Search

Objective Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. Methods We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [11C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Results Parietal and occipital lobar CMBs counts were higher in PiB+ ADCI with moderate WMH than PiB+ ADCI with minimal WMH, whereas PiB− patients with SVCI (ie, 'pure' SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs ( p<0.001). Interpretation Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs. Ann Neurol 2013;73:584-593 [ABSTRACT FROM AUTHOR]

Background and purpose: Previous studies have developed several cognitive composites in preclinical Alzheimer disease (AD). However, more sensitive measures to track cognitive changes and therapeutic efficacy in preclinical AD are needed considering the diverse sociocultural and linguistic backgrounds. This study developed a composite score that can sensitively detect the amyloid‐β (Aβ)‐related cognitive trajectory of preclinical AD using Korean data. Methods: A total of 196 cognitively normal participants who underwent amyloid positron emission tomography were followed‐up with neuropsychological assessments. We developed the Longitudinal Amyloid Cognitive Composite in Preclinical AD (LACPA) using the linear mixed‐effects model (LMM) and z scores. The LMM was also used to investigate the longitudinal sensitivity of the LACPA and the association between time‐varying brain atrophy and the LACPA. Results: Considering the group‐time interaction effects of each subtest, the Seoul Verbal Learning Test‐Elderly version immediate recall/delayed recall/recognition, the Korean Trail Making Test B Time, and the Korean Mini‐Mental State Examination were selected as components of the LACPA. The LACPA exhibited a significant group‐time interaction effect between the Aβ+ and Aβ− groups (t = −3.288, p = 0.001). Associations between time‐varying LACPA and brain atrophy were found in the bilateral medial temporal, right lateral parietal, and right lateral frontal regions, and hippocampal volume. Conclusions: The LACPA may contribute to reduction in time and financial burden when monitoring Aβ‐related cognitive decline and therapeutic efficacy of the disease‐modifying agents specifically targeting Aβ in secondary prevention trials. [ABSTRACT FROM AUTHOR]

Background and purpose: Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long‐term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. Methods: We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta‐amyloid (Aβ) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. Results: During a 8.6‐year follow‐up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aβ positivity (subdistribution hazard ratio [SHR] = 2.73), greater white matter hyperintensity (WMH) volume (SHR = 3.11) and ≥3 microbleeds (SHR = 2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio = 2.07) was an independent predictor of mortality. Conclusions: Our findings suggest that diverse imaging markers may predict long‐term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long‐term outcomes of SVCI. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND AND PURPOSE The acquisition of literacy during childhood may affect the functional organization of the brain. We studied the effects of illiteracy on neuropsychological tests and brain glucose metabolism in later life. METHODS We recruited 12 illiterate elderly farmers who never attended school and acquired no knowledge of reading or writing. These illiterate subjects were compared with literate subjects in terms of neuropsychological performance and brain glucose metabolism. All subjects were over 65 years and had same socioeconomic environment and normal activities of daily living. RESULTS Neuropsychological tests indicated that the performance of illiterate subjects was worse than that of literate subjects in all cognitive domains with the exception of forward digit span, tool-use and tool-free gestures, and verbal generation of grocery items. The SPM analysis showed that illiterate subjects had reduced FDG-uptake relative to literate subjects, predominantly in the rostral part of the left superior frontal gyrus and less strikingly in the left rectal gyrus, right cerebellar declive, and right cerebellar tonsil. In contrast, hypermetabolism was found only in the left precuneus. CONCLUSION These results suggest that reading and writing during childhood is associated with activation of the frontal pole that may play a critical role in complex aspects of human cognition. [ABSTRACT FROM AUTHOR]

Objective: Discovery of a novel antibody would enable diagnosis and early treatment of autoimmune encephalitis. The aim was to discover a novel antibody targeting a synaptic receptor and characterize the pathogenic mechanism. Method: We screened for unknown antibodies in serum and cerebrospinal fluid samples from autoimmune encephalitis patients. Samples with reactivity to rat brain sections and no reactivity to conventional antibody tests underwent further processing for antibody discovery, using immunoprecipitation to primary neuronal cells, mass‐spectrometry analysis, an antigen‐binding assay on an antigen‐overexpressing cell line, and an electrophysiological assay with cultured hippocampal neurons. Results: Two patients had a novel antibody against CaVα2δ (voltage‐gated calcium channel alpha‐2/delta subunit). The patient samples stained neuropils of the hippocampus, basal ganglia, and cortex in rat brain sections and bound to a CaVα2δ‐overexpressing cell line. Knockdown of CaVα2δ expression in cultured neurons turned off the immunoreactivity of the antibody from the patients to the neurons. The patients were associated with preceding meningitis or neuroendocrine carcinoma and responded to immunotherapy. In cultured neurons, the antibody reduced neurotransmitter release from presynaptic nerve terminals by interfering with tight coupling of calcium channels and exocytosis. Interpretation: Here, we discovered a novel autoimmune encephalitis associated with anti‐CaVα2δ antibody. Further analysis of the antibody in autoimmune encephalitis might promote early diagnosis and treatment. ANN NEUROL 2021;89:740–752 [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to compare the diagnostic accuracy of antemortem 11C‐Pittsburgh compound B (PIB) and 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients. Methods: One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non‐AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate–high AD neuropathological change (ADNC). Results: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini‐Mental State Examination = 21.9, PET‐to‐autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non‐AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate–high ADNC (96%, 95% confidence interval [CI] = 89–100% vs 80%, 95% CI = 68–92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76–95% vs 84%, 95% CI = 74–93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92–100%) and specificity was 98% (95% CI = 93–100%). Nine of 24 patients with incongruent reads were found to have co‐occurrence of AD and non‐AD pathologies. Interpretation: In our sample enriched for younger onset cognitive impairment, PIB‐PET had higher sensitivity than FDG‐PET for intermediate–high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389–401 [ABSTRACT FROM AUTHOR]

Objectives: Alzheimer's disease (AD) is the most common neurodegenerative disease which is characterized by the formation of amyloid beta (Aβ) plaques and neurofibrillary tangles. These abnormal proteins induce disturbance in mitochondrial dynamics and defect in autophagy system. Since presenilin‐1 (PS1) is a core component in γ‐secretase complex, the mutations of PS1 gene cause the interference of γ‐secretase activity and lead to the increased Aβ42 secretion. We aimed to characterize the patient‐specific induced pluripotent stem cell (iPSC) line carrying PS1‐S170F mutation. Furthermore, we tested whether disease‐modifying drug can reduce AD pathology in the AD iPSC‐derived neurons. Materials and methods: Mononuclear cells (MNCs) were isolated freshly from the peripheral blood of an autosomal dominant AD (ADAD) patient carrying presenilin‐1 (PS1) mutation (Ser170Phe; PS1‐S170F) and a cognitively normal control. We generated induced pluripotent stem cell (iPSC) lines, which were differentiated into functional cortical neurons. Then, we measured the markers indicative of AD pathogenesis using immunocytochemistry and Western blot. We also investigated the mitochondrial dynamics in the AD iPSC‐derived neurons using Mito‐tracker. Results: We observed that both extracellular and intracellular Aβ levels were dramatically increased in the PS1‐S170F iPSC‐derived neurons, compared with the control iPSC‐derived neurons. Furthermore, PS1‐S170F iPSC‐derived neurons showed high expression levels of p‐Tau, which were detected both in the soma and neurites. The mitochondrial velocity in the PS1‐S170F iPSC‐derived neurons was much reduced, compared with that of the control. We also found a significant decrease of fusion‐related protein Mfn1 (membrane proteins mitofusin 1) and an increase of fission‐related protein DRP1 (dynamin‐related protein 1) in the PS1‐S170F iPSC‐derived neurons. We further observed the defects of autophagy‐related clearance in the PS1‐S170F iPSC‐derived neurons. Finally, we demonstrated the levels of Aβ and p‐Tau can be dramatically reduced by the treatment of LY‐2886721, a BACE1 inhibitor. Conclusions: Taken together, we have established and characterized the pathological features of an AD patient carrying PS1‐S170F mutation using iPSC technology, which will be the first case on this mutation and this iPSC line will serve as a useful resource for studying AD pathogenesis and drug screening in the future. [ABSTRACT FROM AUTHOR]

The authors discuss a study as part of the Clinical Research Center for Dementia of South Korea Study (CREDOS) to assess the occurrence of and risk factors for cognitive disorders, including age, chronic kidney disease, and anemia, that found a lower glomerular filtration rate (GFR) was associated with white matter hyperintensities (WMHs) in vascular dementia (VaD) more than in Alzheimer's disease (AD) or mild cognitive impairment (MCI). A discussion of the results is presented.

Most default mode network ( DMN) studies in patients with amnestic mild cognitive impairment ( aMCI) and Alzheimer's disease ( AD) are based on the comparison of only two groups, namely patients and controls. Information derived from comparing three groups, normal, aMCI and AD, simultaneously may lead us to better understand the progression of dementia. The purpose of this study was to evaluate functional connectivity of DMN in the continuum from normal through aMCI to AD. Differences in functional connectivity were compared between the three groups using independent component analysis. The relationship between functional connectivity and disease progression was investigated using multiple regression analysis with Mini-Mental State Examination ( MMSE) scores. The results revealed differences throughout the left posterior cingulate cortex ( PCC), left middle temporal gyrus ( MTG), right middle frontal gyrus ( MFG) and bilateral parahippocampal gyrus ( PHG). Both patients with aMCI and those with AD showed decreased connectivity in the left PCC and left PHG compared with healthy subjects. Furthermore, patients with AD also showed decreased connectivity in the left MTG and right PHG. Increased functional connectivity was observed in the right MFG of patients with AD compared with other groups. MMSE scores exhibited significant positive and negative correlations with functional connectivity in PCC, MTG and MFG regions. Taken together, increased functional connectivity in the MFG for AD patients might compensate for the loss of function in the PCC and MTG via compensatory mechanisms in corticocortical connections. [ABSTRACT FROM AUTHOR]

ABSTRACT BACKGROUND AND PURPOSE Patients with small vessel disease show high-signal intensity on T2-weighted magnetic resonance (MR) images that represent ischemic cell damage. However, despite a similar degree of ischemic change, the amount and the severity of clinical presentations may vary. We investigated the clinical correlations of ischemic changes using voxel-based morphometric analyses of diffusion tensor imaging (DTI). METHODS Twenty-seven MCI and 34 dementia patients were included who all had significant small vessel disease on magnetic resonance imaging (MRI). In all patients, neuropsychological tests, a rating on the Pyramidal and Extrapyramidal scale (PEPS) for motor deficits, and 3-Tesla MRI including DTI scans were performed. Voxel-based analysis of the fractional anisotropy and mean diffusivity maps were computed. RESULTS Cognitive scores correlated with the DTI abnormalities in supratentorial areas with regional specificity according to each cognitive test. Unexpectedly, cognitive deficits in most neuropsychological tests, even in some frontal tasks, were associated with disruption of posterior white matter integrities. Motor deficits correlated with both supra- and infratentorial lesions. CONCLUSION Our findings suggest that in patients with small vessel disease who show cognitive and motor impairments, a specific distribution of fiber tract damage is more related with clinical deficits than is the severity of the total ischemia. [ABSTRACT FROM AUTHOR]

Automated white matter hyperintensity (WMH) segmentation on magnetic resonance imaging is greatly advantageous for various clinical studies using large-sample data. Accurate localization of WMH can provide more beneficial information for clinical studies, as differences of regional WMH existence may be linked to clinical symptoms. We suggest a fully automated method for WMH quantification and localization without human interaction using T1-weighted and fluid-attenuated inversion-recovery (FLAIR) images. The known sources of false-positive results in the subarachnoid space and brain-cerebrospinal fluid (CSF) interface were removed by applying a WMH candidate-region mask. WMH segmentation was performed based on the Markov random field model. The intensity-substitution method was developed for the accurate localization of WMH, with proper tissue classification and nonlinear registration. The performance of the method was evaluated via comparison with manual delineation; the similarity index and the overlap ratio were 89.94 and 81.90, respectively. © 2011 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 21, 193-200, 2011 [ABSTRACT FROM AUTHOR]