Cognitively Normal Subjects Research Articles

Altered Homotopic Functional Connectivity Within White Matter in the Early Stages of Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with memory loss and cognitive impairment. The white matter (WM) BOLD signal has recently been shown to provide an important role in understanding the intrinsic cerebral activity. Although the altered homotopic functional connectivity within gray matter (GM-HFC) has been examined in AD, the abnormal HFC to WM remains unknown. The present study sought to identify changes in the WM-HFC and anatomic characteristics by combining functional magnetic resonance imaging with diffusion tensor imaging (DTI). Resting-state and DTI magnetic resonance images were collected from the OASIS-3 dataset and consisted of 53 mild cognitive impairment (MCI) patients, 90 very MCI (VMCI), and 100 normal cognitive (NC) subjects. Voxel-mirrored HFC was adopted to examine whether WM-HFC was disrupted in VMCI and MCI participants. Moreover, the DTI technique was used to investigate whether specific alterations of WM-HFC were associated with anatomic characteristics. Support vector machine analyses were used to identify the MCI and VMCI participants using the abnormal WM-HFC as the features. Compared with NC, MCI, and VMCI participants showed significantly decreased GM-HFC in the middle occipital gyrus and inferior parietal gyrus and decreased WM-HFC in the bilateral middle occipital and parietal lobe-WM. In addition, specific WM-functional network alteration for the bilateral sub-lobar-WM was found in MCI subjects. MCI subjects showed abnormal anatomic characteristics for bilateral sub-lobar and parietal lobe-WM. Results of GM-HFC mainly showed common neuroimaging features for VMCI and MCI subjects, whereas analysis of WM-HFC showed specific clinical neuromarkers and effectively compensated for the lack of GM-HFC to distinguish NC, VMCI, and MCI subjects.

Longitudinal assessment of amyloid-beta deposition in initially amyloid-negative non-demented individuals with [11C]-PIB PET imaging.

This study aimed to assess the longitudinal changes in amyloid beta (Aβ) deposition in cortical regions with [11C]-PIB PET in initially amyloid-negative non-demented subjects and evaluate whether amyloid-negative subjects convert to amyloid-positive.Sixteen cognitively normal (CN) and 7 mild cognitive impairment (MCI) subjects (aged 60–75 years), who were amyloid-negative at baseline, underwent 60-minute dynamic [11C]-PIB PET and cognitive assessment over 5.0 to 9.4 years of a long follow-up, and the apolipoprotein-E (APOE) genotype was assessed. Regions of interest were defined in the bilateral cortex on coregistered MRI. Quantitative analysis of [11C]-PIB was performed using the distribution value ratio (DVR). Longitudinal changes in global and regional PIB DVRs were evaluated in the same regions, and the annual rate of change in the PIB DVR was calculated.Seven (30.4%) of 23 initially amyloid-negative non-demented subjects converted to globally amyloid-positive (global PIB DVR ≥1.40) over a follow-up of 6.5 ± 1.4 years (converter). The global PIB DVR in converters increased from 1.22 ± 0.07 at baseline to 1.63 ± 0.15 (n = 7, P < .01) at last follow-up, and an annual increase of global PIB DVR was 0.057 ± 0.019/year (n = 7, P < .01). In contrast, the global PIB DVR in the remaining 16 subjects was 1.15 ± 0.07 at baseline and did not change over a follow-up period (stable). The APOE ε4 allele was present in 4 (57.1%) of the 7 converters, differing from 2 (12.5%) of 16 stable subjects (Fisher's exact test, P < .05). Three amyloid-negative MCI subjects had an annual increase in global PIB DVR above 0.061/year and became positive at 2.8 ± 0.5 years of follow-up, which was faster than 5.0 ± 2.0 years in 4 CN subjects. The regional PIB DVR that increased early above the regional positivity threshold was most frequently found in the right lateral temporal cortex (71.4%), followed by the left frontal cortex (41.8%).Our results suggest that the initially amyloid-negative CN and MCI subjects, especially with APOE ε4, can become globally amyloid-positive over a longer time, based on early regional Aβ deposition in the lateral temporal cortex and/or frontal cortex.

Alterations of core structural network connectome associated with suicidal ideation in major depressive disorder patients

Suicide ideation (SI) is a most high-risk clinical sign for major depressive disorder (MDD). However, whether the rich-club network organization as a core structural network is associated with SI and how the related neural circuits are distributed in MDD patients remain unknown. Total 177 participants including 69 MDD patients with SI (MDDSI), 58 MDD without SI (MDDNSI) and 50 cognitively normal (CN) subjects were recruited and completed neuropsychological tests and diffusion-tensor imaging scan. The rich-club organization was identified and the global and regional topological properties of structural networks, together with the brain connectivity of specific neural circuit architectures, were analyzed. Further, the support vector machine (SVM) learning was applied in classifying MDDSI or MDDNSI from CN subjects. MDDSI and MDDNSI patients both exhibited disrupted rich-club organizations. However, MDDSI patients showed that the differential network was concentrated on the non-core low-level network and significantly destroyed betweeness centrality was primarily located in the regional non-hub regions relative to MDDNSI patients. The differential structural network connections involved the superior longitudinal fasciculus and the corpus callosum were incorporated in the cognitive control circuit and default mode network. Finally, the feeder serves as a potentially powerful indicator for distinguishing MDDSI patients from MDDNSI or CN subjects. The altered rich-club organization provides new clues to understand the underlying pathogenesis of MDD patients, and the feeder was useful as a diagnostic neuroimaging biomarker for differentiating MDD patients with or without SI.

Understanding the role of APOE Gene Polymorphisms in Minimal Atrophy Alzheimer’s Disease by mixture of expert models

Alzheimer’s disease (AD) is a heterogeneous disease. Exploring the characteristics of each AD subtype is the key to disentangling the heterogeneity. Minimal atrophy AD (MAD) is a common AD subtype that yields conflicting results. In order to evaluate this aspect across relatively large heterogeneous AD populations, a total of 192 AD and 228 cognitively normal (CN) subjects were processed by the automated segmentation scheme FreeSurfer, which generates regional cortical thickness measures. A machine learning driven approach, the mixture of expert models, which combines unsupervised modeling of mixtures of distributions with supervised learning of classifiers, was applied to approximates the non-linear boundary between AD and CN subjects with a piece-wise linear boundary. Multiple cortical thicknes patterns of AD were discovered, which includes: bilateral parietal/frontal atrophy AD, left temporal dominant atrophy AD, MAD, and diffuse atrophy AD. MAD had the highest proportions of ApoE4 and ApoE2. Further analysis revealed that ApoE genotype, disease stage and their interactions can partially explain the conflicting observations in MAD.

Prevalence of mild behavioural impairment: a systematic review and meta-analysis.

Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterized by emergent neuropsychiatric symptoms in later life. There has been no systematic review or meta-analysis on the prevalence of MBI. The main aim of the study is to calculate the pooled prevalence of MBI. A search of the literature on MBI in mild cognitive impairment (MCI), cognitively normal (CN), and subjective cognitive impairment (SCI) and CN but at risk (CN-AR) subjects published between 1 January 2003 and 28 September 2020 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the prevalence of MBI. Meta-regression was performed to identify factors contributing to the variance of prevalence rate. A systematic review was also performed to study the impact of MBI in cognitive outcomes and its correlation to the pathology and genetics of Alzheimer's disease. Eleven studies conducted among 15 689 subjects underwent meta-analysis, revealing the pooled prevalence of MBI to be 33.5% (95% confidence interval (CI): 22.6%-46.6%). Seven studies conducted among 1358 MCI subjects underwent meta-analysis, revealing the pooled prevalence to be 45.5% (95%CI: 36.1%-55.3%). Four studies conducted among 13 153 CN subjects underwent meta-analysis, revealing the pooled prevalence to be 17.0% (95%CI: 7.2%-34.9%). Five studies conducted among 1158 SCI or CN-AR subjects underwent meta-analysis, revealing the pooled prevalence to be 35.8% (95%CI: 21.4%-53.2%). A systematic review of 13 studies showed that MBI has a significant impact on cognitive deterioration and is associated with the pathology and genetics of Alzheimer's disease. In MCI, CN, and SCI and CN-AR subjects, MBI is common. Our finding is potentially useful in planning future clinical trials.

Regional microstructural alteration of the corpus callosum in preclinical Alzheimer’s disease

AbstractBackgroundWhile previous studies consistently reported regional microstructural changes of the cerebral white matter (WM) in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), little information is available for such changes in the preclinical stage of AD. We first aimed to investigate regional microstructural alteration of the WM in cognitively normal (CN) older adults with amyloid‐beta (Aβ) deposition. We also tried to develop a prediction model for Aβ positivity in CN using information on WM microstructural alteration and clinical variables that can be easily obtained in memory clinics.MethodSeventy‐five CN older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent comprehensive clinical and neuropsychological assessment, T1 MRI, diffusion tensor imaging (DTI), and [11C]PiB‐PET. All CN subjects were divided into Aβ positive (CN+) and negative (CN‐) based on the level of cerebral Aβ retention on [11C]PiB‐PET. Multivariate stepwise logistic regression analyses were conducted to develop Aβ positivity prediction models.ResultWhen compared to CN‐, CN+ showed high mean diffusivity (MD) value of the genu of the corpus callosum (CC_genu) (F(1,73) = 6.357, p = 0.014, Figure 1). The area under the curve (AUC) of the receiver operating characteristics curve for the Aβ positivity prediction model only using MD of the CC_genu was 0.653 [confidence interval (CI) = 0.511‐0.794]. Model with MD of the CC_genu, age, and word list recall and constructional recall test scores were finally selected. The AUC of the final model was 0.851 [CI = 0.765‐0.937] (Figure 2).ConclusionThe findings indicate that microstructural alteration of the CC_genu occurs even in the stage of preclinical AD. When taken together with episodic memory scores commonly available in clinical practice, information about such regional WM microstructural alteration can be used to screen preclinical AD.

Effect of decreased visual acuity on cortical thickness: A possible risk factor for neurodegeneration

AbstractBackgroundCortical thickness is a biomarker for neurodegeneration. Ample evidence supports the idea that decreased sensory stimuli lead to degeneration of relevant central areas in the brain. We hypothesized that decreased visual stimuli might be associated with cortical atrophy in visual processing areas. Therefore, we investigated the association between visual acuity (VA) and cortical thickness in cognitive normal adults.MethodWe retrospectively analyzed the health screening data from the Health Promotion Center at the Samsung Medical Center from 2008 to 2014. In total, 2,810 cognitive normal subjects who checked corrected VA and Brain MRI were identified. The subjects were divided into 3 groups according to the VA of better eye: Group 1 (VA The higher VA value indicates better VA. Using multivariate regression analysis, cortical thickness of Group 1 and 2 were compared with Group 3. We also analyzed linear association between VA and cortical thickness. The analyses were performed after controlling for age, sex, hypertension, diabetes, hyperlipidemia, and intracranial volume.ResultCompared to Group 3, Group 1 showed cortical thinning in the bilateral occipital, lateral temporal, and lateral parietal areas. Compared to Group 3, Group 2 also showed cortical thinning in the bilateral occipital, right lateral temporal, and bilateral lateral parietal areas. Linear association analysis showed that the lower VA was associated with cortical thinning in the bilateral occipital areas.ConclusionOur results showed that cognitive normal individuals with lower VA have cortical thinning in the posterior part of the brain which is responsible for visual processing. This suggest that good VA may have preventive effect for neurodegeneration.

Acute phase markers in CSF reveal inflammatory changes in Alzheimer’s disease that are impacted by APOE ε4, sex and age but not pathology

AbstractBackgroundNeuroinflammation may accelerate Alzheimer’s disease (AD) progression. We profiled acute phase response (APR) proteins (stimulated by IL‐6 released from pro‐inflammatory glia) in CSF of people along the clinical and pathology (CSF t‐tau/Aβ42) spectrum of AD to investigate the association between disease outcomes and inflammatory changes.MethodsAPR proteins in CSF from 920 subjects in the Swedish BioFINDER study were quantitively analyzed using multiple reaction modelling mass spectrometry: α1‐antitrypsin, α1‐antichymotrypsin, ceruloplasmin, complement C3, α‐fibrinogen, β‐fibrinogen, γ‐fibrinogen, haptoglobin, and hemopexin. Ferritin was measured using multiplex ELISA. CSF t‐tau and Aβ42 was measured using Euroimmun ELISA and the cohort was dichotomized for AD pathology using the t‐tau/Aβ42 ratio. Subjects were also stratified by the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. N per group was: CN t‐tau/Aβ42‐ve=335; CN t‐tau/Aβ42+ve=104; SCD t‐tau/Aβ42‐ve=105; CN t‐tau/Aβ42+ve=44; MCI t‐tau/Aβ42‐ve=78; MCI t‐tau/Aβ42+ve=133; AD t‐tau/Aβ42+ve=121.ResultsIn separate multiple regressions (adjusting for diagnosis, age, sex, APOE‐ε4), CSF t‐tau/Aβ42 status did not affect APR protein levels in CN and SCD subjects (Figure 1). Rather, the APR elevated with symptomatic progression: MCI t‐tau/Aβ42+ve subjects had 4/10 proteins elevated compared to CN tau/Aβ42‐ve subjects (α1 antichymotrypsin, ferritin, α‐fibrinogen, β‐fibrinogen; 0.001&lt;P&lt;0.027), and all 10 proteins were elevated in AD (1.6x10‐8&lt;P&lt;0.017). Surprisingly, the APR was more robustly activated in people with cognitive changes but with low t‐tau/Aβ42 levels (7/10 and 5/10 proteins elevated in SCD and MCI respectively). APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in females and with increased age. The performance of the APR in predicting clinical diagnosis was greater in females, in younger subjects, and those without APOE ε4 (Figure 2).ConclusionsThe APR in CSF reveals inflammatory changes that occur with clinical and not pathological dimensions of AD. The APR has a complex interaction with clinical variables: the extent of the APR is affected by sex and age, not APOE ε4, yet the APR has more influence in non‐ε4 carriers, younger people and females (Figure 3). These data provide new insight into neuroinflammation in AD and how this varies according to demographics.

Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer\u2019s disease

Deficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

Utility of Plasma Neurofilament Light in the 1Florida Alzheimer's Disease Research Center (ADRC).

Background:Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established.Objective:In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance.Methods:309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer’s disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline.Results:pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline.Conclusion:pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

The Brain Chart of Aging: Machine-learning analytics reveals links between brain aging, white matter disease, amyloid burden, and cognition in the iSTAGING consortium of 10,216 harmonized MR scans.

Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aβ) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. A Brain Chart quantifying brain-aging trajectories was established, enabling the systematic evaluation of individuals' brain-aging patterns relative to this large consortium.

Acute phase markers in CSF reveal inflammatory changes in Alzheimer's disease that intersect with pathology, APOE ε4, sex and age.

It is unknown how neuroinflammation may feature in the etiology of Alzheimer's disease (AD). We profiled acute phase response (APR) proteins (α1-antitrypsin, α1-antichymotrypsin, ceruloplasmin, complement C3, ferritin, α-fibrinogen, β-fibrinogen, γ-fibrinogen, haptoglobin, hemopexin) in CSF of 1291 subjects along the clinical and biomarker spectrum of AD to investigate the association between inflammatory changes, disease outcomes, and demographic variables. Subjects were stratified by Aβ42/t-tau as well as the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. In separate multiple regressions (adjusting for diagnosis, age, sex, APOE-ε4) of each APR protein and a composite of all APR proteins, CSF Aβ42/t-tau status was associated with elevated ferritin, but not any other APR protein in CN and SCD subjects. Rather, the APR was elevated along with symptomatic progression (CN < SCD < MCI < AD), and this was elevation was mediated by CSF p-tau181. APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in males and with increased age. The performance of the APR in predicting clinical diagnosis was influenced by APOE ε4 status, sex, and age. These data provide new insight into inflammatory changes in AD and how this intersects with pathology changes and patient demographics.

Sex-Specific Association of Lifetime Body Mass Index with Alzheimer's Disease Neuroimaging Biomarkers.

Background:Although recent studies indicate that the relationship between body mass index (BMI) and Alzheimer’s disease (AD) may differ by both sex and age of BMI measurement, little information is available on sex- or age-specific associations between BMI and AD neuropathologies.Objective:To examined whether sex-specific BMIs measured at different life-stages (in early adulthood, midlife, and late life) were associated with cerebral amyloid-β (Aβ) deposition and AD-signature region cortical thickness (AD-CT) in cognitively normal (CN) older adults.Methods:A total of 212 CN subjects aged 60–90 years (females 108, males 104), who participated in the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE), an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessments, [11C] Pittsburgh Compound B positron emission tomography, and brain magnetic resonance imaging. BMIs at different life stages were calculated. Multiple regression analyses were performed separately for either sex.Results:In males, lower early adulthood or midlife BMI was associated with greater cerebral Aβ deposition, but late life BMI was not. Lower midlife BMI was associated with reduced AD-CT, but the BMI in early adulthood and late life was not. In females, no significant association was observed between any lifetime BMI and Aβ deposition or AD-CT.Conclusion:Our results support a male-specific association between BMI prior to late life, and in vivo AD pathologies. Avoiding underweight status early in life may be important to prevent AD dementia in males, but not females.

Diagnostic potential of urinary monocyte chemoattractant protein-1 for Alzheimer's disease and amnestic mild cognitive impairment.

The chemokine monocyte chemoattractant protein-1 (MCP-1) is involved in the pathogenesis of Alzheimer's disease (AD). This study aimed to investigate whether urinary MCP-1 can distinguish patients with AD, patients with amnestic mild cognitive impairment (aMCI) and cognitively normal (CN) subjects. A total of 754 participants, including 97 patients with AD, 50 patients with aMCI and 84 age- and sex-matched CN controls as well as a cohort of 523 CN subjects of different ages, were enrolled from five hospitals located in different areas of China. Urinary MCP-1 levels were determined using enzyme-linked immunosorbent assays. The correlations between urinary MCP-1 levels and cognition test scores or age were analysed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis. In the cohort of CN subjects of different ages, urinary MCP-1 levels increased with ageing and were correlated with age. The urinary MCP-1 levels were higher in females than in males. In the cohort composed of patients with AD, aMCI and age- and sex-matched CN controls, urinary MCP-1 levels were significantly higher in patients with AD and aMCI than in CN controls. There were no differences in urine MCP-1 levels between the AD group and the aMCI group. The urinary MCP-1 levels were correlated with the Mini-Mental State Examination scores and age, and were able to differentiate patients with AD and aMCI from CN subjects. Urinary MCP-1 is a potential biomarker for the diagnosis of AD and aMCI.

Abstract WP487: Retinal Vessel Tortuosity Correlates With White Matter Hyperintensities and Cerebral Microbleeds in Subjects With Cognitive Decline

Objective: Retinal microvasculature analysis is suitable to study cognitive disorders given retinal and brain vessels share similar properties. Using novel automated technologies, we aimed to investigate whether automatically-quantified retinal vascular changes from retinal fundus photographs predict brain imaging abnormalities in patients with cognitive impairment; and what specific retinal vascular parameters are more predictive of dementia. Methods: In this cross-sectional study, 34 subjects with cognitive complaints underwent neuropsychometric cognitive testing, retinal fundus photography and brain MRI. Retinal vessel tortuosity index (VTI), inflection index (VII) and length (VL) were automatically computed. The number and volume of cerebral microbleeds (CMB) and white matter hyperintensities (WMHI) were measured using SPIN Software (SpinTech, Bingham Farms, MI). The diagnostic groups were compared for demographic, cognitive, retinal and brain imaging parameters using analysis of variance. The association between brain (intracranial volume (ICV), hippocampal volume (HV), lateral ventricle volume (LVV), WMHI and CMB (volume, number), Fazekas scores) and retinal vascular parameters were assessed by using multiple linear regression models. Results: Nine subjects were cognitively normal (CN) and 25 cognitively impaired (CI) (22 with mild cognitive impairment and 3 with dementia). VTI was the only retinal parameter and HV and LVV were the brain parameters that were significantly different between CN and CI subjects (p=0.02). VTI correlated with VL (p=0.02, r=0.33) and branching angle (p=0.004, r=-0.45). The cognitive domains predicted by VTI were abstraction and orientation. VTI correlated with total intracranial volume (p=0.04, r=-0.12). A significant association was demonstrated for VII and WMHI volume (p=0.03, r=0.007), but not Fazekas score. VII and VTI significantly correlated with CMB volume (p=0.04 and 0.03, respectively). Conclusion: Automatically-detected retinal vessel tortuosity indexes predict neuroimaging markers of microvascular disease and total intracranial volume in cognitively impaired individuals. Retinal imaging may be used to screen patients with cognitive disorders.

Discrepancy of subjective and objective sleep problems in Alzheimer’s disease and mild cognitive impairment detected by a home-based sleep analysis

There is a strong relationship between Alzheimer’s disease (AD) and sleep problems, and a sleep condition is informative for evaluating the AD status. In the present study, we evaluated subjective sleep problems in AD and mild cognitive impairment (MCI) with self-check questionnaires and objective sleep problems with a convenient home-based portable device, WatchPAT. A total of 63 subjects with normal cognition (NC) (n = 22), MCI (n = 20), and AD (n = 21) were cross-sectionally investigated. AD patients showed a better self-check Pittsburgh sleep quality index (PSQI) score (*p < 0.05) than NC and MCI patients. On the other hand, WatchPAT analysis showed a significantly reduced rapid eye movement (REM) sleep (*p < 0.05) and increased light sleep in AD patients (*p < 0.05) compared with NC subjects, and mildly reduced REM and increased light sleep in MCI subjects. The present study revealed a gap between the subjective self-check sleep questions and the objective WatchPAT analysis in AD patients. Thus, a home-based sleep study with WatchPAT is a useful tool to detect an objective sleep problem in AD and the risk of MCI conversion into AD.

Spatially Distributed Amyloid-β Reduces Glucose Metabolism in Mild Cognitive Impairment.

Background:Several positron emission tomography (PET) studies have explored the relationship between amyloid-β (Aβ), glucose metabolism, and the APOE ɛ4 genotype. It has been reported that APOE ɛ4, and not aggregated Aβ, contributes to glucose hypometabolism in pre-clinical stages of Alzheimer’s disease (AD) pathology.Objective:We hypothesize that typical measurements of Aβ taken either from composite regions-of-interest with relatively high burden actually cover significant patterns of the relationship with glucose metabolism. In contrast, spatially weighted measures of Aβ are more related to glucose metabolism in cognitively normal (CN) aging and mild cognitive impairment (MCI).Methods:We have generated a score of amyloid burden based on a joint singular value decomposition (SVD) of the cross-correlation structure between glucose metabolism, as measured by [18F]2-fluoro-2-deoxyglucose (FDG) PET, and Aβ, as measured by [18F]florbetapir PET, from the Alzheimer’s Disease Neuroimaging Initiative study. This SVD-based score reveals cortical regions where a reduced glucose metabolism is maximally correlated with distributed patterns of Aβ.Results:From an older population of CN and MCI subjects, we found that the SVD-based Aβ score was significantly correlated with glucose metabolism in several cortical regions. Additionally, the corresponding Aβ network has hubs that contribute to distributed glucose hypometabolism, which, in turn, are not necessarily foci of Aβ deposition.Conclusions:Our approach uncovered hidden patterns of the glucose metabolism-Aβ relationship. We showed that the SVD-based Aβ score produces a stronger relationship with decreasing glucose metabolism than either APOE ɛ4 genotype or global measures of Aβ burden.

Uncinate fasciculus disruption relates to poor recognition of negative facial emotions in Alzheimer's disease: a cross-sectional diffusion tensor imaging study.

Recognising facial emotions involves visual and emotional information processing. Patients with dementia, including dementia of Alzheimer's type (DAT), are known to poorly recognise facial emotions, especially negative facial emotions. In this study, we aimed to assess if DAT patients exhibit poor facial emotional recognition, and to identify a neural basis for how poor facial emotional recognition might occur. Magnetic resonance imaging and diffusion tensor imaging (DTI) analysis were conducted in 20 DAT patients and 15 cognitive normal (CN) subjects. The uncinate fasciculus (UF), inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus were delineated by deterministic tractography. DTI parameters were calculated for each fibre. Facial emotion recognition was evaluated with the Facial Emotion Selection Test (FEST). The relationships between FEST scores and DTI parameters in each fibre were measured by partial correlation analyses with age, gender, and the Mini-Mental State Examination as covariates. Group-wise comparisons between DAT and CN subjects were performed for each DTI parameter in each fibre. DAT patients showed lower FEST negative emotion scores than CN subjects (P < 0.05). The score of negative emotion subscale was negatively correlated (r = -0.770, P < 0.001) to mean diffusivity of the left UF in DAT patients. There were no relationships between negative emotion subscale and the other fibre tracts. DAT patients showed no differences in the DTI parameters for each fibre compared to CN subjects. DAT-related prefrontal-limbic network dysfunction is associated with poor recognition of unpleasant emotions; consequently, worse facial recognition of negative emotion is observed in DAT patients.

Sleep dysregulation, memory impairment, and CSF biomarkers during different levels of neurocognitive functioning in Alzheimer\u2019s disease course

BackgroundAlzheimer's disease (AD) is frequently accompanied by sleep impairment, which can induce AD-related neurodegeneration. We herein investigated the sleep architecture, cognition, and cerebrospinal fluid (CSF) biomarkers (tau proteins and β-amyloid42) during AD progression from subjective cognitive impairment (SCI) to mild cognitive impairment (MCI) and eventually to AD dementia, and compared the results with cognitively normal (CN) subjects.MethodsWe included patients affected by SCI, MCI, mild AD, and moderate-to-severe AD in our study along with CN subjects as controls. All the subjects underwent nocturnal polysomnography to investigate sleep, neuropsychological testing to evaluate cognition, and lumbar puncture for CSF AD biomarkers assessment.ResultsSleep (both rapid eye movement (REM) and non-REM sleep) and memory function are both progressively impaired during the course of AD from SCI to mild and subsequently to moderate AD. Further, sleep dysregulation appears earlier than cognitive deterioration, with a reduction of CSF β-amyloid42 level.ConclusionSleep, memory, and CSF AD biomarkers are closely interrelated in AD progression from the earliest asymptomatic and preclinical stages of the disease related in AD since the earliest and preclinical stages of the disease.

Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer’s disease

Recently, cerebrospinal fluid (CSF) YKL-40 levels were reported to be a promising candidate biomarker of glial inflammation in Alzheimer’s disease (AD). To detect how APOE ε4 affects CSF YKL-40 levels in cognitively normal (CN) states, mild cognitive impairment (MCI) and AD dementia, data from 35 CN subjects, 63 patients with MCI, and 11 patients with AD from a cross-sectional study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were investigated. The results showed that CSF YKL-40 concentrations were increased in the AD dementia group than in the CN group. CSF YKL-40 levels were higher in APOE ε4 carriers than in noncarriers with MCI. No statistically significant difference was found in CSF YKL-40 levels between APOE ε4 carrier and noncarriers in AD and CN subjects. CSF YKL-40 concentrations were tightly related to CSF tau and p-tau concentrations in the MCI group. Analysis implied that APOE ε4 might affect CSF YKL-40 levels in MCI subjects, suggesting a crucial role of APOE ε4 in neuroinflammation in detecting individuals who might convert to AD from MCI and, thus, as an effective predictive factor.