.006–1.067; p=0.018], apolipoprotein ε4 allele (HR, 2.247; 95% CI, 1.512–3.337; p<0.001), Clinical Dementia Rating scale-sum of boxes scores (HR, 1.367; 95% CI, 1.143–1.636; p=0.001), Instrumental Activities of Daily Living scores (HR, 1.035; 95% CI, 1.003–1.067; p=0.029), and lower Mini-Mental State Examination scores (HR, 0.892; 95% CI, 0.839–0.949; p<0.001). Total medical expenses were not different. CONCLUSIONS: Our data are in accordance with previous reports about clinical predictors for the progression from MCI to dementia. Total medical expenses were not different between groups with and without progression.

Anatomical Correlates of the "Closing-In" Phenomenon

BACKGROUND AND PURPOSE: The "closing-in" phenomenon refers to the tendency to copy near or overlap a model while performing figure-copying tasks. The mechanisms underlying the closing-in phenomenon have not been fully elucidated, and previous studies only investigated the mechanisms through neuropsychological tests. We investigated the neuroanatomical correlates of the closing-in phenomenon using voxel-based morphometry (VBM). METHODS: Thirty-eight patients diagnosed with probable Alzheimer's disease (AD) and 21 normal controls were included. All subjects underwent neuropsychological testing to diagnose dementia and magnetization prepared rapid acquisition gradient echo brain magnetic resonance imaging for the voxel-based statistical analysis. The subjects were asked to copy the modified Luria's alternating squares and triangles to quantify the closing-in phenomenon. We applied SPM8 for the VBM analysis to detect gray matter loss associated with the closing-in phenomenon. RESULTS: The patients with probable AD showed a higher closing-in score than that of the normal control subjects (p<0.0001). The VBM analysis revealed more parietal and temporal atrophy in the patients with AD than that in the normal control group. Moreover, atrophy of the orbito-frontal area was associated with the closing-in phenomenon. CONCLUSIONS: The closing-in phenomenon is dysfunction while performing figure-copying tasks and is more common in patients with AD. The analysis of the orbito-frontal area, which is associated with inhibiting primitive reflexes, revealed that the closing-in phenomenon is an imitation behavior commonly observed in patients with frontal lobe damage.

Reduced Gray Matter Volume in Subjective Cognitive Decline: A Voxel-Based Morphometric Study

BACKGROUND AND PURPOSE: Subjective cognitive decline has been proposed as a potential indicator of the preclinical state of Alzheimer's disease (AD). The results of the studies of cortical atrophy on brain MRIs in subjects with subjective cognitive decline are inconsistent across the literatures. We investigated whether subjects with subjective cognitive decline had less gray matter volume compared to controls without subjective cognitive decline as per brain MRI. METHODS: Thirty-six subjects with subjective cognitive decline and thirty-three controls without subjective cognitive decline were recruited retrospectively from among the patients who had visited the department of neurology at Inha University Hospital between January 2008 and December 2010. All subjects had undergone a brain MRI scan including 3D T1-weighted spoiled gradient recalled echo imaging. We used voxel-based morphometry (VBM) to examine gray matter volumes between the two groups, after controlling for age, sex, education, and total intracranial volumes (TIV). RESULTS: There were no significant differences in age, gender, education, and TIV between the two groups. In comparison to controls without subjective cognitive decline, subjects with subjective cognitive decline showed gray matter atrophy in the left superior and medial frontal gyri, left superior and inferior parietal lobules, and right precuneus and insular in the VBM analysis. CONCLUSIONS: Individuals with subjective cognitive decline encountered in clinical settings have greater similarity to an AD gray matter atrophy pattern compared with cognitively normal individuals without subjective cognitive decline.

White Matter Hyperintensity in Ischemic Stroke Patients: It May Regress Over Time / 대한뇌졸중학회지

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are frequently observed on MRI in ischemic stroke patients as well as in normal elderly individuals. Besides the progression of WMH, the regression of WMH has been rarely reported. Thus, we aimed to investigate how WMH change over time in patients with ischemic stroke, particularly focusing on regression. METHODS: We enrolled ischemic stroke patients who underwent brain MRI more than twice with at least a 6 month time-interval. Based on T2-weighted or FLAIR MRI, WMH were visually assessed, followed by semiautomatic volume measurement. Progression or regression of WMH change was defined when 0.25 cc increase or decrease was observed and it was also combined with visible change. A statistical analysis was performed on the pattern of WMH change over time and factors associated with change. RESULTS: A total of 100 patients were enrolled. Their age (mean+/-SD) was 67.5+/-11.8 years and 63 were male. The imaging time-interval (mean) was 28.0 months. WMH progressed in 27, regressed in 9 and progressed in distinctive regions and regressed in others in 5 patients. A multiple logistic regression model showed that age (odds ratio[OR] 2.51, 90% confidence interval[CI] 1.056-5.958), male gender (OR 2.957, 95% CI 1.051-9.037), large vessel disease (OR 1.955, 95% CI 1.171-3.366), and renal dysfunction (OR 2.900, 90% CI 1.045-8.046) were associated with progression. Regarding regression, no significant factor was found in the multivariate analysis. CONCLUSIONS: In 21.5% of ischemic stroke patients, regression of WMH was observed. WMH progression was observed in a third of ischemic stroke patients.

Factors Influencing Skin Tolerability to the Rivastigmine Patch in Patients with Alzheimer's Disease

BACKGROUND AND PURPOSE: The one-day rivastigmine patch is reportedly well tolerated and has minimal side effects. However, Asian patients show more side effects than those in Western countries. We evaluated tolerability of the rivastigmine patch in South Korean patients with Alzheimer's disease (AD) and the specific factors affecting adverse events of the skin. METHODS: A 6-month, open labeled, multi-centered, observational study was carried out in 440 patients with probable AD from July 2009 to September 2010 (NCT01312363). RESULTS: A total of 25.9% of the patients experienced adverse skin events at the rivastigmine patch application site and 17.0% discontinued treatment due to adverse events at the skin application site. The most common adverse events were itching and erythema. Patients with an allergic history and users of electric heating appliances reported skin discomfort. Older age was associated with discontinuing treatment. CONCLUSION: These results suggest that the rivastigmine patch induced some adverse skin events and may contribute to understanding and improving skin tolerability to the rivastigmine patch.

The Effects of Occupational Therapy and Music Therapy on Patients With Mild Cognitive Impairment: A Pilot Study

BACKGROUND: Patients with mild cognitive impairment (MCI) are at an increased risk for developing dementia, especially Alzheimer disease; and pharmacological therapy for MCI is limited. As a result, nonpharmacological mediums have been considered to complement standard drug therapy. In this study, we evaluated the effects of nonpharmacological therapies, occupational therapy and music therapy, on cognitive functions and depressive mood in MCI patients. METHODS: We enrolled patients with MCI from the Mapo Dementia Center and divided them into two groups, group A (n=14) who participated in a cognitive program for 12 months and group B (n=15) who did not participate in a cognitive program. We compared the baseline and followed-up scores of the Korean-version of Mini-Mental State Examination (K-MMSE), the Seoul Neuropsychological Screening Battery (SNSB), and the short version of geriatric depression scale (sGDS) between the two groups. RESULTS: Group A showed improvements in total and language scores in the K-MMSE and digit span backward scores in the SNSB and sGDS. In contrast, group B showed a decline in the Seoul Verbal Learning Test recognition score in the SNSB. Additionally, there were significant intergroup differences in the total and language scores in K-MMSE, the digit span backward score, and the Rey Complex Figure Test-delayed recall scores and depression scores. CONCLUSION: Occupational therapy and music therapy may help to improve cognitive functions and depressive mood in patients with MCI.

Gray and White Matter Degenerations in Subjective Memory Impairment: Comparisons with Normal Controls and Mild Cognitive Impairment

Subjective memory impairment (SMI) is now increasingly recognized as a risk factor of progression to dementia. This study investigated gray and white matter changes in the brains of SMI patients compared with normal controls and mild cognitive impairment (MCI) patients. We recruited 28 normal controls, 28 subjects with SMI, and 29 patients with MCI aged 60 or older. We analyzed gray and white matter changes using a voxel-based morphometry (VBM), hippocampal volumetry and regions of interest in diffusion tensor imaging (DTI). DTI parameters of corpus callosum and cingulum in SMI showed more white matter changes compared with those in normal controls, they were similar to those in MCI except in the hippocampus, which showed more degenerations in MCI. In VBM, SMI showed atrophy in the frontal, temporal, and parietal lobes compared with normal controls although it was not as extensive as that in MCI. Patients with SMI showed gray and white matter degenerations, the changes were distinct in white matter structures. SMI might be the first presenting symptom within the Alzheimer's disease continuum when combined with additional risk factors and neurodegenerative changes.

Blood Pressure and Heart Rate Variability in Alzheimer's Disease

BACKGROUND AND PURPOSE: Altered blood pressure (BP) and heart rate variations (HRVs) have been reported in Alzheimer's disease (AD). However, it is unclear how these two manifestations are associated with AD. Therefore, the objective of this study was to investigate BP and heart rate variability in AD compared to that in normal controls, patients with subjective memory impairment (SMI), and patients with mild cognitive impairment (MCI). METHODS: Case-control comparisons were made among AD (n=37), MCI (n=24), SMI (n=17), and controls (n=25). All patients underwent clinical and neuropsychological assessments with 24-h ambulatory BP and Holter monitoring. RESULTS: Patients with AD had higher pulse pressures than those in other groups. In addition, AD patients experienced blunted nocturnal BP dipping associated with declining cognitive status. AD patients also had larger ranges of HRV in parasympathetic domains compared to other groups, especially at night. CONCLUSIONS: Our results suggest that diurnal sympathetic and parasympathetic cardiac variability were significantly disturbed in mild cholinesterase-naive AD patients. This may be an indirect sign of disturbed integrity to the sleep-wake cycle in mild AD.

The Survey for the Effect of Guideline about Activities of Daily Living in Dementia Patients "Il-sang-ye-chan" Campaign

BACKGROUND: Activities daily living (ADL) disability has a direct influence on the patients' quality of life and on the amount of care needed. It is major factor of care in dementia patients. So Korean Dementia Association suggested guideline about activities of daily living in dementia patients in 2013. The purpose of this article is to investigate the effect of this. METHODS: A total of 110 subjects were enrolled. Assessments included age, sex, education level of patients and caregiver, the duration of disease, pattern of family, economic status. We divided "active practice" group and "passive practice" group by recognition of guideline contents after study. We compared two groups before and after by Korean Mini-Mental State Examination (K-MMSE), Short form of Geriatric Depression Scale-Korean version (S-GDS), Korean version of Zarit's Burden Interview (ZBI-K), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL). Finally, we investigate the level of satisfaction about our guideline. RESULTS: Age of patients, the duration of disease was lower and education level of caregiver and economic status was higher in "active practice group". The pattern of family also differed from two groups. It was observed distinct difference between the variations of two groups in S-GDS, ZBI-K, and ADCS-ADL. The level of satisfaction about our guideline was very high. CONCLUSION: Considering these results, our guideline about activities of daily living is effective to manage dementia patient. Active application of it is needed in clinic or center for dementia.

One-Year Follow-up Pilot Study for Dementia Diagnosis in Elderly with Recall Score of 0 in Korean-version of Mini-Mental State Examination

BACKGROUND: The early stage of Alzheimer disease might show early memory impairment with normal general cognitive function. Our study aimed to investigate elderly with normal Korean version of mini-mental state examination (K-MMSE) score and recall score of 0 for 1 year. We predicted that the patients would show different characteristics and would progress more rapidly compared with normal controls. METHODS: This study was based on the data from complete enumeration survey of Mapo-gu Regional Center for Dementia in 2009. We divided all subjects into three groups: subjects with normal K-MMSE scores and recall score of 0 were group 1-1 (n=152), subjects with abnormal K-MMSE scores were group 1-2 (n=64) and subjects with normal K-MMSE scores and recall score of 1 to 3 were group 1-3 (n=941). We compared basic demographics and social characteristics among the three groups. After 1 year (2010), the subjects in group 1-1 (90 out of 152) underwent follow-up examinations for dementia diagnosis. They were also divided into three groups (2-1, 2-2, 2-3) according to K-MMSE and recall scores. RESULTS: Group 1-1 showed different baseline characteristics compared with normal controls. After 1 year, 25.5% (23 out of 90) of the group 2-1 were diagnosed as mild cognitive impairment (n=16) or dementia (n=7). CONCLUSION: Our study suggested that subjects with normal K-MMSE scores but recall score of 0 are not entirely "normal". Further detailed evaluation might be needed if memory impairment is suspicious although the K-MMSE scores are within normal range.

Clinical Utility of Prominent Hypointense Signals in the Draining Veins on Susceptibility-Weighted Imaging in Acute Cerebral Infarct: As a Marker of Penumbra and a Predictor of Prognosis

PURPOSE: A relative increase in deoxyhemoglobin levels in hypoperfused tissue can cause prominent hypointense signals in the draining veins (PHSV) within areas of impaired perfusion in susceptibility-weighted imaging (SWI). The purpose of this study is to evaluate the usefulness of SWI in patients with acute cerebral infarction by evaluating PHSV within areas of impaired perfusion and to investigate the usefulness of PHSV in predicting prognosis of cerebral infarction. MATERIALS AND METHODS: In 18 patients with acute cerebral infarction who underwent brain MRI with diffusion-weighted imaging and SWI and follow-up brain MRI or CT, we reviewed the presence and location of the PHSV within and adjacent to areas of cerebral infarction qualitatively and measured the signal intensity difference ratio of PHSVs to contralateral normal appearing cortical veins quantitatively on SWI. The relationship between the presence of the PHSV and the change in the extent of infarction in follow-up images was analyzed. RESULTS: Of the 18 patients, 10 patients showed progression of the infarction, and 8 patients showed little change on follow-up imaging. On SWI, of the 10 patients with progression 9 patients showed peripheral PHSV and the newly developed infarctions corresponded well to area with peripheral PHSV on initial SWI. Only one patient without peripheral PHSV showed progression of the infarct. The patients with infarction progression revealed significantly higher presence of peripheral PHSV (p=0.0001) and higher mean signal intensity difference ratio (p=0.006) comparing to the patients with little change. CONCLUSION: SWI can demonstrate a peripheral PHSV as a marker of penumbra and with this finding we can predict the prognosis of acute infarction. The signal intensity difference of PHSV to brain tissue on SWI can be used in predicting prognosis of acute cerebral infarction.

A Semi-Automated Method for Measuring White Matter Hyperintensity Volume

BACKGROUND: White matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) have been considered as a reliable biomarker of small vessel damages. To evaluate the severity of WMHs, it is vital to develop reliable methods to measure the volume of WMHs. We applied open source software to measure WMH volume in the semi-automated way, and tested the reliability and validity by comparing with the commonly used qualitative rating scale. METHODS: Twenty five subjects with variable WMHs were recruited. ANALYZE 10.0 was used for the image processing and volumetric measurement of WMHs. The inhomogeneity and artifacts of signal were corrected with Insight Segmentation and Registration Toolkit in ANALYZE. For the gold standard of the WMH volumetric measurement, threshold method was applied with consensus of manual editing on each slice of the MRI images by two raters. Histogram of the all slices of the Fluid Attenuated Inversion Recovery (FLAIR) MRI was generated to calculate the optimal voxel intensity of threshold, and the lowest voxel threshold was decided as the mean+1.4 SD. The volumes of WMHs were generated by multiplying the area and the thickness of each slice. Inter- and intrarater reliability of the semi-automated volumetric and Scheltens'methods, and the association between the individual methods were analyzed. RESULTS: The semi-automated WMH volume at the threshold of 1.4 SD as well as the gold standard volume was well correlated with the Scheltens' visual scale (r=0.75, p<0.001). The semi-automated volumetry showed the excellent intra-rater (ICC=0.9929; 95% CI, 0.9840-0.9968) and inter-rater reliability (ICC=0.9830; 95% CI, 0.9620-0.9925), superior to the Scheltens' visual rating scale. CONCLUSIONS: The semi-automated volume measurement of the WMHs with Analyze was a valid and a reliable method to quantify subcortical white matter damages of various etiologies.