Accurate Automated Quantification of Dopamine Transporter PET Without MRI Using Deep Learning-based Spatial Normalization.

Purpose: Dopamine transporter imaging is crucial for assessing presynaptic dopaminergic neurons in Parkinson's disease (PD) and related parkinsonian disorders. While 18F-FP-CIT PET offers advantages in spatial resolution and sensitivity over 123I-ß-CIT or 123I-FP-CIT SPECT imaging, accurate quantification remains essential. This study presents a novel automatic quantification method for 18F-FP-CIT PET images, utilizing an artificial intelligence (AI)-based robust PET spatial normalization (SN) technology that eliminates the need for anatomical images. Methods: The proposed SN engine consists of convolutional neural networks, trained using 213 paired datasets of 18F-FP-CIT PET and 3D structural MRI. Remarkably, only PET images are required as input during inference. A cyclic training strategy enables backward deformation from template to individual space. An additional 89 paired 18F-FP-CIT PET and 3D MRI datasets were used to evaluate the accuracy of striatal activity quantification. MRI-based PET quantification using FIRST software was also conducted for comparison. The proposed method was also validated using 135 external datasets. Results: The proposed AI-based method successfully generated spatially normalized 18F-FP-CIT PET images, obviating the need for CT or MRI. The striatal PET activity determined by proposed PET-only method and MRI-based PET quantification using FIRST algorithm were highly correlated, with R 2 and slope ranging 0.96-0.99 and 0.98-1.02 in both internal and external datasets. Conclusion: Our AI-based SN method enables accurate automatic quantification of striatal activity in 18F-FP-CIT brain PET images without MRI support. This approach holds promise for evaluating presynaptic dopaminergic function in PD and related parkinsonian disorders.

Comparative study on structural and functional brain differences in mild cognitive impairment patients with tinnitus.

Objective: Tinnitus may be associated with various brain changes. However, the degenerative changes in patients with tinnitus have not been extensively investigated. We aimed to evaluate degenerative, structural, and functional brain changes in patients with mild cognitive impairment (MCI) who also suffer from tinnitus. Materials and methods: This study included participants aged 60 to 80 years with MCI and a hearing level better than 40 dB. The participants were classified into two groups: MCI with tinnitus (MCI-T) and MCI without tinnitus (MCI-NT). All patients underwent Tinnitus Handicap Inventory (THI), 3 T brain MRI, F18-florapronol PET, and F18-FDG PET. Results: The MCI-T group exhibited higher ß-amyloid deposition in the superior temporal gyrus, temporal pole, and middle temporal gyrus compared to the MCI-NT group (p < 0.05 for all). Additionally, the MCI-T group showed increased metabolism in the inferior frontal gyrus, insula, and anterior cingulate cortex (ACC) (p < 0.005 for all). The THI score was strongly correlated with increased volume in the insula, ACC, superior frontal gyrus, supplementary motor area, white matter near the hippocampus, and precentral gyrus (p < 0.05 for all). Moreover, the MCI-T group demonstrated higher metabolic activity in the default mode network (DMN) and lower activity in the executive control network (ECN) (p < 0.05 for all). In the MCI-T group, the posterior DMN was positively correlated with the visual network and negatively with the ECN, whereas in the MCI-NT group, it correlated positively with the ECN. Conclusion: The MCI-T group exhibited greater ß-amyloid accumulation in the auditory cortex and more extensive changes across various brain networks compared with the MCI-NT group, potentially leading to diverse clinical symptoms such as dementia with semantic deficits or depression. Tinnitus in MCI patients may serve as a biomarker for degenerative changes in the temporal lobe and alterations in brain network dynamics.

Moderation of Amyloid-ß Deposition on the Effect of Cholinesterase Inhibitors on Cognition in Mild Cognitive Impairment.

Background: Clinical trial findings on cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) are inconclusive, offering limited support for their MCI treatment. Given that nearly half of amnestic MCI cases lack cerebral amyloid-ß (Aß) deposition, a hallmark of Alzheimer's disease; this Aß heterogeneity may explain inconsistent results. Objective: This study aimed to assess whether Aß deposition moderates ChEI effects on amnestic MCI cognition. Methods: We examined 118 individuals with amnestic MCI (ages 55-90) in a longitudinal cohort study. Baseline and 2-year follow-up assessments included clinical evaluations, neuropsychological testing, and multimodal neuroimaging. Generalized linear models were primarily analyzed to test amyloid positivity's moderation of ChEI effects on cognitive change over 2 years. Cognitive outcomes included Mini-Mental Status Examination score, the total score of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, and Clinical Dementia Rating-sum of boxes. Results: The analysis found no significant ChEI use x amyloid positivity interaction for all cognitive outcomes. ChEI use, irrespective of Aß status, was associated with more cognitive decline over the 2-year period. Conclusions: Aß pathology does not appear to moderate ChEI effects on cognitive decline in MCI.

Moderation of thyroid hormones for the relationship between amyloid and tau pathology.

BACKGROUND: Altered thyroid hormone levels have been associated with increased risk of Alzheimer's disease (AD) dementia and related cognitive decline. However, the neuropathological substrates underlying the link between thyroid hormones and AD dementia are not yet fully understood. We first investigated the association between serum thyroid hormone levels and in vivo AD pathologies including both beta-amyloid (Aß) and tau deposition measured by positron emission tomography (PET). Given the well-known relationship between Aß and tau pathology in AD, we additionally examined the moderating effects of thyroid hormone levels on the association between Aß and tau deposition. METHODS: This cross-sectional study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. This study included a total of 291 cognitively normal adults aged 55 to 90. All participants received comprehensive clinical assessments, measurements for serum total triiodothyronine (T3), free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH), and brain imaging evaluations including [11C]-Pittsburgh compound B (PiB)- PET and [18F] AV-1451 PET. RESULTS: No associations were found between either thyroid hormones or TSH and Aß and tau deposition on PET. However, fT4 (p = 0.002) and fT3 (p = 0.001) exhibited significant interactions with Aß on tau deposition: The sensitivity analyses conducted after the removal of an outlier showed that the interaction effect between fT4 and Aß deposition was not significant, whereas the interaction between fT3 and Aß deposition remained significant. However, further subgroup analyses demonstrated a more pronounced positive relationship between Aß and tau in both the higher fT4 and fT3 groups compared to the lower group, irrespective of outlier removal. Meanwhile, neither T3 nor TSH had any interaction with Aß on tau deposition. CONCLUSION: Our findings suggest that serum thyroid hormones may moderate the relationship between cerebral Aß and tau pathology. Higher levels of serum thyroid hormones could potentially accelerate the Aß-dependent tau deposition in the brain. Further replication studies in independent samples are needed to verify the current results.

Plasma Leptin and Alzheimer Protein Pathologies Among Older Adults.

Importance: Many epidemiologic studies have suggested that low levels of plasma leptin, a major adipokine, are associated with increased risk of Alzheimer disease (AD) dementia and cognitive decline. Nevertheless, the mechanistic pathway linking plasma leptin and AD-related cognitive decline is not yet fully understood. Objective: To examine the association of plasma leptin levels with in vivo AD pathologies, including amyloid-beta (Aß) and tau deposition, through both cross-sectional and longitudinal approaches among cognitively unimpaired older adults. Design, Setting, and Participants: This was a longitudinal cohort study from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer Disease. Data were collected from January 1, 2014, to December 31, 2020, and data were analyzed from July 11 to September 6, 2022. The study included a total of 208 cognitively unimpaired participants who underwent baseline positron emission tomography (PET) scans for brain Aß deposition. For longitudinal analyses, 192 participants who completed both baseline and 2-year follow-up PET scans for brain Aß deposition were included. Exposure: Plasma leptin levels as assessed by enzyme-linked immunosorbent assay. Main Outcomes and Measures: Baseline levels and longitudinal changes of global Aß and AD-signature region tau deposition measured by PET scans. Results: Among the 208 participants, the mean (SD) age was 66.0 (11.3) years, 114 were women (54.8%), and 37 were apolipoprotein E ε4 carriers (17.8%). Lower plasma leptin levels had a significant cross-sectional association with greater brain Aß deposition (ß = -0.04; 95% CI, -0.09 to 0.00; P = .046), while there was no significant association between plasma leptin levels and tau deposition (ß = -0.02; 95% CI, -0.05 to 0.02; P = .41). In contrast, longitudinal analyses revealed that there was a significant association between lower baseline leptin levels and greater increase of tau deposition over 2 years (ß = -0.06; 95% CI, -0.11 to -0.01; P = .03), whereas plasma leptin levels did not have a significant association with longitudinal change of Aß deposition (ß = 0.006; 95% CI, 0.00-0.02; P = .27). Conclusions and Relevance: The present findings suggest that plasma leptin may be protective for the development or progression of AD pathology, including both Aß and tau deposition.

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities.

BACKGROUND: Growing evidence suggests that not only cerebrovascular disease but also Alzheimer's disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aß) and tau deposition, and WMHs through longitudinal approach. METHODS: Total 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aß deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aß or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aß or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aß or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies. RESULTS: Baseline Aß deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aß or tau deposition for 2 years. We also found a significant interaction effect between baseline Aß deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aß deposition was associated with increase of WMH volume over 2 years in female, but not in male. CONCLUSIONS: Our findings suggest that Aß deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aß increase. The results also did not support any direction of influence between tau deposition and WMHs.

Constipation is linked to accelerated cognitive and motor decline in isolated REM sleep behavior disorder.

INTRODUCTION: Constipation is associated with higher clinical severity and predicts cognitive decline in Parkinson's disease (PD). Whether the non-motor marker is associated with unfavorable motor and cognitive trajectories from the prodromal stage remains unclear. METHODS: In a longitudinal prospective cohort of subjects with isolated REM sleep behavior disorders (iRBD), subjects underwent repeated MDS-UPDRS and Mini-Mental Status Examination (MMSE) assessments. Generalized-estimating-equations (GEE) regression model was used to compare the time-dependent trajectories of MDS-UPDRS-III and MMSE scores between subjects with and without constipation at baseline. RESULTS: Twenty-nine subjects with constipation at baseline (iRBD+constipation) and 24 without (iRBD-constipation) were followed over 4.085 ± 2.645 years. The iRBD+constipation group presented faster decline of both MDS-UPDRS-III and MMSE scores, with additional estimated annual progression of +1.242 and -0.713 points, respectively, compared to the iRBD-constipation group (time*group p < 0.05). CONCLUSION: Constipation in isolated RBD is associated with accelerated progression of cognitive impairment and motor symptoms.

White matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer's disease continuum.

BACKGROUND: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. METHODS: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥ 55 years, including 276 cognitively normal older adults (CN), 142 with mild cognitive impairment (MCI), and 87 AD patients, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. RESULTS: Compared to CN, AD and MCI subjects showed significantly higher RD, MD, and AxD values (all p-values < 0.001) and significantly lower FA values (left p ≤ 0.002, right p ≤ 0.015) after Bonferroni adjustment for multiple comparisons. Most tests of cognition and mood (p < 0.001) as well as higher medial temporal amyloid burden (p < 0.001) were associated with poorer WM integrity in the CBH after Bonferroni adjustment. CONCLUSION: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.

Monoaminergic Degeneration and Ocular Motor Abnormalities in De Novo Parkinson's Disease.

BACKGROUND: Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. OBJECTIVE: The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. METHODS: Drug-naive PD patients who underwent N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography scans and video-oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. RESULTS: One-hundred twenty-four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS-UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey-Complex-Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin-predominant region, but did not correlate with parkinsonism severity scores. CONCLUSION: Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society.

Application of Static Headspace GC-MS Method for Selective 1,4-Dioxane Detection in Food Additives.

Efficient detection methods must be developed for 1,4-dioxane due to its suspected status as a human carcinogen, which is highly mobile in food and environmental resources. In this regard, this experiment has been conducted to develop reliable and selective detection and measurement methods by using static headspace (SH) isolation, followed by gas chromatography-mass spectrometry (GC-MS). A new method was developed for determining the spiked 1,4-dioxane contents in a polyethylene glycol 600 (PEG 600). The optimal condition for SH-GC-MS was discussed. The representative ions of 1,4-dioxane and 1,4-dioxane-d8 in the SIM mode of MS are 88 and 96, respectively, and the peaks of the SIM mode were separated and confirmed. The linear range for the method covers 0.25 to 100 mg/L with a coefficient of determination (R2) ≥ 0.999. The method applicability was demonstrated by spike recovery across a variety of food additives (i.e., chlorine bitartrate, choline chloride, polysorbate 20 and 60, and PEG 1000). All spike recovery from the tested samples was in the range of 89.50-102.68% with a precision of 0.44-11.22%. These findings suggest a new analytical method for food safety inspection, and could be applicable for ensuring the safety of foods and environmental and public health on a broad scale.

Brain olfactory-related atrophy in isolated rapid eye movement sleep behavior disorder.

OBJECTIVE: To investigate structural and functional connectivity changes in brain olfactory-related structures in a longitudinal prospective cohort of isolated REM sleep behavior disorder (iRBD) and their clinical correlations, longitudinal evolution, and predictive values for phenoconversion to overt synucleinopathies, especially Lewy body diseases. METHODS: The cohort included polysomnography-confirmed iRBD patients and controls. Participants underwent baseline assessments including olfactory tests, neuropsychological evaluations, the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, 3T brain MRI, and 18 F-FP-CIT PET scans. Voxel-based morphometry (VBM) was performed to identify regions of atrophy in iRBD, and volumes of relevant olfactory-related regions of interest (ROI) were estimated. Subgroups of patients underwent repeated volumetric MRI and resting-state functional MRI (fMRI) scans after four years. RESULTS: A total of 51 iRBD patients were included, with 20 of them converting to synucleinopathy (mean time to conversion 3.08 years). Baseline VBM analysis revealed atrophy in the right olfactory cortex and gyrus rectus in iRBD. Subsequent ROI comparisons with controls showed atrophy in the amygdala. These olfactory-related atrophies tended to be associated with worse depression, anxiety, and urinary problems in iRBD. Amygdala 18 F-FP-CIT uptake tended to be reduced in iRBD patients with hyposmia (nonsignificant after multiple comparison correction) and correlated with urinary problems. Resting-state fMRI of 23 patients and 32 controls revealed multiple clusters with aberrant olfactory-related functional connectivity. Hypoconnectivity between the putamen and olfactory cortex was associated with mild parkinsonian signs in iRBD. Longitudinal analysis of volumetric volumetric MRI in 22 iRBD patients demonstrated four-year progression of olfactory-related atrophy. Cox regression analysis revealed that this atrophy significantly predicted phenoconversion. INTERPRETATION: Progressive atrophy of central olfactory structures may be a potential indicator of Lewy body disease progression in iRBD.

Body mass index and two-year change of in vivo Alzheimer's disease pathologies in cognitively normal older adults.

BACKGROUND: Low body mass index (BMI) or underweight status in late life is associated with an increased risk of dementia or Alzheimer's disease (AD). However, the relationship between late-life BMI and prospective longitudinal changes of in-vivo AD pathology has not been investigated. METHODS: This prospective longitudinal study was conducted as part of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE). A total of 194 cognitive normal older adults were included in the analysis. BMI at baseline was measured, and two-year changes in brain Aß and tau deposition on PET imaging were used as the main outcomes. Linear mixed-effects (LME) models were used to examine the relationships between late-life BMI and longitudinal change in AD neuropathological biomarkers. RESULTS: A lower BMI at baseline was significantly associated with a greater increase in tau deposition in AD-signature region over 2 years (ß, -0.018; 95% CI, -0.028 to -0.004; p = .008), In contrast, BMI was not related to two-year changes in global Aß deposition (ß, 0.0002; 95% CI, -0.003 to 0.002, p = .671). An additional exploratory analysis for each sex showed lower baseline BMI was associated with greater increases in tau deposition in males (ß, -0.027; 95% CI, -0.046 to -0.009; p = 0.007), but not in females. DISCUSSION: The findings suggest that lower BMI in late-life may predict or contribute to the progression of tau pathology over the subsequent years in cognitively unimpaired older adults.

Erratum: A Comparison Between the Performances of Verbal and Nonverbal Fluency Tests in Discriminating Between Mild Cognitive Impairments and Alzheimer's Disease Patients and Their Brain Morphological Correlates.

[This corrects the article on p. 17 in vol. 21, PMID: 35154337.].

Serum Adiponectin and In Vivo Brain Amyloid Deposition in Cognitively Normal Older Adults: A Cohort Study.

High blood adiponectin has been associated with Alzheimer's disease (AD) dementia and related cognitive decline. We aimed to investigate the association between serum adiponectin level and in vivo AD pathologies. Cross-sectional and longitudinal study designs for the data of the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease, an ongoing prospective cohort study that began in 2014. A total of 283 cognitively normal older adults between 55 and 90 years of age were included in community and memory clinic setting. Participants underwent comprehensive clinical assessments, measurement of serum adiponectin level, and multimodal brain imaging, including Pittsburgh compound-B positron emission tomography (PET), AV-1451 PET, fluorodeoxyglucose (FDG)-PET, and MRI at baseline and 2-year follow-up. Serum adiponectin level was positively associated with global beta-amyloid protein (Aß) retention and change therein over 2 years, but not with other AD neuroimaging markers including tau deposition, AD-related neurodegeneration, and white matter hyperintensities. Blood adiponectin level is associated with increased brain amyloid deposition, which suggests that adiponectin may be a potential target for therapeutic and preventive strategies against AD.

Longitudinal evolution of cortical thickness signature reflecting Lewy body dementia in isolated REM sleep behavior disorder: a prospective cohort study.

BACKGROUND: The isolated rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal condition of Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB). We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD. METHODS: We enrolled 22 DLB patients, 44 healthy controls, and 50 video polysomnography-proven iRBD patients. Participants underwent 3-T magnetic resonance imaging (MRI) and clinical/neuropsychological evaluations. We characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls. We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients. With repeated MRI data during the follow-up in our prospective iRBD cohort, we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia. Finally, we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort. RESULTS: The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction (Trail Making Test-A and B: R = - 0.55, P = 0.024 and R = - 0.56, P = 0.036, respectively) as well as visuospatial impairment (Rey-figure copy test: R = - 0.54, P = 0.0047). The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters (Pearson's correlation, R = 0.74, P = 6.8 × 10-4) but no significant change in parkinsonism-first phenoconverters (R = 0.0063, P = 0.98). The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33 [1.16-74.12]. The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2% accuracy. CONCLUSION: Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population. Replication studies would further validate the utility of this imaging marker in iRBD.

Validation of the REM behaviour disorder phenoconversion-related pattern in an independent cohort.

BACKGROUND: A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. METHODS: Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. RESULTS: The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18-15.39). CONCLUSIONS: The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

White matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer's disease continuum.

BACKGROUND: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. METHODS: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥55 years, including 276 cognitively normal older adults (CN), 142 mild cognitive impairment (MCI), and 87 AD, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. RESULTS: Compared to CN, AD and MCI subjects showed decreased WM integrity in the bilateral CBH. Cognition, mood, and higher amyloid burden were also associated with poorer WM integrity in the CBH. CONCLUSION: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.

Sex differences in the progression of glucose metabolism dysfunction in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD.

Low Ankle-Brachial Index Relates to Alzheimer-Signature Cerebral Glucose Metabolism in Cognitively Impaired Older Adults.

BACKGROUND: Ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with Alzheimer's disease (AD) dementia and related cognitive impairment. Nevertheless, only limited information is available regarding its contribution to brain alterations leading to cognitive decline in late-life. OBJECTIVE: We aimed to investigate the relationship of ABI with in vivo AD pathologies and cerebrovascular injury in cognitively impaired older adults. METHODS: Total 127 cognitively impaired (70 mild cognitive impairment and 57 AD dementia) individuals, who participated in an ongoing prospective cohort study, were included. All participants underwent comprehensive clinical and neuropsychological assessment, ABI measurement, apolipoprotein E (APOE) ɛ4 genotyping, and multi-modal brain imaging including [11C] Pittsburgh Compound B (PiB)-positron emission tomography (PET) and [18F] fludeoxyglucose (FDG)-PET, and MRI. RESULTS: General linear model analysis showed significant relationship between ABI strata (low ABI: <1.00, normal ABI: 1.00-1.29, and high ABI: ≥1.30) and AD-signature region cerebral glucose metabolism (AD-CM), even after controlling age, sex, clinical dementia rating-sum of box, and APOE ɛ4 positivity (p = 0.029). Post hoc comparison revealed that low ABI had significantly lower AD-CM than middle and high ABI, while no difference of AD-CM was found between middle and high ABI. There was no significant difference of global Aß deposition, AD-signature region cortical thickness, and white matter hyperintensity volume between the three ABI strata. CONCLUSION: Our findings suggest that lower ABI, likely related to atherosclerosis, may contribute to the aggravation of AD-related regional neurodegeneration in cognitively impaired older adults.

Grey matter volume loss in Parkinson's disease psychosis and its relationship with serotonergic gene expression: A meta-analysis.

BACKGROUND: Neuroanatomical alterations underlying psychosis in Parkinson's Disease (PDP) remain unclear. We carried out a meta-analysis of MRI studies investigating the neural correlates of PDP and examined its relation with dopaminergic and serotonergic receptor gene expression. METHODS: PubMed, Web of Science and Embase were searched for MRI studies (k studies = 10) of PDP compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images and multiple linear regression analyses was used to examine the relationship between pooled estimates of grey matter volume (GMV) loss in PDP and D1/D2 and 5-HT1a/5-HT2a receptor gene expression estimates from Allen Human Brain Atlas. RESULTS: We observed lower grey matter volume in parietal-temporo-occipital regions (PDP n = 211, PDnP, n = 298). GMV loss in PDP was associated with local expression of 5-HT1a (b = 0.109, p = 0.012) and 5-HT2a receptors (b= -0.106, p = 0.002) but not dopaminergic receptors. CONCLUSION: Widespread GMV loss in the parieto-temporo-occipital regions may underlie PDP. Association between grey matter volume and local expression of serotonergic receptor genes may suggest a role for serotonergic receptors in PDP.