World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia.

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.

A new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities.

The Clinical Research Center for Dementia of South Korea (CREDOS) group developed a new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities (WMHs). In this study, we aimed to evaluate the validity of the CREDOS ischemia classification system. A total of 352 patients with cognitive impairments were included. Their WMH scores were rated using the CREDOS WMH visual rating scale. These patients were divided into 3 groups according to the CREDOS ischemia classification system. The volume of WMH was also automatically measured. The number of lacunes and microbleeds (MBs) were counted. The CREDOS ischemia classification system was revised with factor analysis using vascular risk factors and cerebrovascular disease (CVD) markers (WMH volume, lacunes, and MBs). External validation was performed in another group of patients with cognitive impairment using multinomial logistic regression analysis. The CREDOS WMH visual rating scale showed excellent correlation with the automatically measured volume of WMH. The factor analysis showed that the severe group was expanded to D3P1 and D3P2 in the revised CREDOS ischemia classification system. In the validation group, the presence of vascular risk factors and the severity of CVD markers could be distinguished according to the revised CREDOS ischemia classification. We validated a newly developed classification system for ischemia. This simple visual classification system was capable of providing information on vascular risk factors and CVD markers by simply rating WMH on magnetic resonance imaging.

Neurologic signs in relation to cognitive function in subcortical ischemic vascular dementia: a CREDOS (Clinical Research Center for Dementia of South Korea) study.

The objective of this study was to investigate the relationship between neurologic signs and cognitive dysfunction in subcortical ischemic vascular dementia (SIVD). 121 patients with SIVD were recruited from multiple nationwide hospitals. The patients' neurologic signs were evaluated using the Focal Neurologic Sign Score (FNSS). The FNSS scores did not correlate with the composite neuropsychology scores and Korean Mini-Mental State Examination scores. The FNSS scores correlated with the letter fluency and Rey-Osterrieth Complex Figure (ROCF) copy scores. Using a multivariate regression analysis controlled for age, sex, and educational level, the FNSS scores had a significant relationship with the letter fluency test scores (R (2) = 0.08, ß = -2.28, p = 0.02) and ROCF copy scores (R (2) = 0.08, ß = -0.42, p = 0.03). These findings suggest that the neurologic signs in patients with SIVD do not correlate with global cognitive functions; however, these signs do correlate with executive dysfunction in these patients.

Validation of the Literacy Independent Cognitive Assessment.

BACKGROUND: Low education and illiteracy are associated with an increased risk of dementia. This study aimed to develop a neuropsychological test battery applicable to both illiterate and literate elderly and to assess its reliability and validity for a diagnosis of dementia. METHODS: We developed the Literacy Independent Cognitive Assessment (LICA), which consists of 13 subtests assessing memory, language, visuoconstruction, executive function, attention and calculation. We investigated its reliability and validity on 152 patients with dementia, 66 with mild cognitive impairment and 639 normal controls. RESULTS: The subtests were found to be applicable to most of the illiterate normal controls (97.3%) and were found to have high inter-rater reliabilities (r = 0.85-1.00, p < 0.001) and moderate to high test-retest reliabilities (r = 0.50-0.86, p < 0.001). The LICA performed well in discriminating participants across Clinical Dementia Rating stages and showed excellent internal consistency and good concurrent validity with the Korean Mini-mental State Examination in both literate and illiterate participants. The area under the curve of the receiver operating characteristic was 0.985 in each of the two literacy groups. Sensitivity and specificity of the LICA to make a diagnosis of dementia was 91.9% and 91.8% at the cutoff point of 186.0 in the literate subjects and 96.2% and 91.1% at the cutoff point of 154.5 in the illiterate subjects. The battery was factored into two separate factors consisting of verbal memory tests and tests for other cognitive domains. CONCLUSION: The LICA is a valid and reliable instrument for a diagnosis of dementia in both illiterate and literate elderly.

Impact of white matter changes on activities of daily living in mild to moderate dementia.

The association between white matter changes and activities of daily living (ADL) in a large, well-defined cohort of patients with mild-to-moderate dementia (either Alzheimer's disease or subcortical vascular dementia) were investigated. A total of 289 patients were divided into three groups (140 mild, 99 moderate, and 50 severe) depending on the degree of white matter changes as indicated on brain magnetic resonance image scans. Further, we analyzed the three groups' performances on basic and instrumental ADL. The degree of white matter changes was associated with greater age, hypertension, previous history of stroke, higher Hachinski Ischemic Score, worse global cognitive and functional status, and an increased impairment of basic ADL and instrumental ADL. The increased impairment with regard to the severe group's performance on both the basic and instrumental ADL remained significant after adjustment for age and hypertension. Tasks involving physical activities were most significant. This was the first study investigating the association between white matter changes and ADL in a large, well-defined dementia cohort. The present study suggests that severe white matter changes may be associated with higher impairment on both basic and instrumental ADL.

Effects of medial temporal atrophy and white matter hyperintensities on the cognitive functions in patients with Alzheimer's disease.

AIMS: We conducted this study to investigate the independent association of medial temporal atrophy (MTA) and white matter hyperintensities (WMH) with cognitive impairments of Alzheimer's disease (AD) patients and the interaction between MTA and WMH. METHODS: From 13 centers, a total of 216 AD patients were consecutively recruited and their MTA and WMH were visually rated. We evaluated the association of MTA and WMH with the various cognitive domains, and the interaction between MTA and WMH. RESULTS: MTA independently correlated with scores of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), delayed recalls of the Seoul Verbal Learning Test (SVLT), the Boston Naming Test (BNT), and Word Fluency. WMH independently correlated with MMSE, CDR, Digit Span, and Stroop word reading, but not with delayed recall. There were interactions of WMH and MTA on CDR (p = 0.004), SVLT (p = 0.023), BNT (p = 0.002) and the semantic Word Fluency (p = 0.007). CONCLUSION: MTA and WMH independently affected cognitive deficits in AD patients, with somewhat different patterns where MTA was associated mostly with memory and language, while WMH were associated with attention and frontal executive functions. This study also showed interactions between MTA and WMH on some cognitive deficits and dementia severity, suggesting that they synergistically contribute to cognitive impairment in AD.

Increased telomere length in patients with frontotemporal dementia syndrome.

BACKGROUND: Telomeres are repetitive DNA sequences of TTAGGG at the ends of chromosomes. Many studies have shown that telomere shortening is associated with aging-related diseases, such as cardiovascular diseases, hypertension, diabetes, cancer, and various neurodegenerative diseases, including Alzheimer's disease, vascular dementia, Parkinson's disease, and dementia with Lewy bodies. However, changes in telomere length (TL) in patients with frontotemporal dementia (FTD) syndrome are unclear. Accordingly, in this study, we assessed TL in blood samples from patients with FTD syndrome. METHODS: Absolute TL was measured in peripheral blood leukocytes from 53 patients with FTD syndromes (25 with behavioral variant FTD, 19 with semantic variant primary progressive aphasia [PPA], six with nonfluent/agrammatic variant PPA, and three with amyotrophic lateral sclerosis [ALS] plus) and 28 cognitively unimpaired (CU) controls using terminal restriction fragment analysis. RESULTS: TL was significantly longer in the FTD group than in the CU group. All FTD subtypes had significantly longer TL than controls. There were no significant differences in TL among FTD syndromes. No significant correlations were found between TL and demographic factors in the FTD group. CONCLUSIONS: Longer telomeres were associated with FTD syndrome, consistent with a recent report demonstrating that longer telomeres are related to ALS. Therefore, our results may support a shared biology between FTD and ALS. More studies with larger sample sizes are needed.

Survival in frontotemporal lobar degeneration in a Korean population.

Frontotemporal lobar degeneration (FTLD) can be subdivided into frontotemporal dementia (FTD), FTD combined with motor neuron disease (FTD-MND), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). FTLD has been considered a rare disorder, and its' demographic and survival data have rarely been studied in Asian population. A survival analysis using the Kaplan-Meier method was performed for 121 consecutive patients with clinically diagnosed FTLD who attended the Memory Disorder Clinic at Samsung Medical Center in Seoul, Republic of Korea, between January 1995 and September 2006. The overall median survival from the onset of the first symptom was 9.6 years (95% CI=8.3-10.8 y). The survival was shortest in FTD-MND (3 y) and longest in SD (11.3 y). The median survival time of FTD (9.8 y) was shorter than that of SD and longer than that of FTD-MND and PNFA. The use of the Cox proportional-hazards model to examine the effect of demographics on survival revealed that only age at onset was associated with survival. In general, our data are comparable with those from the Western countries. However, the female proportion was greater across all subtypes of FTLD and the survival of patients with PNFA was shorter than those of other groups.

Analysis of frontotemporal dementia, amyotrophic lateral sclerosis, and other dementia-related genes in 107 Korean patients with frontotemporal dementia.

To identify pathogenic variants in 107 Korean patients with sporadic frontotemporal dementia (FTD), 46 genes related to FTD, amyotrophic lateral sclerosis, and other dementias were screened by next-generation sequencing. Hexanucleotide repeats in C9orf72 gene were also tested by repeat-primed polymerase chain reaction. Next-generation sequencing revealed one known pathogenic variant (c.708+1G>A) in the GRN gene in a patient with behavioral variant FTD (bvFTD). In addition, a novel in-frame deletion (c.2675_2683del) in the CSF1R gene was identified in a patient with bvFTD who had severe bifrontal atrophy with frontal subcortical white matter changes. Novel compound heterozygous variants in the AARS2 gene, c.1040+1G>A and c.636G>A (p.Met212Ile), were found in a patient with bvFTD. Forty-six variants of uncertain significance were detected in other patients. None of the patients had expanded hexanucleotide repeats in C9orf72. These results show that pathogenic variants of known FTD genes are rare in Korean FTD patients but the CSF1R and AARS2 genes should be screened for a genetic diagnosis of FTD or other dementias.

Prognosis of Patients with Behavioral Variant Frontotemporal Dementia Who have Focal Versus Diffuse Frontal Atrophy.

BACKGROUND AND PURPOSE: Only a few studies have investigated the relationship between different subtypes and disease progression or prognosis in patients with behavioral variant frontotemporal dementia (bvFTD). Since a localized injury often produces more focal signs than a diffuse injury, we hypothesized that the clinical characteristics differ between patients with bvFTD who show diffuse frontal lobe atrophy (D-type) on axial magnetic resonance imaging (MRI) scans versus those with focal or circumscribed frontal lobe atrophy (F-type). METHODS: In total, 94 MRI scans (74 scans from bvFTD and 20 scans from age-matched normal controls) were classified into 35 D- and 39 F-type bvFTD cases based on an axial MRI visual rating scale. We compared baseline clinical characteristics, progression in motor and cognitive symptoms, and survival times between D- and F-types. Survival analyses were performed for 62 of the 74 patients. RESULTS: While D-type performed better on neuropsychological tests than F-type at baseline, D-type had higher baseline scores on the Unified Parkinson's Disease Rating Scale (UPDRS) Part III. Evaluations of motor progression showed that the disease duration with motor symptoms was shorter in D-type than F-type. Moreover, the survival time was shorter in D-type (6.9 years) than F-type (9.4 years). Cox regression analyses revealed that a high UPDRS Part III score at baseline contributed to an increased risk of mortality, regardless of the pattern of atrophy. CONCLUSIONS: The prognosis is worse for D-type than for those with F-type. Shorter survival in D-type may be associated with the earlier appearance of motor symptoms.

Erratum to: Prognosis of Patients with Behavioral Variant Frontotemporal Dementia Who have Focal Versus Diffuse Frontal Atrophy.

This corrects the article on p. 234 in vol. 13, PMID: 28748674.

Unstable Body Mass Index and Progression to Probable Alzheimer's Disease Dementia in Patients with Amnestic Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVE: We investigated the influence of body mass index (BMI) status at baseline and changes in BMI over a follow-up period on the development of dementia in amnestic mild cognitive impairment (aMCI) patients. METHODS: The longitudinal data of 747 aMCI patients were used to investigate the relationships among baseline BMI status, subsequent changes in BMI (median follow-up duration: 1.6 years, interquartile range: 1.0-2.3 years), and risk of progression to probable Alzheimer's disease dementia (pADD). The aMCI patients were classified into underweight, normal weight, overweight, and obese subgroups, and further categorized into increased BMI, stable BMI, and decreased BMI subgroups during follow-up using a 4% mean annual change in BMI cut-off value. RESULTS: Compared to the normal weight group, the underweight group had a higher risk of pADD (hazard ratio [HR]: 1.89, 95% confidence interval [CI]: 1.07-3.37) while the obese group had a lower risk (HR: 0.70, 95% CI: 0.49-0.999). After controllingfor baseline BMI status, the decreased BMI (HR: 2.29, 95% CI: 1.41-3.72) and increased BMI (HR: 3.96, 95% CI: 2.62-6.00) groups were at increased risk of progression to pADD. CONCLUSIONS: Our findings suggested that underweight at baseline was associated with a higher risk of progression to pADD, while obesity at baseline predicted a lower risk. Furthermore, significant changes in BMI during the follow-up period reflected an increased risk of progression to pADD, regardless of BMI status at baseline.

Normative Study of the Literacy Independent Cognitive Assessment in Illiterate and Literate Elderly Koreans.

OBJECTIVE: The aim of this study was to provide normative data on the Literacy Independent Cognitive Assessment (LICA) and to explore the effects of age, education/literacy, and gender on the performance of this test. METHODS: Eight hundred and eighty-eight healthy elderly subjects, including 164 healthy illiterate subjects, participated in this study. None of the participants had serious medical, psychiatric, or neurological disorders including dementia. Bivariate linear regression analyses were performed to examine the effects of age, education/literacy, and sex on the score in each of the LICA cognitive tests. The normative scores for each age and education/literacy groups are presented. RESULTS: Bivariate linear regression analyses revealed that total score and all cognitive tests of the LICA were significantly influenced by both age and education/literacy. Younger and more-educated subjects outperformed older and illiterate or less-educated subjects, respectively, in all of the tests. The normative scores of LICA total score and subset score were presented according to age (60-64, 65-69, 70-74, 75-80, and ≥80 years) and educational levels (illiterate, and 0-3, 4-6, and ≥7 years of education). CONCLUSION: These results on demographic variables suggest that age and education should be taken into account when attempting to accurately interpret the results of the LICA cognitive subtests. These normative data will be useful for clinical interpretations of the LICA neuropsychological battery in illiterate and literate elderly Koreans. Similar normative studies and validations of the LICA involving different ethnic groups will help to enhance the dementia diagnosis of illiterate people of different ethnicities.

Clinical and Neuropsychological Characteristics of a Nationwide Hospital-Based Registry of Frontotemporal Dementia Patients in Korea: A CREDOS-FTD Study.

BACKGROUND: We investigated the demographic, clinical, and neuropsychological characteristics of frontotemporal dementia (FTD) from the Clinical Research Center for Dementia of South Korea (CREDOS)-FTD registry. METHODS: A total of 200 consecutive patients with FTD recruited from 16 neurological clinics in Korea were evaluated by cognitive and functional assessments, a screening test for aphasia, behavioral questionnaires, motor assessments, and brain MRI or PET. RESULTS: In our registry, 78 patients were classified as having been diagnosed with behavioral-variant FTD (bvFTD), 70 with semantic dementia (SD), 33 with progressive nonfluent aphasia (PNFA), and 8 with motor neuron disease plus syndrome (MND-plus). The patients with language variants of dementia were older than those with bvFTD. There were no differences in sex ratio, duration of illness, or level of education among the four subgroups. Overall, the patients with bvFTD showed a significantly better performance in cognitive tests. A higher frequency of motor symptoms and a lower frequency of behavioral symptoms were found in PNFA than in bvFTD and SD. The Global Language Index was significantly lower in SD than in bvFTD and PNFA. The MND-plus group had a poorer performance than all the others in all cognitive domains. CONCLUSION: The neuropsychological, behavioral, motor, and language characteristics of the four subtypes are comparable with those from other series. However, the proportion of SD (37.0%), which was similar to that of bvFTD (41.3%), was higher in our registry than in other series.

Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia.

The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients.

Reliability and validity of the short form of the literacy-independent cognitive assessment in the elderly.

BACKGROUND AND PURPOSE: The Literacy-Independent Cognitive Assessment (LICA) has been developed for a diagnosis of dementia and is a useful neuropsychological test battery for illiterate populations as well as literate populations. The objective of this study was to develop the short form of the LICA (S-LICA) and to evaluate the reliability and validity of the S-LICA. METHODS: The subtests of the S-LICA were selected based on the factor analysis and validation study results of the LICA. Patients with dementia (n=101) and normal elderly controls (n=185) participated in this study. RESULTS: Cronbach's coefficient alpha of the S-LICA was 0.92 for illiterate subjects and 0.94 for literate subjects, and the item-total correlation ranged from 0.63 to 0.81 (p<.01).The test-retest reliability of the S-LICA total score was high (r=0.94, p<.001), and the subtests had high test-retest reliabilities (r=0.68-0.87, p<.01). The correlation between the K-MMSE and S-LICA total scores were substantial in both the illiterate subjects (r=0.837, p<.001) and the literate subjects(r=0.802, p<.001). The correlation between the S-LICA and LICA was very high (r=0.989, p<.001). The area under the curve of the receiver operating characteristic was 0.999 for the literate subjects and 0.985 for the illiterate subjects. The sensitivity and specificity of the S-LICA for a diagnosis of dementia were 97% and 96% at the cutoff point of 72 for the literate subjects, and 96% and 93% at the cutoff point of 68 for the illiterate subjects, respectively. CONCLUSIONS: Our results indicate that the S-LICA is a reliable and valid instrument for quick evaluation of patients with dementia in both illiterate and literate elderly populations.

Bilateral Ageusia in a Patient with a Left Ventroposteromedial Thalamic Infarct: Cortical Localization of Taste Sensation by Statistical Parametric Mapping Analysis of PET Images.

Unilateral taste loss is usually observed on the side contralateral to a thalamic infarction, despite gustatory function being represented bilaterally. We report a rare case of bilateral taste loss in a patient with an acute left unilateral thalamic infarction, with unilateral left insular hypometabolism demonstrated by statistical parametric map analysis of PET images. Our observations suggest that the left insular cortex and left ventroposteromedial thalamic nuclei are critical to bilateral gustatory sensation.