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Aims Heart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort. Methods and results Two-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>−14.7%: 95% percentile of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47–4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51–8.43; P = 0.004) but not other subtypes. Conclusion LV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain–heart interaction and may help improve stroke primary prevention strategies.

ImportanceThe risk of ischemic stroke is higher among patients with left atrial (LA) enlargement. Left atrial strain (LAε) and LA strain rate (LASR) may indicate LA dysfunction when LA volumes are still normal. The association of LAε with incident ischemic stroke in the general population is not well established.ObjectiveTo investigate whether LAε and LASR are associated with new-onset ischemic stroke among older adults.DesignThe Cardiovascular Abnormalities and Brain Lesions study was conducted from September 29, 2005, to July 6, 2010, to investigate cardiovascular factors associated with subclinical cerebrovascular disease. A total of 806 participants in the Northern Manhattan Study who were aged 55 years or older without history of prior stroke or atrial fibrillation (AF) were included, and annual follow-up telephone interviews were completed May 22, 2022. Statistical analysis was performed from June through November 2022.ExposuresLeft atrial strain and LASR were assessed by speckle-tracking echocardiography. Global peak positive longitudinal LAε and positive longitudinal LASR during ventricular systole, global peak negative longitudinal LASR during early ventricular diastole, and global peak negative longitudinal LASR during LA contraction were measured. Brain magnetic resonance imaging was used to detect silent brain infarcts and white matter hyperintensities at baseline.Main Outcomes and MeasuresRisk analysis with cause-specific Cox proportional hazards regression modeling was used to assess the association of positive longitudinal LAε and positive longitudinal LASR with incident ischemic stroke, adjusting for other stroke risk factors, including incident AF.ResultsThe study included 806 participants (501 women [62.2%]) with a mean (SD) age of 71.0 (9.2) years; 119 participants (14.8%) were Black, 567 (70.3%) were Hispanic, and 105 (13.0%) were White. During a mean (SD) follow-up of 10.9 (3.7) years, new-onset ischemic stroke occurred in 53 participants (6.6%); incident AF was observed in 103 participants (12.8%). Compared with individuals who did not develop ischemic stroke, participants with ischemic stroke had lower positive longitudinal LAε and negative longitudinal LASR at baseline. In multivariable analysis, the lowest (ie, closest to zero) vs all other quintiles of positive longitudinal LAε (adjusted hazard ratio [HR], 3.12; 95% CI, 1.56-6.24) and negative longitudinal LASR during LA contraction (HR, 2.89; 95% CI, 1.44-5.80) were associated with incident ischemic stroke, independent of left ventricular global longitudinal strain and incident AF. Among participants with a normal LA size, the lowest vs all other quintiles of positive longitudinal LAε (HR, 4.64; 95% CI, 1.55-13.89) and negative longitudinal LASR during LA contraction (HR, 11.02; 95% CI 3.51-34.62) remained independently associated with incident ischemic stroke.Conclusions and RelevanceThis cohort study suggests that reduced positive longitudinal LAε and negative longitudinal LASR are independently associated with ischemic stroke in older adults. Assessment of LAε and LASR by speckle-tracking echocardiography may improve stroke risk stratification in elderly individuals.

This study aimed to examine whether magnetoencephalography (MEG) is useful to detect early stage Alzheimer’s disease (AD). We analyzed MEG data from the early stage AD group (n = 20; 6 with mild cognitive impairment due to AD and 14 with AD dementia) and cognitively normal control group (NC, n = 27). MEG was recorded during resting eyes closed (EC) and eyes open (EO), and the following 6 values for each of 5 bands (θ1: 4-6, θ2: 6-8, α1: 8-10, α2: 10-13, β: 13-20 Hz) in the cerebral 68 regions were compared between the groups: (1) absolute power during EC and (2) EO, (3) whole cerebral normalization (WCN) power during EC and (4) EO, (5) difference of the absolute powers between the EC and EO conditions (the EC-EO difference), and (6) WCN value of the EC-EO difference. We found significant differences between the groups in the WCN powers during the EO condition, and the EC-EO differences. Using a Support Vector Machine classifier, a discrimination accuracy of 83% was obtained and an AUC in an ROC analysis was 0.91. This study demonstrates that MEG during resting EC and EO is useful in discriminating between early stage AD and NC.

ObjectiveTo examine associations between measures of obesity in middle to early-old age with later-life MRI markers of brain aging.MethodsWe analyzed data from the Northern Manhattan MRI Sub-Study (n = 1,289). Our exposures of interest were body mass index (BMI), waist circumference (WC), waist-to-hip ratio, and plasma adiponectin levels. Our outcomes of interest were total cerebral volume (TCV), cortical thickness, white matter hyperintensity volume (WMHV), and subclinical brain infarcts (SBI). Using multivariable linear and logistic regression models adjusted for sociodemographics, health behaviors, and vascular risk factors, we estimated β coefficients (or odds ratios) and 95% confidence intervals (CIs) and tested interactions with age, sex, and race/ethnicity.ResultsOn average at baseline, participants were aged 64 years and had 10 years of education; 60% were women and 66% were Caribbean Hispanic. The mean (SD) time lag between baseline and MRI was 6 (3) years. Greater BMI and WC were significantly associated with thinner cortices (BMI β [95% CI] −0.089 [−0.153, −0.025], WC β [95% CI] −0.103 [−0.169, −0.037]) in fully adjusted models. Similarly, compared to those with BMI ConclusionsAdiposity in early-old age is related to reduced global gray matter later in life in this diverse sample. Future studies are warranted to elucidate causal relationships and explore region-specific associations.

ObjectiveTo establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC).MethodsPhysical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out.ResultsThe 3 patients exhibited intellectual disability and progressive intellectual decline accompanied by psychiatric symptoms. Gait difficulty with spasticity and pyramidal weakness appeared at the ages of 20s–30s. Brain MRI revealed TCC with atrophic changes in the frontotemporal lobes, caudate nuclei, and cerebellum. Exome sequence analysis revealed a novel homozygous c.2654C>A (p. Ala885Asp) variant in the ATP13A2, a gene responsible for a complicated form of hereditary spastic paraplegia (SPG78), Kufor-Rakeb syndrome, and neuronal ceroid lipofuscinosis. The predominant clinical presentations of the patients include progressive intellectual disability and gait difficulty with spasticity and pyramidal weakness, consistent with the diagnosis of SPG78. Of note, prominent psychiatric symptoms and extrapyramidal signs including rigidity, dystonia, and involuntary movements preceded the spastic paraparesis.ConclusionsOur study further broadens the clinical spectrum associated with ATP13A2 mutations.

Silent brain infarctions (SBI) and white matter hyperintensities (WMH) are associated with increased risk for stroke ([1][1]). Left atrial (LA) functional impairment is associated with increased cardiovascular events including stroke ([2][2]). Although LA volume measurement is the gold standard for

Elevated blood pressure (BP) level is one of the most consistently identified risk factors for silent brain disease. BP values obtained at the proximal segment of the aorta (central BP) are more directly involved than brachial BP in the pathogenesis of cardiovascular disease. However, the association between central BP and silent cerebrovascular disease has not been clearly established. Participants in the CABL (Cardiovascular Abnormalities and Brain Lesions) study (n=993; mean age, 71.7±9.3 years; 37.9% men) underwent 2-dimensional echocardiography, arterial wave reflection analysis for determination of central BPs, and brain magnetic resonance imaging. Central BPs were calculated from the radial pulse waveform. Subclinical silent cerebrovascular disease was defined as silent brain infarction and white matter hyperintensity volume. Both brachial ( P =0.014) and central pulse pressure ( P =0.026) were independently associated with silent brain infarctions after adjustment for clinical variables, but not adjusting for each other. None of the brachial BP values was associated with upper quartile of white matter hyperintensity volume in multivariable analysis. Both central systolic BP ( P P

Background and purposeWe previously reported the usefulness of iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy for differentiation of dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) in a cross-sectional multicentre study. The aim of this study was, by using reassessed diagnosis after 3-year follow-up, to evaluate the diagnostic accuracy of 123I-MIBG scintigraphy in differentiation of probable DLB from probable AD.MethodsWe undertook 3-year follow-up of 133 patients with probable or possible DLB or probable AD who had undergone 123I-MIBG myocardial scintigraphy at baseline. An independent consensus panel made final diagnosis at 3-year follow-up. Based on the final diagnosis, we re-evaluated the diagnostic accuracy of 123I-MIBG scintigraphy performed at baseline.ResultsSixty-five patients completed 3-year follow-up assessment. The final diagnoses were probable DLB (n=30), possible DLB (n=3) and probably AD (n=31), and depression (n=1). With a receiver operating characteristic curve analysis of heart-to-mediastinum (H/M) ratios for differentiating probable DLB from probable AD, the sensitivity/specificity were 0.77/0.94 for early images using 2.51 as the threshold of early H/M ratio, and 0.77/0.97 for delayed images using 2.20 as the threshold of delayed H/M ratio. Five of six patients who were diagnosed with possible DLB at baseline and with probable DLB at follow-up had low H/M ratio at baseline.ConclusionsOur follow-up study confirmed high correlation between abnormal cardiac sympathetic activity evaluated with 123I-MIBG myocardial scintigraphy at baseline and the clinical diagnosis of probable DLB at 3-year follow-up. Its diagnostic usefulness in early stage of DLB was suggested.Trial registration numberUMIN00003419.

Objectives The exacerbating factors of myasthenia gravis (MG) are unknown. However, it has been speculated that infections may play a role in disease progression. Methods We calculated the adjusted anti-acetylcholine receptor antibody (Adj-AChR-Ab) titers (range, 0-1) in 58 MG patients between 2006 and 2012. We determined the relationship between Adj-AChR-Ab titer and infection incidence. Results A cross-correlation function (CCF) analysis of Adj-AChR-Ab titer and incidence of Mycoplasma pneumoniae (M. pneumoniae) (r = 0.449, P 0.0001) and influenza virus (r = 0.411, P 0.001) infections indicated significant correlations. MG with thymoma was highly correlated with M. pneumoniae infection (r = 0.798, P 0.0001). The relative risk for Adj-AChR-Ab titer was 1.407 for M. pneumoniae (95% CI, 1.193-1.661 for an increase in one infected patient per monitoring point) and 1.158 for influenza (95% CI, 1.071-1.253 for 100 infected patients). Conclusion Variation of Adj-AChR-Ab titer is significantly influenced by the presence of M. pneumoniae and influenza virus infections.

Cardiac 123I-meta-iodobenzylguanidine (MIBG) uptake is quantified using the heart-to-mediastinum ratio (HMR) with an Anger camera. The relationship between HMR determined using D-SPECT with a cadmium–zinc–telluride detector and an Anger camera is not fully understood. Therefore, the present study aimed to define this relationship using images derived from a phantom and from patients. Cross-calibration phantom studies using an Anger camera with a low-energy high-resolution (LEHR) collimator and D-SPECT, and clinical 123I-MIBG studies proceeded in 40 consecutive patients (80 studies). In the phantom study, a conversion coefficient (CC) was defined based on phantom experiments and applied to the Anger camera and the D-SPECT detector. The HMR was calculated using anterior images with the Anger camera and anterior planograms with D-SPECT. First, the HMR from D-SPECT was cross-calibrated to the Anger camera, and then, the HMR from both cameras were converted to the medium-energy general-purpose collimator condition (CC 0.88; ME88 condition). The relationship between HMR and corrected and uncorrected methods was examined. A 123I-MIBG washout rate was calculated using both methods with and without background subtraction. Based on the phantom experiments, the CC of the Anger camera with an LEHR collimator and of D-SPECT using an anterior planogram was 0.55 and 0.63, respectively. The original HMR from the Anger camera and D-SPECT was 1.76 ± 0.42 and 1.86 ± 0.55, respectively (p

AIMS: Although ambulatory blood pressure (BP) is a better predictor of cardiovascular outcomes than office BP, its association with subclinical cerebrovascular disease is not clarified. We investigated the associations of office and ambulatory BP values with subclinical cerebrovascular disease in a population based, predominantly elderly cohort without prior stroke. METHODS AND RESULTS: Eight hundred and twenty-eight participants underwent 24-h ambulatory BP monitoring (ABPM), 2D echocardiography and brain magnetic resonance imaging in the Cardiac Abnormalities and Brain Lesion (CABL) study. Daytime, night-time, and 24-h BPs, nocturnal dipping pattern, morning surge (MS), and 24-h variability were assessed. Subclinical cerebrovascular disease was defined as silent brain infarcts (SBIs) and white matter hyperintensity volume (WMHV). The association of BP measures with the presence of SBI and upper quartile of log-WMHV (log-WMHV4) was analysed. SBIs were detected in 111 patients (13.4%). Mean log-WMHV was −0.99 ± 0.94. In multivariable analysis, only night-time systolic BP (SBP) was significantly associated with SBI [odds ratio (OR) 1.15 per 10 mmHg, P = 0.042], independent of cardiovascular risk factors, and pertinent echocardiographic parameters. Although daytime, night-time, 24-h BPs, and non-dipping pattern were all significantly associated with log-WMHV4 (all P

Background and Purpose— Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. Methods— We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community-based stroke-free sample. Results— There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85–1425 RU/mL) had greater white matter hyperintensity volume (β=0.19 %ICV; 95% CI, 0.04–0.33 %ICV; P =0.01) compared with those in the lowest quartile (range=15–49 RU/mL), adjusted for demographics, vascular risk factors, and estimated glomerular filtration rate. These findings remained significant in those without evidence of chronic kidney disease (estimated glomerular filtration rate 2 ). Elevated FGF23 was not associated with SBI overall after adjusting for demographic factors and estimated glomerular filtration rate, but sex modified the effect of FGF23 on odds of SBI ( P for interaction=0.03). FGF23 was associated with significantly greater odds of SBI only in men (odds ratio, 1.7; 95% CI, 1.1–2.7; P =0.03) after full adjustment. Conclusions— These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging–defined brain infarction in men, independent of chronic kidney disease. Data on elevated FGF23 and subclinical cerebrovascular damage progression are needed.

An 80-year-old man developed dysarthria, quadriplegia, sensory disturbance and ataxia in all limbs. Brain and spinal magnetic resonance imaging (MRI) revealed multiple enhanced lesions. Cerebrospinal fluid (CSF) levels of adenosine deaminase (ADA) remarkably elevated. Tuberculosis DNA was not detected, and tuberculosis was not cultured either in the CSF. Brain biopsy revealed the inflammatory demyelinating lesions. With the diagnosis of multiple sclerosis, corticosteroid therapy resulted in rapid improvement of his symptoms and MRI abnormalities. CSF levels of ADA also decreased. Multiple sclerosis should be included in differential diagnosis of disorders with ADA elevation in the CSF. © 2017 Elsevier B.V., Embargo Period 12 months

Background and Purpose— Although increased heart rate (HR) is a predictor of cardiovascular events and mortality, its possible association with subclinical cerebrovascular disease, which is prevalent in the elderly, has not been evaluated. This study aimed to investigate the association of daytime, nighttime, 24-hour HR, and HR variability with subclinical cerebrovascular disease in an elderly cohort without history of stroke. Methods— The study cohort consisted of 680 participants (mean age, 73±7 years; 42% men) in sinus rhythm who underwent 24-hour ambulatory blood pressure and HR monitoring, 2-dimensional echocardiography, and brain magnetic resonance imaging as part of the CABL study (Cardiac Abnormalities and Brain Lesion). Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume (WMHV). The relationship of HR measures with the presence of silent brain infarct and upper quartile of log WMHV (log WMHV4) was analyzed. Results— Presence of silent brain infarct was detected in 93 participants (13.7%); mean log WMHV was −0.92±0.93 (median, −1.05; min, −5.88; max, 1.74). Multivariate analysis showed that only nighttime HR (adjusted odds ratio, 1.29 per 10 bpm; 95% confidence interval, 1.03–1.61; P =0.026) was significantly associated with log WMHV4, independent of traditional cardiovascular risk factors, ambulatory systolic blood pressure, and echocardiographic parameters. No similar association was observed for daytime HR and HR variability. There was no significant association between all HR measures and silent brain infarct. Conclusions— In a predominantly elderly cohort, elevated nighttime HR was associated with WMHV, suggesting an independent role of HR in subclinical cerebrovascular disease.

Objectives To determine whether infectious burden (IB) is associated with worse performance and decline on a battery of neuropsychological tests. Design Prospective cohort study (Northern Manhattan Study (NOMAS)). Setting Community. Participants A subsample of 588 stroke-free NOMAS participants with IB and cognitive data (mean age 71 ± 8, 62% female, 14% white, 16% black, 70% Hispanic) and 419 with repeat cognitive testing. Measurements Samples used for IB data were collected at baseline. Two waves of neurocognitive assessments occurred during follow-up. Participants underwent a neuropsychological battery and had repeated testing (mean time span 6 ± 2 years). Using factor analysis–derived domain-specific Z scores for language, memory, executive function, and processing speed, associations between a quantitative stroke risk-weighted IB index (IBI), based on five common infections (Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, herpes simplex viruses 1 and 2), and cognitive performance and decline in each domain was examined. Results Adjusting for demographic characteristics, socioeconomic status, crystallized cognitive abilities, and vascular risk factors, the IBI was inversely associated with executive function at baseline (beta = −0.10, P = .01) but not with baseline language, memory, or processing speed performance in adjusted analyses. The IBI was associated with cognitive decline in the memory domain, adjusting for demographic and vascular risk factors (P = .02). Conclusion A quantitative stroke risk-weighted measure of IB explained variability in baseline executive function performance and associated with decline in memory. Past exposure to common infections may contribute to vascular cognitive impairment and warrants further study.

Background The effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples. Methods and Results Stroke‐free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non‐Hispanic white, 17% non‐Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6–9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI , 1.1–1.9), ischemic stroke ( HR : 1.3; 95% CI , 1.0–1.8), and cryptogenic stroke ( HR : 2.2; 95% CI , 1.1–4.4). White and black but not Hispanic participants had increased stroke risk ( P HR : 1.9; 95% CI , 1.1–3.3), ischemic stroke ( HR : 2.2; 95% CI , 1.3–3.8), lacunar ( HR : 4.0; 95% CI , 1.3–12.3), and cryptogenic stroke ( HR : 3.6; 95% CI , 1.0–12.7), without significant heterogeneity across race/ethnic groups. Greater white matter hyperintensity volume increased both vascular ( HR : 1.3; 95% CI , 1.1–1.7) and nonvascular ( HR : 1.2; 95% CI , 1.0–1.5) mortality among Hispanic and white but not black participants ( P =0.040 for heterogeneity). Subclinical brain infarct was associated with increased vascular mortality among Hispanic participants only ( HR : 2.9; 95% CI , 1.4–5.8). Conclusions In this urban US sample, subclinical cerebrovascular lesions increased the risk of clinical stroke and vascular mortality and varied by race/ethnicity and lesion type.

Background— Silent brain infarcts (SBIs) and white matter hyperintensities are subclinical cerebrovascular lesions associated with incident stroke and cognitive decline. Left ventricular ejection fraction (LVEF) is a predictor of stroke in patients with heart failure, but its association with subclinical brain disease in the general population is unknown. Left ventricular global longitudinal strain (GLS) can detect subclinical cardiac dysfunction even when LVEF is normal. We investigated the relationship of LVEF and GLS with subclinical brain disease in a community-based cohort. Methods and Results— LVEF and GLS were assessed by 2-dimensional and speckle-tracking echocardiography in 439 participants free of stroke and cardiac disease from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. SBIs and white matter hyperintensities were assessed by brain MRI. Mean age of the study population was 69±10 years, 61% were women, LVEF was 63.8±6.4%, GLS was −17.1±3.0%. SBIs were detected in 53 participants (12%), white matter hyperintensity volume was 0.63±0.86%. GLS was significantly lower in participants with SBI versus those without (−15.7±3.5% versus −17.3±2.9%, P P =0.60). In multivariate analysis, lower GLS was associated with SBI (odds ratio/unit decrease=1.18; 95% confidence interval, 1.05–1.33; P P =0.98). Lower GLS was associated with greater white matter hyperintensity volume (adjusted β=0.11, P P =0.42). Conclusions— Lower GLS was independently associated with subclinical brain disease in a community-based cohort without overt cardiac disease. GLS can provide additional information on cerebrovascular risk burden beyond LVEF assessment.

Objectives: The purpose of this study was to assess the relationship of left atrial (LA) phasic volumes and LA reservoir function with subclinical cerebrovascular disease in a stroke-free community...

Background: This multicentre open-label trial examined the efficacy and safety of the traditional Japanese medicine, or Kampo medicine, yokukansan (YKS), for behavioural and psychological symptoms of dementia (BPSD) in patients with dementia with Lewy bodies. Methods: Sixty-three dementia with Lewy bodies patients with probable BPSD (M : W, 30 : 33; mean age, 78.2 ± 5.8 years) were enrolled and treated with YKS for 4 weeks. Results: Significant improvements in Neuropsychiatric Inventory scores (mean decrease, 12.5 points; P < 0.001) and Zarit Burden Interview-Japanese edition tests (mean decrease, 3.6 points; P= 0.024) were observed. In patients who consented to an assessment after 2 weeks of treatment, a time-dependent significant improvement was observed in the Neuropsychiatric Inventory score (n= 23; mean decrease, 14.4; P < 0.001), each subscale, including delusions and hallucinations, the Zarit Burden Interview-Japanese edition (n= 22; mean decrease, 8.2; P < 0.01) and the behavioural pathology in Alzheimer's disease insomnia subscale. The Mini-Mental State Examination and the Disability Assessment for Dementia (DAD) showed no significant change. Adverse events were observed in 11 (18%) patients. Three patients (5%) discontinued YKS due to adverse reactions, namely, spasticity and exacerbation of BPSD, edema, and nausea. Hypokalaemia (

Differential diagnosis of dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD) and other dementias is essential for better management. Metaiodobenzylguanidine (MIBG) is a physiological analogue of norepinephrine, and 123I-MIBG myocardial scintigraphy has been used as a noninvasive tool for estimating myocardial sympathetic nerve damage due to various disorders such as heart and neurologic diseases. Degeneration of the cardiac sympathetic nerves is a neuropathological feature of Lewy body diseases including Parkinson’s disease and DLB. Multiple single-center studies, including ours, reported very high sensitivity and specificity of 123I-MIBG myocardial scintigraphy for the differential diagnosis of DLB from AD and other dementias; further, our first multicenter study of DLB with the standardized technique [1] substantiated the high diagnostic accuracy of 123I-MIBG myocardial scintigraphy, which was comparable to that of 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) SPECT multicenter study [2]. In the current version of the consensus diagnostic criteria for DLB [3], 123I-FP-CIT SPECT was listed as one of the suggestive features of DLB, whereas 123I-MIBG myocardial scintigraphy was listed as one of the supportive features. As 123I-MIBG myocardial scintigraphy has been proved to have high diagnostic specificity, it is recommended to upgrade the abnormal MIBG myocardial scintigraphy to one of the suggestive features of DLB.

Background and Purpose— Aortic arch plaque (AAP) is a risk factor for ischemic stroke, but its association with subclinical cerebrovascular disease is not established. We investigated the association between AAP and subclinical cerebrovascular disease in an elderly stroke-free community-based cohort. Methods— The CABL study (Cardiovascular Abnormalities and Brain Lesions) was designed to investigate cardiovascular predictors of silent cerebrovascular disease in the elderly. AAPs were assessed by suprasternal transthoracic echocardiography in 954 participants. Silent brain infarcts and white matter hyperintensity volume (WMHV) were assessed by brain magnetic resonance imaging. The association of AAP thickness with silent brain infarcts and WMHV was evaluated by logistic regression analysis. Results— Mean age was 71.6±9.3 years; 63% were women. AAP was present in 658 (69%) subjects. Silent brain infarcts were detected in 138 participants (14.5%). In multivariate analysis adjusted for potential confounders, AAP thickness and large AAP (≥4 mm in thickness) were significantly associated with the upper quartile of WMHV (WMHV-Q4; odds ratio =1.17; 95% confidence interval, 1.04–1.32; P =0.009 and odds ratio =1.79; 95% confidence interval, 1.40–3.09; P =0.036, respectively), but not with silent brain infarcts (odds ratio =1.08; 95% confidence interval, 0.94–1.23; P =0.265 and odds ratio =1.46; 95% confidence interval, 0.77–2.77; P =0.251, respectively). Conclusions— Aortic arch atherosclerosis was associated with WMHV in a stroke-free community-based elderly cohort. This association was stronger in subjects with large plaques and independent of cardiovascular risk factors. Aortic arch assessment by transthoracic echocardiography may help identify subjects at higher risk of subclinical cerebrovascular disease, who may benefit from aggressive stroke risk factors treatment.

BackgroundAlthough abnormal left ventricular geometric patterns have prognostic value for morbidity and mortality, their possible association with silent cerebrovascular disease has not been extensively evaluated.MethodsWe examined 665 participants in the CABL study who underwent transthoracic echocardiography and brain magnetic resonance imaging. Participants were divided into 4 geometric patterns: normal geometry (n=397), concentric remodeling (n=89), eccentric hypertrophy (n=126), and concentric hypertrophy (n=53). Subclinical cerebrovascular disease was defined as silent brain infarcts (SBIs) and white matter hyperintensity volume (WMHV; expressed as log-transformed percentage of the total cranial volume).ResultsSilent brain infarcts were observed in 94 participants (14%). Mean log-WMHV was -0.97±0.93. Concentric hypertrophy carried the greatest risk for both SBI (adjusted odds ratio [OR] 3.39, P

To test the hypothesis that Alzheimer's disease (AD) patients with posterior cingulate/precuneus (PCP) atrophy would be a distinct disease form in view of metabolic decline. Eighty-one AD patients underwent (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and structural magnetic resonance imaging (MRI). Positron emission tomography and voxel-based morphometry (VBM) Z-score maps were generated for the individual patients using age-specific normal databases. The patients were classified into 3 groups based on atrophic patterns (no-Hipp-PCP, atrophy in neither hippocampus nor PCP; Hipp, hippocampal atrophy; PCP, PCP atrophy). There were 16 patients classified as no-Hipp-PCP, 55 as Hipp, and 10 as PCP. The Mini Mental State Examination (MMSE) score was similar among the groups. The greater FDG decline than atrophy was observed in all groups, including the no-Hipp-PCP. The PCP group was younger, and was associated with a greater degree of FDG decline in PCP than the others. There are diverse atrophic patterns in a spectrum of AD. In particular, a subset of patients show PCP atrophy, which is associated with greater metabolic burden.

Purpose: This study was performed to demonstrate that the results obtained with a calibration phantom could be used as a tool for standardizing measurement of heart to mediastinum (H/M) ratio in cardiac metaiodobenzylguanidine (MIBG) imaging. Methods: Images of the phantom containing 123I-MIBG were acquired on the cameras in 10 hospitals (11 camera types) to determine the relationship between H/M ratios using different collimators: low-energy (LE) and medium-energy (ME)/low-medium-energy (LME) collimators. The effect of standardization on the ME-comparable H/M ratio was examined in two settings: a Japanese standard MIBG database (n = 62) and multicentre studies (n = 49). In a multicentre study, probable Alzheimer's disease (AD, n = 18) and probable dementia with Lewy bodies (DLB, n = 31) were studied and standardized by the calibration phantom method. Results: Linear regression equations between LE and ME collimators were obtained for the phantom study in all institutions. When the H/M ratio with an LE collimator was corrected based upon the calibration phantom, the corrected values were comparable to those obtained using ME collimators. The standard database also exhibited a normal distribution after standardization as determined by skewness and goodness-of-fit test. A mixture of the populations by LE and ME collimators showed significant separation of AD and DLB groups (F ratio = 24.9 for the late H/M), but the corrected values resulted in higher F ratios for both early and late H/M (F ratio = 34.9 for the late H/M). Conclusion: Standardization of H/M ratios by the heart-chest calibration phantom method is feasible among different collimator types. This method could be practically used for multicentre comparison of H/M ratios. © 2011 Springer-Verlag.

OBJECTIVES ¹⁸F-FDG PET with voxel-based statistical image analysis plays an important role in the diagnosis of Alzheimer's disease (AD). However, the effect of an age-matched and sex-matched or mismatched normal database (NDB) on the diagnostic performance of ¹⁸F-FDG PET has not yet been investigated systematically. The aim of this study was to determine whether an age-matched and sex-matched NDB is necessary for the detection of AD using ¹⁸F-FDG PET. METHODS We generated 11 NDB sets for ¹⁸F-FDG PET, including six age-specific NDB sets consisting of participants ranging in age from 20 to 70 years, one age-non-specific NDB set, one age-matched NDB set, two sex-specific NDB sets, each consisting of 20 men or 20 women, and one sex-matched NDB set. The average z-scores in predefined AD-specific regions of interest of the PET images were calculated using those NDB sets and a receiver-operating characteristic analysis was carried out to assess the diagnostic performance of ¹⁸F-FDG PET to discriminate 46 patients with AD from 50 normal controls. RESULTS There was no significant difference in each area under the receiver-operating characteristic curve using either age-matched/mismatched NDB sets or sex-matched/mismatched NDB sets. CONCLUSION The diagnostic performance of ¹⁸F-FDG PET was rather insensitive to differences in age or sex in the NDB, indicating that exact age-matched or sex-matched NDB may not be essential for discriminating patients with AD from normal participants using ¹⁸F-FDG PET.

Objective: To examine the independent association between physical activity and subclinical cerebrovascular disease as measured by silent brain infarcts (SBI) and white matter hyperintensity volume (WMHV). Methods: The Northern Manhattan Study (NOMAS) is a population-based prospective cohort examining risk factors for incident vascular disease, and a subsample underwent brain MRI. Our primary outcomes were SBI and WMHV. Baseline measures of leisure-time physical activity were collected in person. Physical activity was categorized by quartiles of the metabolic equivalent (MET) score. We used logistic regression models to examine the associations between physical activity and SBI, and linear regression to examine the association with WMHV. Results: There were 1,238 clinically stroke-free participants (mean age 70 ± 9 years) of whom 60% were women, 65% were Hispanic, and 43% reported no physical activity. A total of 197 (16%) participants had SBI. In fully adjusted models, compared to those who did not engage in physical activity, those in the upper quartile of MET scores were almost half as likely to have SBI (adjusted odds ratio 0.6, 95% confidence interval 0.4–0.9). Physical activity was not associated with WMHV. Conclusions: Increased levels of physical activity were associated with a lower risk of SBI but not WMHV. Engaging in moderate to heavy physical activities may be an important component of prevention strategies aimed at reducing subclinical brain infarcts.

Background and purpose: The present study aims to clarify the clinical features of non-hypertensive cerebral amyloid angiopathy-related lobar intracerebral hemorrhage (CAA-L-ICH). Methods: We investigated clinical, laboratory, and neuroimaging findings in 41 patients (30, women; 11, men) with pathologically supported CAA-L-ICH from 303 non-hypertensive Japanese patients aged ≥55, identified via a nationwide survey as symptomatic CAA-L-ICH. Results: The mean age of patients at onset of CAA-L-ICH was 73.2 ± 7.4 years; the number of patients increased with age. The corrected female-to-male ratio for the population was 2.2, with significant female predominance. At onset, 7.3% of patients received anti-platelet therapy. In brain imaging studies, the actual frequency of CAA-L-ICHs was higher in the frontal and parietal lobes; however, after correcting for the estimated cortical volume, the parietal lobe was found to be the most frequently affected. CAA-L-ICH recurred in 31.7% of patients during the average 35.3-month follow-up period. The mean interval between intracerebral hemorrhages (ICHs) was 11.3 months. The case fatality rate was 12.2% at 1 month and 19.5% at 12 months after initial ICH. In 97.1% of patients, neurosurgical procedures were performed without uncontrollable intraoperative or post-operative hemorrhage. Conclusions: Our study revealed the clinical features of non-hypertensive CAA-L-ICH, including its parietal predilection, which will require further study with a larger number of patients with different ethnic backgrounds.

Background and Purpose— We examined white matter hyperintensity volume (WMHV) and subclinical infarction (no history of clinical stroke; SI) in relation to performance on tests of sequencing, cognitive flexibility, and sensorimotor ability. Methods— The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, Black, and White participants. A subsample (n=656) has undergone measurement of WMHV, SI, and neuropsychological testing. Linear regression was used to examine WMHV and SI in relation to performance on tests of sequencing as measured by Color Trails 1, cognitive flexibility as measured by Color Trails 2, and sensorimotor ability as measured by Grooved Pegboard, using generalized estimating equations (GEE) to account for the correlation among the cognitive tests and other covariates. Results— Considering performance on the tests of sequencing, cognitive flexibility, and sensorimotor ability simultaneously using GEE, WMHV and subclinical infarction were each associated with worse cognitive performance globally. There was a threshold effect for WMHV with those in the upper quartile performing significantly worse on the tests of cognitive flexibility and sensorimotor ability. Those with frontal SI performed worse on the test of cognitive flexibility and those with deep SI, worse on the test of sequencing. Conclusions— Both SI and WMHV were associated with globally worse cognitive performance. Participants with WMH affecting more than 0.75% of cranial volume had significantly slower performance on a task of cognitive flexibility and sensorimotor ability than those in the lowest quartile. The effects of SI on cognitive performance varied by location.

The aim of this study was to compare optimized voxel-based morphometry (VBM) and 18 F-FDG PET for discrimination between patients with Alzheimer’s disease (AD) and healthy subjects in relation to age. Methods: The study population consisted of 2 groups; the first group (27 AD patients and 40 control subjects) was used to determine the locations of significant abnormalities for both PET and VBM using statistical parametric mapping, and the second group (34 AD patients and 50 control subjects) was used to compare the diagnostic performance of PET and VBM. In the second group, a z-score map for PET or VBM of each subject was obtained by comparison with the mean and SD of PET or gray-matter MR images of the control subjects. Receiver-operating-characteristic (ROC) curve analysis was then performed to compare the diagnostic performance between PET and VBM. Furthermore, group 2 was divided into the early- and late-onset subgroups, and ROC analysis was performed for each subgroup. Results: In the first group, VBM revealed a significant decrease in gray-matter concentration in the hippocampus complex in AD, whereas PET showed a significant reduction in 18 F-FDG uptake in the posterior cingulate and parietotemporal lobe. The diagnostic performance of PET (0.988 6 0.008; mean 6 SE), as measured by the area under the ROC curve, was higher than that of VBM with (0.782 6 0.059) or without (0.832 6 0.049) modulation. PET yielded a sensitivity, specificity, and overall accuracy of 100%, 92%, and 95%, respectively, whereas for VBM the sensitivity, specificity, and accuracy were 74%, 92%, and 85%. Modulation for the VBM did not improve these values (56%, 94%, and 79%, respectively). When the early- and late-onset subjects were analyzed separately, the superiority of 18 F-FDG PET was significant only in the early-onset subgroup. Conclusion: The present study indicates that the detection of metabolic alteration by 18F-FDG PET yields a better diagnostic performance for the discrimination between AD patients and healthy control subjects than does the morphologic approach by VBM, particularly in the early-onset subjects.

Background and Purpose— White matter hyperintensities have been associated with increased risk of stroke, cognitive decline, and dementia. Chronic kidney disease is a risk factor for vascular disease and has been associated with inflammation and endothelial dysfunction, which have been implicated in the pathogenesis of white matter hyperintensities. Few studies have explored the relationship between chronic kidney disease and white matter hyperintensities. Methods— The Northern Manhattan Study is a prospective, community-based cohort of which a subset of stroke-free participants underwent MRIs. MRIs were analyzed quantitatively for white matter hyperintensities volume, which was log-transformed to yield a normal distribution (log-white matter hyperintensity volume). Kidney function was modeled using serum creatinine, the Cockcroft-Gault formula for creatinine clearance, and the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate. Creatinine clearance and estimated glomerular filtration rate were trichotomized to 15 to 60 mL/min, 60 to 90 mL/min, and >90 mL/min (reference). Linear regression was used to measure the association between kidney function and log-white matter hyperintensity volume adjusting for age, gender, race–ethnicity, education, cardiac disease, diabetes, homocysteine, and hypertension. Results— Baseline data were available on 615 subjects (mean age 70 years, 60% women, 18% whites, 21% blacks, 62% Hispanics). In multivariate analysis, creatinine clearance 15 to 60 mL/min was associated with increased log-white matter hyperintensity volume (β 0.322; 95% CI, 0.095 to 0.550) as was estimated glomerular filtration rate 15 to 60 mL/min (β 0.322; 95% CI, 0.080 to 0.564). Serum creatinine, per 1-mg/dL increase, was also positively associated with log-white matter hyperintensity volume (β 1.479; 95% CI, 1.067 to 2.050). Conclusions— The association between moderate–severe chronic kidney disease and white matter hyperintensity volume highlights the growing importance of kidney disease as a possible determinant of cerebrovascular disease and/or as a marker of microangiopathy.

Risk factors for subclinical brain infarcts (SBI) have not been well studied, especially in Hispanic and black populations who may be at higher risk for vascular disease. We examined the prevalence and determinants of SBI in a multiethnic community cohort.The Northern Manhattan Study (NOMAS) includes 892 stroke-free participants who underwent brain MRI. Baseline demographic and vascular risk factor data were collected. The presence of SBI was determined from the size, location, and imaging characteristics of the lesion based on fluid attenuated inversion recovery (FLAIR) T1 and T2, and proton density MRI sequences. We calculated the prevalence of SBI and cross-sectional associations with sociodemographic and vascular risk factors, using logistic regression to adjust for relevant covariates.Among 892 subjects (mean age 71.3 years), 158 (17.7%) had SBI (13.5% had 1 lesion, 4.3% had1 lesion). Of the total 216 infarcts, most were small (1 cm, 82.4%) and subcortical (82.9%). SBI prevalence increased with age (65: 9.7%; 65 to 75: 16.4%;75: 26.1%), was increased among men (21.3% vs 15.2% in women), and was increased among blacks (24.0% vs 18.1% in whites and 15.8% in Hispanics). The presence of SBI was independently associated with older age (per year: OR 1.06, 95% CI 1.04 to 1.09), male sex (OR 1.79, 95% CI 1.22 to 2.61), and hypertension (OR 2.08, 95% CI 1.35 to 3.22) adjusting for age, sex, race-ethnicity, and vascular risk factors. A significant interaction (p = 0.002) between race and age was observed such that younger black subjects had greater odds of having SBI.SBI were detected in nearly 18% of subjects in a multiethnic community-based cohort. Age, male sex, and hypertension were independently associated with SBI. Subclinical cerebral infarcts are more prevalent than symptomatic infarcts and may increase the true public health burden of stroke.

Deposition of alpha-synuclein (alphaS) aggregates inside brain cells is a pathological hallmark of several neurodegenerative diseases, including Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Recently, extracellular alphaS was detected in cerebrospinal fluid (CSF) and plasma of humans. We investigated whether CSF influences alphaS aggregation in vitro using fluorescence spectroscopy with thioflavin S and electron microscopy. We found that CSF obtained from Alzheimer's disease (AD) and DLB patients enhanced the alphaS fibril formation compared with tauopathy and non-central nervous system disease. Thus, CSF of AD and DLB characterized by aggregation of Abeta or alphaS might promote falphaS formation.

Background Microbleeds (MBs) are frequently observed in Alzheimer's disease (AD); however, the relevance to AD pathophysiology has not been elucidated. Objectives We investigated correlation of MBs, especially cerebral amyloid angiopathy (CAA)-related MBs with cognitive function, gray matter volume, and glucose metabolism in AD. Methods We performed magnetic resonance imaging including T2*-weighted imaging sequence for 206 patients with AD. Among them, 158 AD patients with no focal brain lesions except for MBs were investigated with cognitive tests, voxel-based morphometry, and 18F-fluorodeoxyglucose positron emission tomography in a cross-sectional observational study. Results Of the 158 patients with no hemorrhagic and/or ischemic stroke lesions except for MBs, 27 patients had MBs, in which 17 patients showed CAA-related MBs that located only in cortex/subcortex (CAA-related MBs), and 10 patients showed CAA-unrelated MBs that located in deep regions regardless of the presence of MBs in cortical/subcortical regions. There were slightly but significant differences in cognitive functions between the patients without MBs, those with CAA-related MBs, and those with CAA-unrelated MBs. MBs were recognized frequently in the occipital lobe in the patients with CAA-related MBs. The patients with CAA-related MBs showed gray matter atrophy in the temporal lobe and cerebellum, and glucose hypometabolism in the temporal lobe compared with those without MBs. Conclusions Our results indicate that MBs, particularly CAA-related MBs would cause gray matter atrophy and glucose hypometabolism in AD.

ObjectiveMemory has been examined in subjects with imaging markers of cerebrovascular disease, but learning has been less well studied. We examined the relationship among subclinical cerebrovascular disease, cerebral volumes, and verbal learning in an ethnically and racially diverse community sample.MethodsA clinically stroke-free subset of Northern Manhattan Study participants underwent cognitive testing and brain MRI with quantification of white matter hyperintensity volume (WMHV) and total cerebral volume (TCV) using semiautomated segmentation. We used generalized linear regression and mixed models to examine the association between imaging findings and verbal learning.ResultsThere were 1,272 participants (61% women, mean age 70 ± 9 years). Participants with greater WMHV and smaller TCV remembered fewer total words on a list-learning task (β = -0.83 per SD change in WMHV, 95% confidence interval [CI] = -1.22 to -0.45, p < 0.0001; and β = 0.48 per SD change in TCV, 95% CI = 0.05 to 0.90, p = 0.03, respectively). Subclinical brain infarction (SBI) was not associated with total words learned (β = -0.04, 95% CI = -1.08 to 1.00, p = 0.94). Those with greater WMHV had increased odds of a flatter learning slope. After excluding participants with SBI, the association between total words learned and WMHV remained significant. All measurements were adjusted for age, education, race/ethnicity, medical insurance status, and the presence of SBI.ConclusionsWhite matter hyperintensities, a marker of cerebral small vessel disease, may have an impact on learning slope. This suggests that verbal learning performance can be incorporated into neuropsychological measures for vascular cognitive impairment and that cerebrovascular disease discovered on imaging affects the ability to learn new information.

Background: Leisure time physical activity (LTPA) has been associated with a lower risk of dementia, but whether the effects are specific to particular cognitive abilities or improvement in functional status remains unclear. We examined LTPA in relation to domain-specific neurocognitive (NC) performance and change over time in a diverse community sample. Methods: Data on LTPA was collected during enrollment (1993-2001) into the Northern Manhattan Study (NOMAS), a prospective cohort study of risk factors for stroke and cognitive decline, using a validated in-person questionnaire, and two waves of NC assessments were done on a subcohort of participants undergoing brain MRI an mean of six and 12 years later (NC1: 2003-2008; NC2: 2008-2014). Baseline LTPA was defined in two manners: (1) maximum intensity of all activities performed categorized as moderate-heavy, light, and none; (2) total summarized as a continuous variable with the metabolic equivalent (MET) score, a composite of total reported intensity and time. Factor analysis-derived construct-relevant cognitive domains, including memory (MEM), executive function (EXEC), processing speed (PS), and language ability (LA), were computed by averaging z-transformed NC test scores. We used multivariable linear regression to examine LTPA in relation to baseline domain-specific NC performance, and change in performance over time, adjusting for socio-demographics, vascular risk factors, and MRI markers of cerebrovascular injury (white matter hyperintensity volume and total cerebral volume, both adjusted for total intracranial volume, and silent brain infarcts). Results: There were 1236 participants (mean age=64 years, 61% women, 67% Latino, 18% black, 15% white) with LTPA and NC data, and 879 with a second NC assessment. Moderate-to-heavy activity was associated with higher baseline LA (p Conclusions: Leisure time physical activity is independently protective against a decline in processing speed and memory, and was partly mediated by MRI markers. Leisure-time physical activity may protect against dementia through preventing cerebrovascular correlates of brain injury.

金沢大学医薬保健研究域医学系, We report a 38-year-old Japanese woman who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with a novel mutation (TGT to TAT) at nucleotide position 1241 (C388Y) in exon 7 of the Notch3 gene (NOTCH3). Immunostaining of a skin biopsy with a Notch3 monoclonal antibody is a beneficial method for the screening of CADASIL, particularly in the case of rare mutations outside the mutation hotspots in NOTCH3 as shown in this patient.

Cerebrovascular disease is common and associated with cognitive deficits and increased risk for dementia. Until recently, only limited attention has focused on advances in imaging techniques to better define and quantify the spectrum of asymptomatic cerebrovascular disease commonly seen on magnetic resonance imaging, such as abnormal white matter signals. Abnormal signals in cerebral white matter, although nonspecific, are increased in prevalence and severity in association with aging and cerebrovascular risk factors among older individuals. The ubiquitous occurrence of these abnormal white matter signals commonly referred to as white matter hyperintensities (WMHs) and the association with cerebrovascular risk and cognitive impairment among older individuals make scientific evaluation of WMHs an important and much needed avenue of research. In this section, we review current methods of WMH analysis. Strengths and limitation of both quantitative and qualitative methods are discussed initially, followed by a brief review of current magnetic resonance imaging segmentation and mapping techniques that make it possible to assess the anatomical location of WMHs. We conclude by discussing future analytic methods designed to better understand the pathophysiology and cognitive consequences of WMHs.

Several previous studies have identified biochemical markers for Alzheimer's disease (AD): cerebrospinal fluid (CSF)-beta-amyloid peptide42 (CSF-Abeta42), CSF-total tau protein (CSF-tau) and CSF-phosphorylated tau protein (CSF-ptau). Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) as well as AD are diseases with tauopathies. CSF-Abeta42, CSF-tau, and CSF-ptau have not been rigorously investigated in PSP and CBD. In the present study, we assessed CSF-Abeta42, CSF-tau, and CSF-ptau as biochemical markers for PSP and CBD, compared with AD. The subjects consisted of 18 cases of PSP, 9 cases with CBD, 69 cases with AD, and 43 control subjects. Genotyping or phenotyping of apolipoprotein E (apoE) was also performed. CSF-Abeta42 levels were significantly decreased in patients with PSP and CBD as well as in AD patients. The ratio of CSF-ptau to CSF-Abeta42 provided high diagnostic accuracy to distinguish both PSP from AD, and CBD from AD. ApoE genotype/phenotype was not associated with CSF-Abeta42 levels in all groups. We concluded that CSF-Abeta42 levels are reduced in PSP and CBD as well as in AD.

We report a patient with steroid-responsive peripheral neuropathy which developed with chronic natural killer cell lymphocytosis (CNKL). A 70-year-old female with a 2-week history of progressive motor and sensory neuropathy showed a marked increase of natural killer (NK) cells in the blood, and was diagnosed as having CNKL. Nerve conduction studies (NCS) revealed a mixed axonal and demyelinating neuropathy. A sural nerve biopsy revealed infiltration of NK cells into the nerve fascicles, and demyelinating changes with axonal degeneration. The infiltrating NK cells were adjacent to myelinated fibers, showing damage of Schwann cell membrane. Treatment with oral prednisolone resulted in rapid improvement of the sensory disturbance and weakness with a significant decrease of NK cells in the blood and disappearance of the conduction blocks in NCS. This is the first case of CNKL associated neuropathy in which infiltration of NK cells was demonstrated in the nerve fascicles. Our observations suggest that the infiltrating NK cells may directly damage myelin and Schwann cells, thus causing demyelination.

Recently, reliable and clear evidence for the usefulness of 123I-MIBG scintigraphy in the diagnosis of Parkinson's disease (PD) has been accumulated and it has become increasingly popular as one of the most accurate means of diagnosing the disease. PD, one of the most common neurodegenerative disorders, is characterized by resting tremor, rigidity, bradykinesia or akinesia, and postural instability. The disease is characterized pathologically by distinctive neuronal inclusions called Lewy bodies in many surviving cells of dopaminergic neurons of the substantia nigra pars compacta and other specific brain regions. Furthermore Lewy body type degeneration in the cardiac plexus has been observed in PD. In PD, cardiac MIBG uptake is reduced markedly even in the early disease stages; therefore, MIBG imaging can be used as an indicator of the presence of PD rather than disease severity. Other parkinsonian syndromes such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration demonstrate normal cardiac MIBG uptake or only mild reduction of MIBG uptake, indicating that MIBG imaging is a powerful method to differentiate PD from other parkinsonian syndromes. Dementia with Lewy bodies (DLB) also shows severe reduction of MIBG uptake, whereas Alzheimer's disease (AD) demonstrates normal MIBG uptake, permitting differentiation of DLB from AD using MIBG scintigraphy. In pure autonomic failure, which shares similar pathological findings with PD and is thought to be associated with diffuse loss of sympathetic terminal innervation, cardiac MIBG uptake also decreases markedly. Considering all the data together, marked reduction of cardiac MIBG uptake seems to be a specific marker of Lewy body disease and thus extremely useful in the differentiation from other diseases with similar symptoms without Lewy bodies.