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Behavioral variant frontotemporal dementia (bvFTD) is the most common form of frontotemporal dementia, and tau pathology can be found in 40%–50% of bvFTD patients. In this study, we sought to investigate 18 F-flortaucipir-binding patterns and their correlates in clinically diagnosed bvFTD patients by comparing with results for Alzheimer's disease (AD) patients. We enrolled 20 bvFTD, 20 AD, and 20 age-matched healthy subjects who underwent neuropsychological tests, magnetic resonance imaging, and tau positron emission tomography scans with 18 F-flortaucipir. Regional standardized uptake value ratios for the cerebral cortex and underlying white matter were compared between the 2 groups. The bvFTD patients showed increased 18 F-flortaucipir binding in the putamen and globus pallidus when compared to the healthy controls. In addition, bvFTD was associated with increased binding in the white matter regions underlying the frontal, anterior cingulate, and insula cortices. The bvFTD patients may exhibit predominantly subcortical 18 F-flortaucipir-binding pattern that is distinct from the patterns seen in AD patients. We hypothesize that the clinical characteristics of bvFTD patients may be attributable to the dysfunctional frontal-subcortical networks. However, concerns remain regarding unknown “off-target” binding in the white matter and the basal ganglia. [ABSTRACT FROM AUTHOR]

We aimed to categorize subjective memory impairment (SMI) individuals based on their patterns of cortical thickness and to propose simple models that can classify each subtype. We recruited 613 SMI individuals and 613 age- and gender-matched normal controls. Using hierarchical agglomerative cluster analysis, SMI individuals were divided into 3 subtypes: temporal atrophy (12.9%), minimal atrophy (52.4%), and diffuse atrophy (34.6%). Individuals in the temporal atrophy (Alzheimer's disease–like atrophy) subtype were older, had more vascular risk factors, and scored the lowest on neuropsychological tests. Combination of these factors classified the temporal atrophy subtype with 73.2% accuracy. On the other hand, individuals with the minimal atrophy (non-neurodegenerative) subtype were younger, were more likely to be female, and had depression. Combination of these factors discriminated the minimal atrophy subtype with 76.0% accuracy. We suggest that SMI can be largely categorized into 3 anatomical subtypes that have distinct clinical features. Our models may help physicians decide next steps when encountering SMI patients and may also be used in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB–positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment. [Copyright &y& Elsevier]

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]

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]

Previous studies on Alzheimer's disease-type cognitive impairment (ADCI) and subcortical vascular cognitive impairment (SVCI) has rarely explored spatiotemporal heterogeneity. This study aims to identify distinct spatiotemporal cortical atrophy patterns in ADCI and SVCI. 1,338 participants (713 ADCI, 208 SVCI, and 417 cognitively unimpaired elders) underwent brain magnetic resonance imaging (MRI), amyloid positron emission tomography, and neuropsychological tests. Using MRI, this study measures cortical thickness in five brain regions (medial temporal, inferior temporal, posterior medial parietal, lateral parietal, and frontal areas) and utilizes the Subtype and Stage Inference (SuStaIn) model to predict the most probable subtype and stage for each participant. SuStaIn identifies two distinct cortical thinning patterns in ADCI (medial temporal: 65.8%, diffuse: 34.2%) and SVCI (frontotemporal: 47.1%, parietal: 52.9%) patients. The medial temporal subtype of ADCI shows a faster decline in attention, visuospatial, visual memory, and frontal/executive domains than the diffuse subtype (p-value < 0.01). However, there are no significant differences in longitudinal cognitive outcomes between the two subtypes of SVCI. Our study provides valuable insights into the distinct spatiotemporal patterns of cortical thinning in patients with ADCI and SVCI, suggesting the potential for individualized therapeutic and preventive strategies to improve clinical outcomes. Using the SuStaIn model on 1,338 individuals, this study reveals distinct cortical atrophy in Alzheimer's disease-type cognitive impairment and subcortical vascular cognitive impairment, revealing varying cognitive decline trajectories. [ABSTRACT FROM AUTHOR]

Background: Age at onset was suggested as one possible risk factor for motor dysfunction in Alzheimer's disease (AD). Objective: We investigated the association of motor symptoms with cognition or neurodegeneration in patients with AD, and whether this association differs by the age at onset. Methods: We included 113 amyloid positive AD patients and divided them into early-onset AD (EOAD) and late-onset AD (LOAD), who underwent the Unified Parkinson's Disease Rating Scale (UPDRS)-Part III (=UPDRS) scoring, Mini-Mental State Examination (MMSE)/Clinical Deterioration Rating Sum-of-Boxes (CDR-SOB), and magnetic resonance image (MRI). Multiple linear regression was used to evaluate the association of UPDRS and MMSE/CDR-SOB or MRI neurodegeneration measures, and whether the association differs according to the group. Results: The prevalence of motor symptoms and their severity did not differ between the groups. Lower MMSE (β= –1.1, p < 0.001) and higher CDR-SOB (β= 2.0, p < 0.001) were significantly associated with higher UPDRS. There was no interaction effect between MMSE/CDR-SOB and AD group on UPDRS. Global or all regional cortical thickness and putaminal volume were negatively associated with UPDRS score, but the interaction effect of neurodegeneration and AD group on UPDRS score was significant only in parietal lobe (p for interaction = 0.035), which showed EOAD to have a more pronounced association between parietal thinning and motor symptoms. Conclusion: Our study suggested that the severity of motor deterioration in AD is related to the severity of cognitive impairment itself rather than age at onset, and motor symptoms might occur through multiple mechanisms including cortical and subcortical atrophy. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist.Objective: We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET).Methods: Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD.Results: Evans' index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all.Conclusion: Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH. [ABSTRACT FROM AUTHOR]

Background/Aims: The natural history of Alzheimer's disease (AD) has rarely been studied in the Korean population. Our study on survival analyses in Korean AD patients potentially provides a basis for cross-cultural comparisons. Methods: We studied 724 consecutive patients from a memory disorder clinic in a tertiary hospital in Seoul, who were diagnosed as having AD between April 1995 and December 2005. Deaths were identified by the Statistics Korea database. The Kaplan-Meier method was used for survival analysis, and a Cox proportional hazard model was used to assess factors related to patient survival. Results: The overall median survival from the onset of first symptoms and from the time of diagnosis was 12.6 years (95% confidence interval 11.7-13.4) and 9.3 years (95% confidence interval 8.7-9.9), respectively. The age of onset, male gender, history of diabetes mellitus, lower Mini-Mental State Examination score, and higher Clinical Dementia Rating score were negatively associated with survival. There was a reversal of risk of AD between early-onset and later-onset AD, 9.1 years after onset. Conclusions: The results of our study show a different pattern of survival compared to those studies carried out with western AD populations. Mortality risk of early-onset AD varied depending on the duration of follow-up. Copyright © 2013 S. Karger AG, Basel [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]

We developed machine learning (ML) algorithms to predict abnormal tau accumulation among patients with prodromal AD. We recruited 64 patients with prodromal AD using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. Supervised ML approaches based on the random forest (RF) and a gradient boosting machine (GBM) were used. The GBM resulted in an AUC of 0.61 (95% confidence interval [CI] 0.579–0.647) with clinical data (age, sex, years of education) and a higher AUC of 0.817 (95% CI 0.804–0.830) with clinical and neuropsychological data. The highest AUC was 0.86 (95% CI 0.839–0.885) achieved with additional information such as cortical thickness in clinical data and neuropsychological results. Through the analysis of the impact order of the variables in each ML classifier, cortical thickness of the parietal lobe and occipital lobe and neuropsychological tests of memory domain were found to be more important features for each classifier. Our ML algorithms predicting tau burden may provide important information for the recruitment of participants in potential clinical trials of tau targeting therapies. [ABSTRACT FROM AUTHOR]

Background: Amyloid-β (Aβ) evaluation in amnestic mild cognitive impairment (aMCI) patients is important for predicting conversion to Alzheimer's disease. However, Aβ evaluation through Aβ positron emission tomography (PET) is limited due to high cost and safety issues.Objective: We therefore aimed to develop and validate prediction models of Aβ positivity for aMCI using optimal interpretable machine learning (ML) approaches utilizing multimodal markers.Methods: We recruited 529 aMCI patients from multiple centers who underwent Aβ PET. We trained ML algorithms using a training cohort (324 aMCI from Samsung medical center) with two-phase modelling: model 1 included age, gender, education, diabetes, hypertension, apolipoprotein E genotype, and neuropsychological test scores; model 2 included the same variables as model 1 with additional MRI features. We used four-fold cross-validation during the modelling and evaluated the models on an external validation cohort (187 aMCI from the other centers).Results: Model 1 showed good accuracy (area under the receiver operating characteristic curve [AUROC] 0.837) in cross-validation, and fair accuracy (AUROC 0.765) in external validation. Model 2 led to improvement in the prediction performance with good accuracy (AUROC 0.892) in cross validation compared to model 1. Apolipoprotein E genotype, delayed recall task scores, and interaction between cortical thickness in the temporal region and hippocampal volume were the most important predictors of Aβ positivity.Conclusion: Our results suggest that ML models are effective in predicting Aβ positivity at the individual level and could help the biomarker-guided diagnosis of prodromal AD. [ABSTRACT FROM AUTHOR]

Background: Balance impairments are common in patients with Alzheimer's disease (AD) dementia.Objective: We sought to determine the stage along the AD spectrum during which balance impairments appear and identify factors associated with a decline in balance function.Methods: Our cross-sectional study included 295 participants; 71 were cognitively normal (CN), 96 reported subjective cognitive decline (SCD), 72 had amnestic mild cognitive impairment (MCI), and 56 had AD dementia. The balance and mobility function was assessed using the Timed Up and Go test (TUG) and the One-Leg Standing Test (OLST).Results: Participants in the MCI and AD dementia groups were older than those in the cognitively normal and SCD groups. TUG and OLST test scores were linearly correlated with Mini-Mental Status Examination-Korean Version score (MMSE-KC). TUG score increased with greater AD spectrum severity (all p < 0.001), whereas OLST score showed a precipitous impairment starting in the SCD group (all p < 0.001), even after adjusting for age, sex, MMSE-KC, Geriatric depression scale, and body mass index. Based on subgroup analyses, in females and apolipoprotein E (APOE) ɛ4 carriers, there was significant balance/mobility impairment in the SCD group when compared to the CN group.Conclusion: Our results suggest that balance/mobility is related to cognitive function and that balance/mobility impairment can be observed beginning in the SCD stage. Furthermore, CN females and APOEɛ4 carriers had better balance and mobility when compared to females and APOEɛ4 carriers along the ADD spectrum/with cognitive impairment respectively. [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]

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]

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]

Background: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures.Objective: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden.Methods: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer's disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11C] PiB-PET scanning and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition.Results: Total SVD score was associated with the performance of frontal (β - 4.31, SE 2.09, p = 0.040) and visuospatial (β - 0.95, SE 0.44, p = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness.Conclusion: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption. [ABSTRACT FROM AUTHOR]

Recently, we reported that earlier stages of Alzheimer's disease (AD) can be categorized into 3 following anatomical subtypes using a hierarchical cluster analysis of cortical thickness across the entire brain: medial temporal-dominant (MT), parietal-dominant (P), and diffuse atrophy (D). The goal of this study was to investigate the rates of cognitive decline in these anatomical subtypes. Of the patients included in the prior study, 100 AD patients (MT, n = 36; P, n = 20; D, n = 44) who underwent follow-up neuropsychological assessments over a 3-year period were included. A linear mixed model analysis was performed to compare the longitudinal changes in neuropsychological test scores. The P subtype exhibited the most rapid cognitive decline in attention, language, visuospatial, memory, and frontal executive function, whereas MT and D subtypes did not differ in their longitudinal decline. When repeating the analyses with early-onset AD, which is known to progress faster than late-onset AD, only the P subtype showed such rapid progression. The P subtype appears to be a unique subtype of AD characterized by an aggressive rate of progression. [ABSTRACT FROM AUTHOR]

Background We compared the validity of models of subcortical ischemic depression (SID) and depression-executive dysfunction syndrome (DED) in predicting functional disability in the elderly. Methods We obtained data from elderly Korean subjects (n = 1356) aged 60 years or older at baseline from the CREDOS study from November 2005 to July 2014. A generalized estimating equation (GEE) model was constructed to measure functional disability using instrumental activity of daily living as a primary outcome. A risk factor of interest was SID and DED evaluated by a visual rating scale of deep white matter hyperintensity in MRI, Stroop test and Geriatric Depression Scale (GDS) score. Receiver-operating-characteristic plots and area under the curve (AUC) test were applied to examine the difference of the two definitions of vascular depression with predicted values of functional disability outcome. Results The mean (SD) follow-up duration of the participants was 1.7 (0.9) years. The GEE model showed that presence of SID at baseline predicted functional disability compared to non-depressed subjects (GDS score: Odds ratio [OR] 1.76; 95% CI 1.23, 2.53; p = 0.002). The association was also statistically significant among the DED group (OR 1.48; 95% CI 1.15, 1.92; p = 0.003). There were no significant differences in predicting functional disability (95% CI: −0.003 to 0.009, p = 0.366) according to AUC differences between SID and DED. Conclusions The results will be useful in evaluating the cardinal features of the vascular depression hypothesis in predicting functional disability. [ABSTRACT FROM AUTHOR]

Resting-state functional magnetic resonance imaging (RS FMRI) has been widely used to analyze functional alterations in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) patients. Although many clinical studies of aMCI and AD patients using RS FMRI have been undertaken, conducting a meta-analysis has not been easy because of seed selection bias by the investigators. The purpose of our study was to investigate the functional differences in aMCI and AD patients compared with healthy subjects in a meta-analysis. Thus, a multimethod approach using regional homogeneity, amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and global brain connectivity was used to investigate differences between three groups based on previously published data. According to the choice of RS FMRI approach used, the patterns of functional alteration were slightly different. Nevertheless, patients with aMCI and AD displayed consistently decreased functional characteristics with all approaches. All approaches showed that the functional characteristics in the left parahippocampal gyrus were decreased in AD patients compared with healthy subjects. Although some regions were slightly different according to the different RS FMRI approaches, patients with aMCI and AD showed a consistent pattern of decreased functional characteristics with all approaches. [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]

The general population is exposed to numerous environmental pollutants, and it remains unclear which pollutants affect the brain, accelerating brain aging and increasing the risk of dementia. The Environmental-Pollution-Induced Neurological Effects study is a multi-city prospective cohort study aiming to comprehensively investigate the effect of different environmental pollutants on brain structures, neuropsychological function, and the development of dementia in adults. The baseline data of 3,775 healthy elderly people were collected from August 2014 to March 2018. The eligibility criteria were age ≥50 years and no self-reported history of dementia, movement disorders, or stroke. The assessment included demographics and anthropometrics, laboratory test results, and individual levels of exposure to air pollution. A neuroimaging sub-cohort was also recruited with 1,022 participants during the same period, and brain magnetic resonance imaging and neuropsychological tests were conducted. The first follow-up environmental pollutant measurements will start in 2022 and the follow-up for the sub-cohort will be conducted every 3-4 years. We have found that subtle structural changes in the brain may be induced by exposure to airborne pollutants such as particulate matter 10 μm or less in diameter (PM10), particulate matter 2.5 μm or less in diameter (PM2.5) and Mn10, manganese in PM10; Mn2.5, manganese in PM2.5. PM10, PM2.5, and nitrogen dioxide in healthy adults. This study provides a basis for research involving large-scale, long-term neuroimaging assessments in community-based populations. [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]

Abstract: Early-onset Alzheimer''s disease (EOAD) has been shown to progress more rapidly than late-onset Alzheimer''s disease (LOAD). However, no studies have compared the topography of brain volume reduction over time. The purpose of this 3-year longitudinal study was to compare EOAD and LOAD in terms of their rates of decline in cognitive testing and topography of cortical thinning. We prospectively recruited 36 patients with AD (14 EOAD and 22 LOAD) and 14 normal controls. All subjects were assessed with neuropsychological tests and with magnetic resonance imaging at baseline, Year 1, and Year 3. The EOAD group showed more rapid decline than the LOAD group in attention, language, and frontal-executive tests. The EOAD group also showed more rapid cortical thinning in widespread association cortices. In contrast, the LOAD group presented more rapid cortical thinning than the EOAD group only in the left parahippocampal gyrus. Our study suggests that patients with EOAD show more rapid cortical atrophy than patients with LOAD, which accounts for faster cognitive decline on neuropsychological tests. [Copyright &y& Elsevier]