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Abstract: Although patients with amnestic mild cognitive impairment (aMCI) are at higher risk of developing Alzheimer's disease (AD), their pathologies could be heterogeneous. We aimed to evaluate structural changes in amyloid-negative and amyloid-positive aMCI patients. Forty-eight aMCI patients who underwent Pittsburgh compound B (PiB) positron emission tomography were recruited. They were classified as PiB (−) aMCI (N = 16) and PiB (+) (N = 32). Hippocampal shape and regional cortical thickness were compared with 41 subjects with normal cognition (NC). Relative to NC, PiB(−) aMCI exhibited hippocampal deformity in the right cornu ammonis 1, whereas PiB(+) aMCI exhibited hippocampal deformity in bilateral subiculum and cornu ammonis 1 subregions. Relative to NC, PiB(−) aMCI showed cortical thinning in the left medial prefrontal and right anterior temporal regions, whereas PiB(+) aMCI exhibited cortical thinning in bilateral medial temporal regions, temporoparietal junctions and precuneus, and prefrontal cortices. Our findings suggest that structural changes in PiB(−) aMCI might be due to several possible pathologic changes, whereas structural changes in PiB(+) aMCI reflect AD-like structural changes. [Copyright &y& Elsevier]

Background: Patients with early-onset Alzheimer's disease (EOAD) may differ from those with late-onset Alzheimer's disease (LOAD) in cognitive impairment profiles and clinical course. Postmortem studies also reported that EOAD has a greater pathologic burden than LOAD. We examined the effects of age at onset on the burden and distribution of amyloid plaques in patients with AD, using a statistical parametric mapping (SPM) and regions of interest (ROIs) analyses of the Pittsburgh compound B (PiB)-PET. Methods: We initially recruited 72 patients with AD who had completed the [11C] PiB-PET scan, but four patients were excluded due to familial AD or incomplete MRI data. Of the 68 patients, 61 were classified as PiB-positive (PiB+) and seven as PiB-negative (PiB-) using the measured global PiB uptake ratio values. Of the 61 patients with PiB+ AD, in order to maximize the effect of onset age, we excluded 20 patients in their 60 s. Thus among the remaining 41 patients, the amyloid deposition of only 17 patients with EOAD (age onset <60 years) and 24 patients with LOAD (onset age &nvge;70 years) were compared. Results: There were no significant differences in the global mean PiB index between EOAD and LOAD patients, whereas SPM and ROIs analyses showed that those with EOAD retained higher levels of PiB in the bilateral basal ganglia, bilateral thalamus, left superior temporal cortex, and left cuneus compared to those with LOAD. Conclusion: Our findings demonstrated that EOAD patients differed from those with LOAD in the topography of amyloid deposition, which may partly account for the findings from previous studies that extrapyramidal symptoms and frontal dysfunction are more common in EOAD than in LOAD patients. [ABSTRACT FROM AUTHOR]

Background: Amnestic mild cognitive impairment (aMCI) is regarded as a prodromal stage of Alzheimer's disease (AD). Given that patients with early-onset AD (EOAD) and with late-onset AD (LOAD) are known to have different clinical courses, symptoms and neuroimaging findings, early-onset (EOMCI) and late-onset aMCI (LOMCI) might be expected to have similar differences as EOAD versus LOAD. Methods: Our study involving 425 patients with aMCI (124 EOMCI, 301 LOMCI), who were followed for around 1.5 years, and 958 normal control subjects (NC) investigated neuropsychological characteristics and prediction of progression to AD in patients with EOMCI versus LOMCI. Neuropsychological scores were compared between EOMCI, LOMCI and NC with analyses of covariance controlling age, gender, education and disease duration. The risk of AD conversion was evaluated by Cox proportional hazard analyses. Results: The baseline neuropsychological performances were comparable between EOMCI and LOMCI. Visuospatial memory for EOMCI and verbal memory scores for LOMCI were significant predictors of AD conversion. Conclusion: Our study indicates that EOMCI with visuospatial memory impairment, which implies underlying right predominant pathology, and LOMCI with poor verbal memory, which suggests underlying left predominant pathology, are individual conditions at an increased risk of conversion to AD. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Amnestic mild cognitive impairment (MCI) is considered to be a prodromal stage of Alzheimer's disease. Likewise, subcortical vascular MCI (svMCI) is considered as a prodromal stage of subcortical vascular dementia (SVaD). The objective of this study was to investigate neuropsychiatric features in patients with svMCI compared to healthy controls and patients with SVaD. We evaluated 31 patients with svMCI, 42 with SVaD, and 28 healthy controls who underwent neuropsychiatric assessments using the Neuropsychiatric Inventory (NPI) and the Frontal Behavioral Inventory (FBI). On both the NPI and FBI, SVaD patients had the most severe neuropsychiatric symptoms, followed by svMCI patients and then healthy controls, suggesting that svMCI might be a prodromal stage of SVaD in terms of neuropsychiatric abnormalities. When we compared the differences of mean scores between negative and positive symptoms in FBI, negative symptoms tended to be more predominant than positive symptoms in both svMCI and SVaD patients, but the tendency was stronger in SVaD patients than in svMCI patients. These results suggest that vascular cognitive impairment with small vessel disease would start with both negative and positive neuropsychiatric symptoms and progress to present more severe negative symptoms. These behavioral ratings may be useful for early detection of vascular cognitive impairment associated with small vessel disease. [ABSTRACT FROM AUTHOR]

Abstract: Patients with probable Alzheimer''s disease (AD) and the amnesic form of mild cognitive impairment (aMCI) often demonstrate several types of neuropsychological deficits. These deficits are often related to cortical atrophy, induced by neuronal degradation. The purpose of this study is to investigate whether different anatomic patterns of cortical atrophy are associated with specific neuropsychological deficits. The participants were 170 patients with AD and 99 patients with aMCI. All participants underwent the Seoul Neuropsychological Screening Battery (SNSB), which includes tests that assess attention, language, visuospatial functions, verbal and visual memory, and frontal/executive functions. Cortical atrophy (thinning) was quantified by measuring the thickness of the cortical mantle across the entire brain using automated, three-dimensional magnetic resonance imaging. The relationship between cortical thickness and neuropsychological performance was analysed using stepwise multiple linear regression analyses. These analyses (corrected P <.001) showed that several specific brain regions with cortical thinning were associated with cognitive dysfunction including: digit span backward, verbal and picture recall, naming and fluency, drawing–copying, response inhibition and selective attention. Some of the other functions, however, were not associated with specific foci of cortical atrophy (digit span forward, the word reading portion of the Stroop test, word and picture recognition). Our study, involving a large sample of participants with aMCI and AD, provides support for the postulate that cortical thinning-atrophy in specific anatomic loci are pathological markers for specific forms of cognitive dysfunction. [Copyright &y& Elsevier]

Abstract: Objective: Vascular cognitive impairment associated with small vessel disease (sVCI) may manifest as both cognitive and motor dysfunctions. However, few instruments exist for systematically assessing motor symptoms in sVCI, even though many neuropsychological tests exist to evaluate cognitive function. We developed a new scale for assessing motor impairments and evaluated the reliability and validity of the scale in patients with sVCI. Methods: A new motor scale, called the PEPS (Pyramidal and Extra Pyramidal Scale for sVCI), consisted of 34 items (for 60 total points) with 5 subdomains: corticospinal, corticobulbar, extrapyramidal signs, gait abnormalities, and gait severity. The PEPS was compared between 75 patients with sVCI and 73 control patients who had dementia or mild cognitive impairment (MCI) without ischemia. Results: The PEPS had good interrater and test–retest reliability, and it was moderately to highly correlated with the UPDRS, NIHSS, MMSE, CDR, and ADL scales. An optimal cut-off score of PEPS to discriminate dementia or MCI patients with ischemia from those without ischemia was 6.5 with a sensitivity of 88% and a specificity of 100%. Conclusion: The PEPS is a reliable and valid scale that can be used to assess and monitor motor impairment in patients with vascular cognitive impairment due to small vessel disease. [Copyright &y& Elsevier]

Abstract: Mental confusion or delirium can occur after application of scopolamine patch. However, predisposing factors for scopolamine-induced delirium are not known. It is expected that undetected incipient dementia or mild cognitive impairment (MCI) may be prone to develop mental confusion after applying the scopolamine patch. For the past 5 years, we found seven elderly women who had experienced transdermal scopolamine-induced mental confusion. They underwent neuropsychological tests after recovery from mental confusion (mean duration from onset to the test: 66 days). The results showed that all the patients were impaired in at least one of cognitive domains, fulfilling the criteria of MCI. These findings suggest that scopolamine patch-induced mental confusion should be included in the differential diagnoses of mental confusion in elderly, especially in travel situation, and that older people with undetected MCI are prone to develop scopolamine patch-induced mental confusion. [Copyright &y& Elsevier]

Background: Amyloid-β (Aβ) commonly coexists and impacts prognosis in subcortical vascular cognitive impairment (SVCI). Objective: This study aimed to examine the differences in clinical and neuroimaging variables between Aβ-positive and Aβ-negative SVCI and to propose a prediction model for Aβ positivity in clinically diagnosed SVCI patients. Methods: A total of 130 patients with SVCI were included in model development, and a separate cohort of 70 SVCI patients was used in external validation. The variables for the prediction model were selected by comparing the characteristics of the Aβ-negative and Aβ-positive SVCI groups. The final model was determined using a stepwise method. The model performance was evaluated using the receiver operating characteristic (ROC) curve and a calibration curve. A nomogram was used for visualization. Results: Among 130 SVCI patients, 70 (53.8%) were Aβ-positive. The Aβ-positive SVCI group was characterized by older age, tendency to be in the dementia stage, a higher prevalence of APOEɛ4, a lower prevalence of lacune, and more severe medial temporal atrophy (MTA). The final prediction model, which excluded MTA grade following the stepwise method for variable selection, demonstrated good accuracy in distinguishing between Aβ-positive and Aβ-negative SVCI, with an area under the curve (AUC) of 0.80. The external validation demonstrated an AUC of 0.71. Conclusions: The findings suggest that older age, dementia stage, APOEɛ4 carrier, and absence of lacunes may be predictive of Aβ positivity in clinically diagnosed SVCI patients. [ABSTRACT FROM AUTHOR]

Background: Cholesterol plays important roles in β-amyloid (Aβ) metabolism and atherosclerosis. However, the relationships of plasma cholesterol levels with Aβ and cerebral small vessel disease (CSVD) burdens are not fully understood in Asians. Herein, we investigated the relationships between plasma cholesterol profile components and Aβ and CSVD burdens in a large, non-demented Korean cohort. Methods: We enrolled 1,175 non-demented participants (456 with unimpaired cognition [CU] and 719 with mild cognitive impairment [MCI]) aged ≥ 45 years who underwent Aβ PET at the Samsung Medical Center in Korea. We performed linear regression analyses with each cholesterol (low-density lipoprotein cholesterol [LDL-c], high-density lipoprotein cholesterol [HDL-c], and triglyceride) level as a predictor and each image marker (Aβ uptake on PET, white matter hyperintensity [WMH] volume, and hippocampal volume) as an outcome after controlling for potential confounders. Results: Increased LDL-c levels (β = 0.014 to 0.115, p = 0.013) were associated with greater Aβ uptake, independent of the APOE e4 allele genotype and lipid-lowering medication. Decreased HDL-c levels (β = − 0.133 to − 0.006, p = 0.032) were predictive of higher WMH volumes. Increased LDL-c levels were also associated with decreased hippocampal volume (direct effect β = − 0.053, p = 0.040), which was partially mediated by Aβ uptake (indirect effect β = − 0.018, p = 0.006). Conclusions: Our findings highlight that increased LDL-c and decreased HDL-c levels are important risk factors for Aβ and CSVD burdens, respectively. Furthermore, considering that plasma cholesterol profile components are potentially modified by diet, exercise, and pharmacological agents, our results provide evidence that regulating LDL-c and HDL-c levels is a potential strategy to prevent dementia. [ABSTRACT FROM AUTHOR]

Abstract The concept of cognitive reserve (CR) originated from discrepancies between the degree of brain pathology and the severity of clinical manifestations. CR has been characterized through CR proxies, such as education and occupation complexity; however, such approaches have inherent limitations. Although several methods have been developed to overcome these limitations, they fail to reflect the entire Alzheimer's disease (AD) pathology. Meanwhile, graph theory analysis, one of most powerful and flexible approaches, have established remarkable network properties of the brain. The functional and structural brain networks are damaged in neurodegenerative diseases. Therefore, network analysis has been applied to clarify the characteristics of the disease or give insight. Here, using multimodal neuroimaging, we propose an intuitive model to estimate CR based on its original definition, and explore the neural substrates of CR from the perspective of networks and functional connectivity. A total of 87 subjects (21 AD, 32 mild cognitive impairment, and 34 normal aging) underwent tau and amyloid PET, 3D T1-weighted MR, and resting-state fMRI. We hypothesized CR as a residual of actual cognitive performance and expected performance to be related to quantitative factors, such as AD pathology, demographics, and a genetic factor. Then, we correlated this marker using education and occupation complexity as conventional CR proxies. We validated this marker by testing whether it would modulate the effect of brain pathology on memory function. To examine the neural substrates associated with CR, we performed graph analysis to investigate the association between the CR marker and network measures at different granularities in total subjects, AD spectrum and normal aging, respectively. The CR marker from our model was well associated with education and occupation complexity. More directly, the CR marker was revealed to modify the relationship between brain pathology and memory function among AD spectrum. The CR marker was correlated with the global efficiency of the entire network, nodal clustering coefficient, and local efficiency of the right middle-temporal pole. In connectivity analysis, one cluster of edges centered on right middle-temporal pole was significantly correlated with the CR marker. In subgroup analysis, the network measures of right middle-temporal pole still correlated with the CR marker among AD spectrum. However, right precentral gyrus was revealed to be associated with the CR marker in normal aging. This study demonstrates that our intuitive model using multimodal neuroimaging and network perspective adequately and comprehensively captures CR. From a network perspective, CR is associated with the capacity to process information efficiently in the brain. The right middle-temporal pole was revealed to be a pivotal neural substrate of CR in AD spectrum. These findings foster understanding of AD and will be useful to help identify individuals with vulnerability or resistance to AD pathology, and characterize patients for intervention or drug trials. Highlights • We generated an equation to quantify cognitive reserve (CR) reflecting overall AD neuropathology using multimodal neuroimaging techniques. • CR was proved to modify the relationship between brain pathology and memory function in AD spectrum. • CR was associated with global network efficiency and nodal clustering coefficient and local efficiency of the right middle-temporal pole. • Graph parameters of right middle-temporal pole was revealed to modulate the effect of brain atrophy on cognition in AD spectrum. [ABSTRACT FROM AUTHOR]

Abstract We categorized patients with amnestic mild cognitive impairment (aMCI) based on cortical atrophy patterns and evaluated whether the prognosis differed across the subtypes. Furthermore, we developed a classifier that learns the cortical atrophy pattern and predicts subtypes at an individual level. A total of 662 patients with aMCI were clustered into 3 subtypes based on cortical atrophy patterns. Of these, 467 patients were followed up for more than 12 months, and the median follow-up duration was 43 months. To predict individual-level subtype, we used a machine learning–based classifier with a 10-fold cross-validation scheme. Patients with aMCI were clustered into 3 subtypes: medial temporal atrophy, minimal atrophy (Min), and parietotemporal atrophy (PT) subtypes. The PT subtype had higher prevalence of APOE ε4 carriers, amyloid PET positivity, and greater risk of dementia conversion than the Min subtype. The accuracy for binary classification was 89.3% (MT vs. Rest), 92.6% (PT vs. Rest), and 86.6% (Min vs. Rest). When we used ensemble model of 3 binary classifiers, the accuracy for predicting the aMCI subtype at an individual level was 89.6%. Patients with aMCI with the PT subtype were more likely to have underlying Alzheimer's disease pathology and showed the worst prognosis. Our classifier may be useful for predicting the prognosis of individual aMCI patients. Highlights 1. Amnestic MCI patients were clustered into medial temporal, minimal, and parietotemporal atrophy subtypes. 2. Patients with parietotemporal atrophy subtype showed the worst prognosis. 3. The accuracy for predicting the aMCI subtype at an individual level was 89.6%. [ABSTRACT FROM AUTHOR]

Background: Accessible and cost-effective diagnostic tools are urgently needed to accurately quantify blood biomarkers to support early diagnosis of Alzheimer's disease (AD). In this study, we investigated the ability of plasma amyloid-beta (Aβ)42/Aβ40 ratio measured by an antibody-free mass-spectrometric (MS) method, ABtest-MS, to detect early pathological changes of AD. Methods: This cohort study included data from the baseline and 2-year follow-up visits from the Fundació ACE Healthy Brain Initiative (FACEHBI) study. Plasma Aβ42/Aβ40 was measured with ABtest-MS and compared to 18F-Florbetaben PET as the reference standard (cutoff for early amyloid deposition of 13.5 centiloids). Cross-validation was performed in an independent DPUK-Korean cohort. Additionally, associations of plasma Aβ42/Aβ40 with episodic memory performance and brain atrophy were assessed. Results: The FACEHBI cohort at baseline included 200 healthy individuals with subjective cognitive decline (SCD), of which 36 (18%) were Aβ-PET positive. Plasma Aβ42/Aβ40 levels were significantly lower in Aβ-PET positive individuals (median [interquartile range, IQR], 0.215 [0.203–0.236]) versus Aβ-PET negative subjects (median [IQR], 0.261 [0.244–0.279]) (P <.001). Plasma Aβ42/Aβ40 was significantly correlated with Aβ-PET levels (rho = −0.390; P <.001) and identified Aβ-PET status with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% confidence interval [CI], 0.80–0.93). A cutoff for the Aβ42/Aβ40 ratio of 0.241 (maximum Youden index) yielded a sensitivity of 86.1% and a specificity of 80.5%. These findings were cross-validated in an independent DPUK-Korean cohort (AUC 0.86 [95% CI 0.77–0.95]). Lower plasma Aβ42/Aβ40 ratio was associated with worse episodic memory performance and increased brain atrophy. Plasma Aβ42/Aβ40 at baseline predicted clinical conversion to mild cognitive impairment and longitudinal changes in amyloid deposition and brain atrophy at 2-year follow-up. Conclusions: This study suggests that plasma Aβ42/Aβ40, as determined by this MS-based assay, has potential value as an accurate and cost-effective tool to identify individuals in the earliest stages of AD, supporting its implementation in clinical trials, preventative strategies and clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies showed that white matter hyperintensities (WMH) are related to cognitive decline in patients with mild cognitive impairment (MCI) or dementia. Moreover, periventricular WMH (periventricular white matter hyperintensities (PWMH)) and deep WMH (deep white matter hyperintensities (DWMH)) may have different effects on cognition. The purpose of this study is to investigate the contributions of PWMH and DWMH to the topography of cortical thinning and to investigate the relationship among WMH, cortical thinning, and cognitive impairments. Participants included 226 patients with Alzheimer''s disease or subcortical vascular dementia, and 135 patients with amnestic MCI or subcortical vascular MCI. Cortical thickness was measured using the surface based method. The topography of cortical thinning related to WMH was distributed in the frontal and perisylvian regions, which was similar to that of PWMH. In contrast, there were only small areas of cortical thinning inversely associated with DWMH, which were distributed in medial frontal and lingual gyrus. PWMH, but not DWMH, were associated with the frontal thinning and executive dysfunction; where both PWMH and frontal thinning were independently associated with executive dysfunction. Our results suggest that PWMH are associated with frontal thinning, which is further associated with frontal executive dysfunction. [Copyright &y& Elsevier]

The clinical outcomes of patients with amyloid beta-positive (Aβ+) mild cognitive impairment (MCI) are heterogeneous. We therefore developed prediction models for distinguishable cognitive trajectories in Aβ+ participants with MCI. We included 238 Aβ+ participants with MCI from the Alzheimer's Disease Neuroimaging Initiative to develop a group-based trajectory model and 63 Aβ+ participants with MCI from the Samsung Medical Center for external validation. Three distinguishable classes, slow decliners (18.5%), intermediate decliners (42.9%), and fast decliners (38.7%), were identified. Intermediate decliners were associated with older age, higher AV45 standardized uptake value ratios (SUVR) and lower fluorodeoxyglucose (FDG) SUVR than slow decliners. Fast decliners were associated with older age, presence of APOE ε4 , higher AV45 SUVR and lower FDG SUVR than slow decliners. Prediction models of cognitive decline showed good discrimination and calibration capabilities in the development and validation data sets. Our analysis yields novel insights into the cognitive trajectories of Aβ+ patients with MCI, which will facilitate their effective stratification in Aβ-targeted clinical trials. [ABSTRACT FROM AUTHOR]

Imaging biomarkers support the diagnosis of Alzheimer's disease (AD). We aimed to determine whether combining automated brain volumetry on MRI and quantitative measurement of tau deposition on [18F] THK-5351 PET can aid discrimination of AD spectrum. From a prospective database in an IRB-approved multicenter study (NCT02656498), 113 subjects (32 healthy control, 55 mild cognitive impairment, and 26 Alzheimer disease) with baseline structural MRI and [18F] THK-5351 PET were included. Cortical volumes were quantified from FDA-approved software for automated volumetric MRI analysis (NeuroQuant). Standardized uptake value ratio (SUVR) was calculated from tau PET images for 6 composite FreeSurfer-derived regions-of-interests approximating in vivo Braak stage (Braak ROIs). On volumetric MRI analysis, stepwise logistic regression analyses identified the cingulate isthmus and inferior parietal lobule as significant regions in discriminating AD from HC and MCI. The combined model incorporating automated volumes of selected brain regions on MRI (cingulate isthmus, inferior parietal lobule, hippocampus) and SUVRs of Braak ROIs on [18F] THK-5351 PET showed higher performance than SUVRs of Braak ROIs on [18F] THK-5351 PET in discriminating AD from HC (0.98 vs 0.88, P = 0.033) but not in discriminating AD from MCI (0.85 vs 0.79, P = 0.178). The combined model showed comparable performance to automated volumes of selected brain regions on MRI in discriminating AD from HC (0.98 vs 0.94, P = 0.094) and MCI (0.85 vs 0.78; P = 0.065). [ABSTRACT FROM AUTHOR]

Predicting amyloid positivity in patients with mild cognitive impairment (MCI) is crucial. In the present study, we predicted amyloid positivity with structural MRI using a radiomics approach. From MR images (including T1, T2 FLAIR, and DTI sequences) of 440 MCI patients, we extracted radiomics features composed of histogram and texture features. These features were used alone or in combination with baseline non-imaging predictors such as age, sex, and ApoE genotype to predict amyloid positivity. We used a regularized regression method for feature selection and prediction. The performance of the baseline non-imaging model was at a fair level (AUC = 0.71). Among single MR-sequence models, T1 and T2 FLAIR radiomics models also showed fair performances (AUC for test = 0.71–0.74, AUC for validation = 0.68–0.70) in predicting amyloid positivity. When T1 and T2 FLAIR radiomics features were combined, the AUC for test was 0.75 and AUC for validation was 0.72 (p vs. baseline model < 0.001). The model performed best when baseline features were combined with a T1 and T2 FLAIR radiomics model (AUC for test = 0.79, AUC for validation = 0.76), which was significantly better than those of the baseline model (p < 0.001) and the T1 + T2 FLAIR radiomics model (p < 0.001). In conclusion, radiomics features showed predictive value for amyloid positivity. It can be used in combination with other predictive features and possibly improve the prediction performance. [ABSTRACT FROM AUTHOR]

Background: Although amyloid PET of typical Alzheimer's disease (AD) shows diffuse ß-amyloid (Aß) deposition, some patients show focal deposition. The clinical significance of this focal Aß is not well understood. We examined the clinical significance of focal Aß deposition in terms of cognition as well as Aß and tau cerebrospinal fluid (CSF) levels. We further evaluated the order of Aß accumulation by visual assessment. Methods: We included 310 subjects (125 cognitively unimpaired, 125 mild cognitive impairment, and 60 AD dementia) from 9 referral centers. All patients underwent neuropsychological tests and 18F-flutemetamol (FMM) PET. Seventy-seven patients underwent CSF analysis. Each FMM scan was visually assessed in 10 regions (frontal, precuneus and posterior cingulate, lateral temporal, parietal, and striatum of each hemisphere) and was classified into three groups: No-FMM, Focal-FMM (FMM uptake in 1–9 regions), and Diffuse-FMM (FMM uptake in all 10 regions). Results: 53/310 (17.1%) subjects were classified as Focal-FMM. The cognitive level of the Focal-FMM group was better than that of Diffuse-FMM group and worse than that of No-FMM group. Among the Focal-FMM group, those who had FMM uptake to a larger extent or in the striatum had worse cognitive levels. Compared to the Diffuse-FMM group, the Focal-FMM group had a less AD-like CSF profile (increased Aß42 and decreased t-tau, t-tau/Aß42). Among the Focal-FMM group, Aß deposition was most frequently observed in the frontal (62.3%) and least frequently observed in the striatum (43.4%) and temporal (39.6%) regions. Conclusions: We suggest that focal Aß deposition is an intermediate stage between no Aß and diffuse Aß deposition. Furthermore, among patients with focal Aß deposition, those who have Aß to a larger extent and striatal involvement show clinical features close to diffuse Aß deposition. Further longitudinal studies are needed to evaluate the disease progression of patients with focal Aß deposition. [ABSTRACT FROM AUTHOR]

Purpose: To assess the in vivo whole-brain relationship between uptake of [18F]THK-5351 on PET and cortical atrophy on structural MRI according to the presence and severity of Alzheimer's disease (AD). Materials and methods: Sixty-five participants (21 normal controls, 32 mild cognitive impairment [MCI] subjects, and 12 AD patients) were enrolled from a prospective multicenter clinical trial (NCT02656498). Structural MRI and [18F]THK-5351 PET were performed within a 2-month interval. Cortical volume and standardized uptake value ratios (SUVR) were calculated from MRI and PET images, respectively, for 35 FreeSurfer-derived cortical regions. Pearson's correlation coefficients between SUVR and cortical volume were calculated for the same regions, and correlated regions were compared according to disease severity and β-amyloid PET positivity. Results: No significantly correlated regions were found in the normal controls. Negative correlations between SUVR and cortical volume were found in the MCI and AD groups, mainly in limbic locations in MCI and isocortical locations in AD. The AD group exhibited stronger correlations (r = −0.576–0.781) than the MCI group (r = 0.368–0.571). Hippocampal atrophy did not show any correlation with SUVR in the β-amyloid PET-negative group, but negatively correlated with SUVR (r = −0.494, P =.012) in the β-amyloid PET-positive group. Conclusions: Regional THK-5351 uptake correlated more strongly with cortical atrophy in AD compared with MCI, thereby demonstrating a close relationship between the neuro-pathologic process and cortical atrophy. Hippocampal atrophy was associated with both β-amyloid and THK-5351 uptake, possibly reflecting an interaction between β-amyloid and tau deposition in the neurodegeneration process. [ABSTRACT FROM AUTHOR]

Background: Subjective memory complaints (SMC) are a risk factor for Alzheimer's disease.Objective: We aimed to explore the association between SMC and regional amyloid-β (Aβ) deposition in mild cognitive impairment (MCI).Methods: Sixty-eight individuals with MCI were recruited. [18F]Florbetaben PET scans were performed. T1-weighted 3D volumes were also acquired for co-registration with PET and for defining the regions of interest (ROI). Two step exploratory partial correlation analyses between SMC and Aβ deposition were performed with covariates of age, sex, education, and depression. Furthermore, for the priori ROI that had the most significant partial correlation, we investigated the correlation between the SMC and regional Aβ burden using a multiple linear regression model controlling for depression, age, sex, and education.Results: Significant positive correlations between the SMC and Aβ burden was found in the medial temporal ROI (first step) and in the left parahippocampus ROI (second step). In the priori left parahippocampus, we found significant correlation between the SMC and Aβ burden (R2 = 0.473, p = 0.014).Conclusions: Our study suggested that the SMC was associated with amyloid accumulation, especially in the left parahippocampus, in individuals with MCI. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the association between small vessel disease (SVD) burden, a combination of multiple SVD markers and cognitive dysfunction after stroke.Methods: The study sample comprised 451 patients with first-ever acute ischemic stroke. Cognitive functions were assessed with the Mini-Mental State Examination (MMSE) at 3, 9, and 15 months after the index stroke. Cognitive impairment was defined as an MMSE score of ≤26. A total SVD score, indicating SVD burden, was constructed by summing the scores of the 4 SVD markers (white matter hyperintensities [WMHs], lacunes, cerebral microbleeds, and perivascular spaces) ascertained by magnetic resonance imaging (range: 0-4). The association between SVD burden and cognitive dysfunction was assessed with linear mixed models or generalized estimating equation models, as appropriate.Results: The majority of patients had mild-to-moderate stroke and at least one identifiable SVD marker. Cognitive impairment was found in about one-third of patients. After adjusting for confounding factors, the SVD burden was associated with MMSE scores (β = -0.37, P = .003) and cognitive impairment (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.02-1.42). SVD burden was specifically associated with the performance of MMSE subscores including orientation to place and time, calculation, and word recall. Of the SVD markers, WMHs was the most robust predictor of decrease in MMSE scores (β = -0.25, P = .01) and cognitive impairment (OR = 1.14, 95% CI = 1.01-1.29).Conclusion: Cerebral SVD burden is associated with decreased MMSE scores, suggesting cognitive dysfunction during the first year after mild-to-moderate acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Background: Peripheral high-density lipoprotein cholesterol (HDL-C) has been known to influx into the brain and be inversely associated with the risk of Alzheimer's disease (AD). However, recent prospective studies of the association between HDL-C and AD have yielded inconsistent results. Here, we examined the association between the endothelial lipase (EL), which is known to be major determinant of HDL-C levels, and cognitive function. Method: We compared plasma from 20 patients with Alzheimer's disease (AD), 38 persons with mild cognitive impairment, and 51 cognitively normal controls. Plasma EL levels were measured using the enzyme-linked immunosorbent assay. Results: EL levels were inversely correlated with HDL-C, as previously reported; however, there were no mean differences in plasma EL between the diagnostic groups. An analysis by classification of dementia severity according to clinical dementia rating (CDR) showed that the EL levels were significantly higher in the CDR1 group (mild dementia), as compared to CDR0 (no dementia), CDR0.5 (very mild), and CDR2 (moderate) groups. Prior to moderate dementia stage, trends analysis showed that EL levels tended to increase with increasing severity (p for trend = 0.013). Consistently, elevated EL levels were significantly correlated with the mini-mental state examination (MMSE) score (r = − 0.29, p = 0.003). Logistic regression for association between plasma EL and cognitive impairment (MMSE score ≤ 25) showed that participants with EL levels in the upper range (> 31.6 ng/ml) have a higher adjusted odds ratio of cognitive impairment than those within the lower EL range. Conclusion: Findings from the present study reflect the association of EL and cognition, suggesting that the individuals with elevated plasma EL concentration are at an increased risk of cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Frontal behavioral impairment (FrBI) is commonly observed in various degenerative diseases and refers to various behavioral symptoms.Objective: We investigated the effects of the presence of FrBI on cortical thickness, and the longitudinal neuropsychological changes in people in the predementia stage.Methods: A total of 794 individuals completed neuropsychological tests and the Frontal Behavioral Inventory (FBI) Questionnaire, and underwent magnetic resonance (MR) scanning. Participants were analyzed and grouped into non-FrBI (FBI = 0) or FrBI (FBI≥1). Cortical thickness was measured on MR images using a surface-based method.Results: In total, 281 people with subjective cognitive decline (SCD) and 513 with amnestic mild cognitive impairment (aMCI) were assessed for FrBI. Relative to people without FrBI, those with FrBI presented reduced cortical thickness in the frontal, anterior temporal and lateral parietal regions (p < 0.05, FDR corrected). People with FrBI developed Alzheimer's disease, rather than behavioral variant frontotemporal dementia, as observed over seven years. Mixed effects models reported that people with FrBI have greater cognitive decline than those with non-FrBI in multiple domains, including language, memory, and executive functions (p < 0.05, FDR corrected). Furthermore, while negative FrBI symptoms (e.g., deficit behaviors) were associated with greater declines in multiple domains, positive FrBI symptoms (e.g., disinhibition symptoms) were related to declines in visuospatial function and verbal memory. Finally, the occurrence of both types of symptoms correlated with multi-domain cognitive decline.Conclusions: FrBI predicted worse clinical outcomes, including reduced cortical thickness and cognitive decline, which are not necessarily specific to frontal dysfunction. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease, tau pathology spreads hierarchically from the inferior temporal lobe throughout the cortex, ensuing cognitive decline and dementia. Similarly, circumscribed patterns of pathological tau have been observed in normal ageing and small vessel disease, suggesting a spatially ordered distribution of tau pathology across normal ageing and different diseases. In vitro findings suggest that pathological tau may spread 'prion-like' across neuronal connections in an activity-dependent manner. Supporting this notion, functional brain networks show a spatial correspondence to tau deposition patterns. However, it remains unclear whether higher network-connectivity facilitates tau propagation. To address this, we included 55 normal aged elderly (i.e. cognitively normal, amyloid-negative), 50 Alzheimer's disease patients (i.e. amyloid-positive) covering the preclinical to dementia spectrum, as well as 36 patients with pure (i.e. amyloid-negative) vascular cognitive impairment due to small vessel disease. All subjects were assessed with AV1451 tau-PET and resting-state functional MRI. Within each group, we computed atlas-based resting-state functional MRI functional connectivity across 400 regions of interest covering the entire neocortex. Using the same atlas, we also assessed within each group the covariance of tau-PET levels among the 400 regions of interest. We found that higher resting-state functional MRI assessed functional connectivity between any given region of interest pair was associated with higher covariance in tau-PET binding in corresponding regions of interest. This result was consistently found in normal ageing, Alzheimer's disease and vascular cognitive impairment. In particular, inferior temporal tau-hotspots, as defined by highest tau-PET uptake, showed high predictive value of tau-PET levels in functionally closely connected regions of interest. These associations between functional connectivity and tau-PET uptake were detected regardless of presence of dementia symptoms (mild cognitive impairment or dementia), amyloid deposition (as assessed by amyloid-PET) or small vessel disease. Our findings suggest that higher functional connectivity between brain regions is associated with shared tau-levels, supporting the view of prion-like tau spreading facilitated by neural activity. [ABSTRACT FROM AUTHOR]

Background: Most clinical trials focus on amyloid-β positive (Aβ+) amnestic mild cognitive impairment (aMCI), but screening failures are high because only a half of patients with aMCI are positive on Aβ PET. Therefore, it becomes necessary for clinicians to predict which patients will have Aβ biomarker.Objective: We aimed to compare clinical factors, neuropsychological (NP) profiles, and apolipoprotein E (APOE) genotype between Aβ+ aMCI and Aβ-aMCI and to develop a clinically useful prediction model of Aβ positivity on PET (PET-Aβ+) in aMCI using a nomogram.Methods: We recruited 523 aMCI patients who underwent Aβ PET imaging in a nation-wide multicenter cohort. The results of NP measures were divided into following subgroups: 1) Stage (Early and Late-stage), 2) Modality (Visual, Verbal, and Both), 3) Recognition failure, and 4) Multiplicity (Single and Multiple). A nomogram for PET-Aβ+ in aMCI patients was constructed using a logistic regression model.Results: PET-Aβ+ had significant associations with NP profiles for several items, including high Clinical Dementia Rating Scale Sum of Boxes score (OR 1.47, p = 0.013) and impaired memory modality (impaired both visual and verbal memories compared with visual only, OR 3.25, p = 0.001). Also, presence of APOEɛ4 (OR 4.14, p < 0.001) was associated with PET-Aβ+. These predictors were applied to develop the nomogram, which showed good prediction performance (C-statistics = 0.79). Its prediction performances were 0.77/0.74 in internal/external validation.Conclusions: The nomogram consisting of NP profiles, especially memory domain, and APOEɛ4 genotype may provide a useful predictive model of PET-Aβ+ in patients with aMCI. [ABSTRACT FROM AUTHOR]

Background/objective: Vascular risk factors and neurovascular dysfunction may be closely related to cognitive impairment and dementia. In this study, we evaluated the association between hemodynamic markers and longitudinal cognitive changes in patients with mild cognitive impairment (MCI). Furthermore, we investigated whether hemodynamic markers could predict the risk of progression to Alzheimer's disease (AD) in patients with MCI.Methods: A total of 68 subjects with amnestic MCI were recruited. Using transcranial Doppler (TCD) ultrasonography, cerebrovascular reactivity was evaluated with a breath-holding test (breath holding index; BHI) in addition to the mean flow velocity (MFV) and pulsatility index (PI) of the middle cerebral artery. We followed subjects for 24 months and each subject underwent neuropsychological testing and TCD ultrasonography, annually. According to the follow-up neuropsychological studies and clinical interviews at 12 months, we divided the patients with MCI into two groups: patients with stable cognitive performance and patients who progressed to AD.Results: Lower BHI and higher PI were observed in patients who progressed to AD. The changes of MMSE score over the first 12 months correlated with lower baseline MMSE score and changes of MFV and BHI. The changes of MMSE score over 24 months were closely related to higher baseline resistance index and PI values. Multivariate logistic regression showed that abnormal baseline BHI value could predict a conversion from MCI to AD.Conclusions: We confirmed there is a close association between hemodynamic changes represented by TCD markers and cognitive decline, supporting the clinical value of hemodynamic markers in predicting MCI patients who will progress to AD. [ABSTRACT FROM AUTHOR]

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: We examined the efficacy of group-based cognitive intervention (GCI) and home-based cognitive intervention (HCI) in amnestic mild cognitive impairment (aMCI) and intervention effects on serum brain-derived neurotrophic factor (BDNF).Methods: In this randomized and rater-blinded trial, 293 patients with aMCI from 18 nationwide hospitals were randomized: 96 to the GCI group, 98 to the HCI group and 99 to the control group. For 12 weeks, subjects receiving GCI participated twice per week in group sessions led by trained instructors, and those receiving HCI completed homework materials 5 days per week. They were assessed at baseline, postintervention (PI) and at the 6-month follow-up after the intervention. The primary endpoint was the change from baseline to PI in the modified Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog).Results: In comparison to the controls (a 0.8-point decrease), the subjects receiving GCI (a 2.3-point decrease, p = 0.01) or HCI (a 2.5-point decrease, p = 0.02) showed significant improvements in the modified ADAS-Cog at PI, respectively. By the 6-month follow-up, those receiving GCI or HCI had better scores in the modified ADAS-Cog than the controls. The changes in BDNF levels significantly correlated with the changes in the modified ADAS-Cog in the GCI (r = -0.29, p = 0.02 at PI) and HCI (r = -0.27, p = 0.03 at 6-month follow-up) groups, respectively.Conclusions: The GCI and HCI resulted in cognitive improvements in aMCI. An enhanced brain plasticity may be a component of the mechanism underpinning the cognitive improvements associated with the cognitive interventions. [ABSTRACT FROM AUTHOR]

The white matter tract-specific correlates of neuropsychological deficits are not fully established in patients with subcortical vascular cognitive impairment (SVCI), where white matter tract damage may be a critical factor in cognitive impairment. The purpose of this study is to investigate the tract-specific correlates of neuropsychological deficits in SVCI patients using tract-specific statistical analysis (TSSA). We prospectively recruited 114 SVCI patients, and 55 age-, gender-, and education-matched individuals with normal cognition (NC). All participants underwent diffusion weighted imaging and neuropsychological testing. We classified tractography results into fourteen major fiber tracts and analyzed group comparison and correlation with cognitive impairments. Relative to NC subjects, SVCI patients showed decreased fractional anisotropy values in bilateral anterior-thalamic radiation, cingulum, superior-longitudinal fasciculus, uncinate fasciculus, corticospinal tract, and left inferior-longitudinal fasciculus. Focal disruptions in specific tracts were associated with specific cognitive impairments. Our findings suggest that disconnection of specific white matter tracts, especially those neighboring and providing connections between gray matter regions important to certain cognitive functions, may contribute to specific cognitive impairments in SVCI. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate if multi-domain cognitive training, especially robot-assisted training, alters cortical thickness in the brains of elderly participants. A controlled trial was conducted with 85 volunteers without cognitive impairment who were 60 years old or older. Participants were first randomized into two groups. One group consisted of 48 participants who would receive cognitive training and 37 who would not receive training. The cognitive training group was randomly divided into two groups, 24 who received traditional cognitive training and 24 who received robot-assisted cognitive training. The training for both groups consisted of daily 90-min-session, five days a week for a total of 12 weeks. The primary outcome was the changes in cortical thickness. When compared to the control group, both groups who underwent cognitive training demonstrated attenuation of age related cortical thinning in the frontotemporal association cortices. When the robot and the traditional interventions were directly compared, the robot group showed less cortical thinning in the anterior cingulate cortices. Our results suggest that cognitive training can mitigate age-associated structural brain changes in the elderly. Trial Registration: ClnicalTrials.gov [ABSTRACT FROM AUTHOR]

We evaluate the longitudinal outcomes of amnestic mild cognitive impairment (aMCI) according to the modality of memory impairment involved. We recruited 788 aMCI patients and followed them up. aMCI patients were categorized into three groups according to the modality of memory impairment: Visual-aMCI, only visual memory impaired; Verbal-aMCI, only verbal memory impaired; and Both-aMCI, both visual and verbal memory impaired. Each aMCI group was further categorized according to the presence or absence of recognition failure. Risk of progression to dementia was compared with pooled logistic regression analyses while controlling for age, gender, education, and interval from baseline. Of the sample, 219 (27.8%) aMCI patients progressed to dementia. Compared to the Visual-aMCI group, Verbal-aMCI (OR = 1.98, 95% CI = 1.19-3.28, p = 0.009) and Both-aMCI (OR = 3.05, 95% CI = 1.97-4.71, p < 0.001) groups exhibited higher risks of progression to dementia. Memory recognition failure was associated with increased risk of progression to dementia only in the Visual-aMCI group, but not in the Verbal-aMCI and Both-aMCI groups. The Visual-aMCI without recognition failure group were subcategorized into aMCI with depression, small vessel disease, or accelerated aging, and these subgroups showed a variety of progression rates. Our findings underlined the importance of heterogeneous longitudinal outcomes of aMCI, especially Visual-aMCI, for designing and interpreting future treatment trials in aMCI. [ABSTRACT FROM AUTHOR]

Abstract: Neuropsychiatric symptoms (NPS) affect the quality of life of patients with dementia and increase the burden on caregivers. We aimed to evaluate how small vessel disease (SVD) such as lacunae or white matter hyperintensities (WMH), and amyloid burden affect NPS. We recruited 127 patients with subcortical vascular cognitive impairment who were assessed with brain magnetic resonance imaging, Pittsburgh compound-B (PiB) positron emission tomography and the neuropsychiatric inventory (NPI). To explore the association between lacunae, WMH, or PiB retention ratio and NPS, we performed multivariate regression analysis after controlling for possible confounders. Each additional lacuna, especially in the frontal region, was associated with higher odds of depression, apathy, aberrant motor behavior, nighttime behavior, appetite changes, and higher score of total NPI; larger WMH volume, especially in the frontal region, was associated with higher odds of apathy and higher score of total NPI. Furthermore, for the effects of lacunae or WMH on total NPI score we set Clinical Dementia Rating Sum of Boxes as the mediator. Greater PiB retention ratio was associated with higher odds of delusions and irritability. The SVD and amyloid pathologies did not show interactive effects on NPS. Our findings suggested that SVD and amyloid burden independently affected specific NPS. [Copyright &y& Elsevier]

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: Anemia and subcortical ischemic change might be associated with increased risks for cognitive impairment among the elderly. This study examined the associations among anemia, WMH and cognitive function in patients with amnestic MCI. We recruited 278 subjects with amnestic MCI from the Clinical Research Center for Dementia of South Korea (CREDOS), a hospital-based cohort study. A standardized neuropsychological battery, containing tests of language, visuospatial function, verbal memory and executive function, was used for all patients. Anemia was defined as a hemoglobin concentration below 12g/dl for women and below 13g/dl for men. The severity of WMH was also examined using brain magnetic resonance imaging (MRI). After multivariable adjustments, anemia and WMH were associated with poorer performance on cognitive function tests (anemia: Stroop test, F =4.17, p =0.042; WMH: Stroop test, F =6.45, p =0.002; Rey-complex figure test-copy, F =4.08, p =0.018). Moreover, a significant interaction between anemia and the severity of WMH was observed in performance on the Go/no go test (F =4.50, p =0.012) and the Stroop test (F =3.36, p =0.037). In post hoc analysis, anemic patients with severe WMH had significantly worse scores on measure of executive function (Go/no go test, p =0.011; Stroop test, p =0.001). Anemia and WMH had interactive effects on executive function impairment among the elderly with amnestic MCI. [Copyright &y& Elsevier]

Abstract: There are functional and structural neocortical hemispheric asymmetries in people with normal cognition. These asymmetries may be altered in patients with Alzheimer''s disease (AD) because there is a loss of neuronal connectivity in the heteromodal cortex. The purpose of this study is to test the hypothesis that individuals with amnestic mild cognitive impairment (aMCI), mild AD, and moderate to severe AD have progressive reductions in thickness asymmetries of the heteromodal neocortex. Right-handed elderly volunteers including normal cognition (NC), aMCI, and AD underwent 3-D volume imaging for cortical thickness. Although the cortical asymmetry pattern observed in normal cognition brains was generally maintained in aMCI and AD, there was a progressive decrease in the degree of asymmetry, especially in the inferior parietal lobule. A reduction of neocortical asymmetries may be a characteristic sign that occurs in patients with AD. Future studies are needed to evaluate whether this loss is specific to AD and if measurements of asymmetry can be used as diagnostic markers and for monitoring disease progression. [Copyright &y& Elsevier]

Depression with mild cognitive impairment (MCI) may be associated with a high risk of dementia. Likewise, anemia and subcortical ischemic changes might be associated with depression in the elderly individuals. We examined the relationship between anemia, subcortical ischemic changes, and depressive symptoms in 388 elderly patients with MCI (74.0% women, mean age = 71.8) who were evaluated at the Clinical Research Center for Dementia of South Korea. Blood samples were drawn from all consenting participants and depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). We also evaluated the severity of white matter hyperintensities (WMH) on brain using magnetic resonance imaging (MRI). After a multivariable adjustment, we found no significant differences in GDS-15 score between anemic and nonanemic groups (F = 3.0, P = .085) and among WMH level groups (F = 0.6, P = .574) independently. However, the interaction between anemia and the severity of WMH was significantly associated with depressive symptoms (analysis of covariance, F = 7.8, P < .001). In post hoc tests, a higher depressive symptom score was observed in anemic participants with severe WMH. Anemia with severe subcortical ischemic changes appears to be related to depressive symptoms in patients with MCI. [ABSTRACT FROM AUTHOR]

White matter hyperintensity (WMH) has been recognised as a surrogate marker of small vessel disease and is associated with cognitive impairment. We investigated the dynamic change in WMH in patients with severe WMH at baseline, and the effects of longitudinal change of WMH volume on cognitive decline and cortical thinning. Eighty-seven patients with subcortical vascular mild cognitive impairment were prospectively recruited from a single referral centre. All of the patients were followed up with annual neuropsychological tests and 3T brain magnetic resonance imaging. The WMH volume was quantified using an automated method and the cortical thickness was measured using surface-based methods. Participants were classified into WMH progression and WMH regression groups based on the delta WMH volume between the baseline and the last follow-up. To investigate the effects of longitudinal change in WMH volume on cognitive decline and cortical thinning, a linear mixed effects model was used. Seventy patients showed WMH progression and 17 showed WMH regression over a three-year period. The WMH progression group showed more rapid cortical thinning in widespread regions compared with the WMH regression group. However, the rate of cognitive decline in language, visuospatial function, memory and executive function, and general cognitive function was not different between the two groups. The results of this study indicated that WMH volume changes are dynamic and WMH progression is associated with more rapid cortical thinning. [ABSTRACT FROM AUTHOR]

Background: Neuropsychological tests (NPTs) are important tools for informing diagnoses of cognitive impairment (CI). However, interpreting NPTs requires specialists and is thus time-consuming. To streamline the application of NPTs in clinical settings, we developed and evaluated the accuracy of a machine learning algorithm using multi-center NPT data.Methods: Multi-center data were obtained from 14,926 formal neuropsychological assessments (Seoul Neuropsychological Screening Battery), which were classified into normal cognition (NC), mild cognitive impairment (MCI) and Alzheimer's disease dementia (ADD). We trained a machine learning model with artificial neural network algorithm using TensorFlow (https://www.tensorflow.org) to distinguish cognitive state with the 46-variable data and measured prediction accuracies from 10 randomly selected datasets. The features of the NPT were listed in order of their contribution to the outcome using Recursive Feature Elimination.Results: The ten times mean accuracies of identifying CI (MCI and ADD) achieved by 96.66 ± 0.52% of the balanced dataset and 97.23 ± 0.32% of the clinic-based dataset, and the accuracies for predicting cognitive states (NC, MCI or ADD) were 95.49 ± 0.53 and 96.34 ± 1.03%. The sensitivity to the detection CI and MCI in the balanced dataset were 96.0 and 96.0%, and the specificity were 96.8 and 97.4%, respectively. The 'time orientation' and '3-word recall' score of MMSE were highly ranked features in predicting CI and cognitive state. The twelve features reduced from 46 variable of NPTs with age and education had contributed to more than 90% accuracy in predicting cognitive impairment.Conclusions: The machine learning algorithm for NPTs has suggested potential use as a reference in differentiating cognitive impairment in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Although amnestic mild cognitive impairment (aMCI) is generally considered to be a prodromal stage of Alzheimer's disease, patients with aMCI show heterogeneous patterns of progression. Moreover, there are few studies investigating data-driven cognitive trajectory in aMCI. We therefore classified patients with aMCI based on their cognitive trajectory, measured by clinical dementia rating sum of boxes (CDR-SOB). Then, we compared the clinical and neuroimaging features among groups classified by cognitive trajectory. Methods: We retrospectively recruited 278 patients with aMCI who underwent three or more timepoints of neuropsychological testing. They also had magnetic resonance imaging (MRI) including structured three-dimensional volume images. Cortical thickness was measured using surface-based methods. We performed trajectory analyses to classify our aMCI patients according to their progression and investigate their cognitive trajectory using CDR-SOB. Results: Trajectory analyses showed that patients with aMCI were divided into three groups: stable (61.8%), slow decliner (31.7%), and fast decliner (6.5%). Changes throughout a mean follow-up duration of 3.7 years in the CDR-SOB for the subgroups of stable/slow/fast decliners were 1.3-, 6.4-, and 12-point increases, respectively. Decliners were older and carried apolipoprotein E4 (APOE4) genotypes more frequently than stable patients. Compared with the stable group, decliners showed a higher frequency of aMCI patients with both visual and verbal memory dysfunction, late stage aMCI, and multiple domain dysfunction. In addition, compared with the stable group, the slow decliners showed cortical thinning predominantly in bilateral parietotemporal areas, while the fast decliners showed cortical thinning predominantly in bilateral frontotemporal areas. Both decliner groups showed worse cognitive function in attention, language, visuospatial, memory, and frontal/executive domains than the stable group. Conclusions: Our data-driven trajectory analysis provides new insights into heterogeneous cognitive trajectories of aMCI and further suggests that baseline clinical and neuroimaging profiles might predict aMCI patients with poor prognosis. [ABSTRACT FROM AUTHOR]

Background: The protective effect of education has been well established in Alzheimer's disease, whereas its role in patients with isolated cerebrovascular diseases remains unclear. We examined the correlation of education with cortical thickness and cerebral small vessel disease markers in patients with pure subcortical vascular mild cognitive impairment (svMCI) and patients with pure subcortical vascular dementia (SVaD). Methods: We analyzed 45 patients with svMCI and 47 patients with SVaD with negative results on Pittsburgh compound B positron emission tomographic imaging who underwent structural brain magnetic resonance imaging. The main outcome was cortical thickness measured using surface-based morphometric analysis. We also assessed the volumes of white matter hyperintensities (WMH) and numbers of lacunes as other outcomes. To investigate the correlation of education with cortical thickness, WMH volume, and number of lacunes, multiple linear regression analyses were performed after controlling for covariates, including Mini Mental State Examination, in the svMCI and SVaD groups. Results: In the SVaD group, higher education was correlated with more severe cortical thinning in the bilateral dorsolateral frontal, left medial frontal, and parahippocampal areas, whereas there was no correlation of education with cortical thickness in the svMCI group. There was no correlation between education and cerebral small vessel disease, including WMH and lacunes, in both patients with svMCI and patients with SVaD. Conclusions: Our findings suggest that the compensatory effects of education on cortical thinning apply to patients with SVaD, which might be explained by the cognitive reserve hypothesis. [ABSTRACT FROM AUTHOR]