AD Group Research Articles

Decline in cognitive trajectories in the neuropathological spectrum of Lewy Body disease

AbstractBackgroundPathological Lewy body disease (LBD) may commonly present clinically as Parkinson’s disease dementia (PDD), Dementia with Lewy bodies (DLB) or Alzheimer’s disease dementia (ADD). Neuropathological definitions also include a group in which ADD is present, but the postmortem Lewy pathology does not meet threshold density and distribution levels for the neuropathological diagnosis of DLB (ADLB). Little is known about the cognitive profiles of patients with ADLB and despite common underlying pathology, studies delineating neuropsychological profiles in LBD are fraught with inconsistencies. We characterized the longitudinal cognitive trajectories defined by neuropsychological profiles in cases along the pathological spectrum of LBD.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a cognitive diagnosis of dementia at death and who at minimum, had two neuropsychological evaluations were included. Final neuropathological diagnosis was determined as LBD (neocortical or limbic LB ± AD), ADLB, and AD pathology only. LBD cases were categorized by their cognitive clinical syndromes as PDD and DLB. Global cognition was evaluated using MMSE. Neuropsychological domains of Memory, Executive function, language, attention, and visuospatial were evaluated. Mixed linear methods were used to predict longitudinal change for a given baseline MMSE.Result287 participants and 1874 participant‐years of data were included in this study. LBD (n = 115), and ADLB (52) groups were predominantly male, while AD (n = 114) group was primarily female. Baseline MMSE was similar across all pathologic groups. Linear mixed modelling methods showed faster decrease in memory domain scores (decreasing 0.22 units/year – 0.42 units/year faster, p = 0.01) in ADLB group compared to other groups. Significantly faster decline was noted in LBD and ADLB group in clock drawing (p<0.001), fluency scores (declining 1.02 unit/year faster p<0.001) compared to AD group. There was no difference between PDD and DLB clinical subgroups.ConclusionIn autopsy confirmed cases, ADLB had an accelerated trajectory of decline in memory tasks, while AD, and LBD appeared to have similar trajectories. In contrast, all groups with Lewy bodies progressed faster and showed accelerated decline compared to AD in measures of frontal‐subcortical functions. These results may inform antemortem classification of patients and diagnostic accuracy in these groups.

Using subject‐specific disease progression as an estimation of the disease time to model longitudinal neurodegeneration in AD

AbstractBackgroundWhen patients with clinically probable‐AD get their diagnosis, it is difficult to determine exactly when the disease started. Moreover, not all subjects progress in the same manner and rate. However, clinical measurements such as cognitive scores can help give an estimation of where in the disease trajectory each patient stands. To address the issue of estimating the time of disease onset, we investigated a new technique that leverages cognitive test scores to estimate a latent timeline that models the subject‐specific disease progression.MethodWe used the work of Kühnel et al. (2021) to model the progression of AD using cognitive scores (ADAS13 and MMSE). This method aligns patients along a continuous latent timeline based on their predicted disease progression. Data included the MRI scans of 677 amyloid‐positive subjects from ADNI. Scan resolution was increased to 0.5mm isotropic voxel‐size by super‐sampling (Manjón et al. 2010) before non‐linear registration to an ADNI‐based unbiased template. The resulting deformation fields were used to compute the Jacobian determinant map for each subject and find mean atrophy for different ROIs. we were then able to plot the changes in different regions of the brain across the estimated disease progression timeline and compare slopes for the two methods.ResultAssuming a zero time‐shift for normal subjects, the average time‐shift for the eMCI, lMCI, and AD group was 36.8, 87.5, and 128.8 months respectively. Using the latent time‐shift variable to offset the individual baseline scans, we were able to plot the changes in different regions of the brain across the disease timeline. The results for Hippocampus are shown in figure 1, comparing the estimated timeline to the age as the time‐related axes. We saw much sharper slopes (‐0.01 vol/estimated_time vs ‐0.0025 vol/age) when using the individualized time offset.ConclusionCalendar time is perhaps not a good measure for disease progression. The new method offers an estimation of a latent timeline that models the subject‐specific disease progression and may better model the longitudinal changes in different brain regions, and in turn, would enable us to better compare the magnitude and speed of degeneration across brain regions.

Changes of the texture and volume of brain MRI in Suspected Non Alzheimer Pathology and Alzheimer’s disease

AbstractBackgroundSuspected Non Alzheimer Pathology (SNAP) is a biomarker‐defined syndrome that encompasses a group of individuals with neurodegeneration, but no evidence of amyloid deposition. However, it is still unclear whether SNAP represents distinct pathology separate from AD. We examined the differences in the volume and texture of key regions of interest (ROIs) in brain MRI between SNAP and AD to discuss the different causes of neurodegeneration.MethodWe enrolled all participants from dementia clinics of Seoul National University Bundang Hospital. We obtained three‐dimensional structural T1‐weighted magnetic resonance images of the participants using 3.0 Tesla Achieva Scanner and compared the texture and volume of ROIs between the groups using analysis of variance with Bonferroni post hoc comparisons.ResultThe SNAP group showed comparable volumes to the AD group in all ROIs. Compared with regional volume, regional texture showed different features between SNAP and AD. The SNAP group showed different texture in precuneus, posterior cingulate cortex, superior parietal cortex and inferior parietal cortex. In these regions, the entropy which reflects the randomness of spatial distribution of gray levels was higher in the AD group compared to the SNAP group.ConclusionThis study demonstrated that the texture change of SNAP was different from that of AD despite a similar volume change. In conclusion, our study suggests that MRI texture can be used for detection of microstructural changes in the early stage of the disease.

A CenTauR scale based on 18F‐MK6240

AbstractBackgroundA standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.Method375 18F‐MK6240 PET & T1w scan pairs (HC Aß‐ = 179/MCI Aß+ = 98/AD Aß+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aß‐ (<10CL) and AD Aß+ (>25CL) individuals younger than 75y, with MMSE = 20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aß‐ and 29 AD Aß+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.ResultThe mean and standard deviation (std) for the HC and AD groups are reported in Table 1. Using a single transformation resulted in the following equation: Ct = 100x(SUVR‐0.97)/2.26 Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.ConclusionThe region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.

A CenTauR scale based on 18F‐MK6240

AbstractBackgroundA standardized scale for the quantification of tau PET imaging would allow comparison and combination of data across tracers and sites resulting in large meta‐analysis and the application of universal cut‐offs. The proposed approach called CenTauR (CTR) was evaluated on 18F‐MK6240 using both global and regional anchoring.Method375 18F‐MK6240 PET & T1w scan pairs (HC Aβ‐ = 179/MCI Aβ+ = 98/AD Aβ+ = 98) from AIBL&ADNeT were spatially normalised using SPM8 and SUVR normalised using the cerebellar cortex. PET scans were then quantified in 4 composite ROIs [Mesial‐Temporal (Me), Meta‐Temporal (MT), Temporo‐Parietal (TP) and Frontal (FT)] from a previously defined “universal” cortical mask. To anchor the 0 and 100 CTR, we only included HC Aβ‐ (<10CL) and AD Aβ+ (>25CL) individuals younger than 75y, with MMSE ≥20, we also excluded HC participants with a quantification higher than the 75%tile in the Me and AD patients with a quantification lower than the 25%tile in the MT, resulting in 68 HC Aβ‐ and 29 AD Aβ+. We investigated two CTR scaling approaches using either a single transform based on the TP anchors to transform SUVR into CTR for all composites or using region‐based equations scaled with regional anchors.ResultThe mean and standard deviation (std) for the HC and AD groups are reported in Table 1.Using a single transformation resulted in the following equation:Ct = 100x(SUVR‐0.97)/2.26Region‐based equations can be extrapolated from Table 1. Figures 1 and 2 show that regional CTR overstretches quantification in FT compared to single equation‐derived CTR. Thresholds set at 2 std above the HC were 2.38, 9.43, 7.66, 1.82, and 6.16 CTR for Me, MT, TP, FT and Global respectively, and were 7.05, 7.48, 7.66, 10.20, 7.68 CTR when using regional equation‐derived CTR.ConclusionThe region‐based approach provided slightly more consistent CTR distributions in the HC across the ROIs however, this approach tends to over‐stretch the CTR values in the frontal region.

Neuroinflammatory biomarkers in neurodegenerative disease: Insights from the ONDRI Cohort

AbstractBackgroundNeuroinflammation (NI) has been implicated in both the pathogenesis of and neuroprotection against neurodegenerative diseases (NDs)(Psenicka et al., 2021). Plasma glial fibrillary acidic protein (GFAP), and Neurofilament light (NFL) are measures of astrogliosis and neurodegeneration, respectively. Amyloid beta (Aβ)42/40 ratio (Aβ42 concentration to total Aβ concentration) below 0.068 is associated with AD pathology (Baldeiras et al., 2018). Neuroimaging‐based inflammatory biomarkers have been proposed, including free‐water diffusion (FWD)(Pasternak et al., 2009). Here we investigated FWD as a candidate biomarker for NI in AD compared to non‐AD dementia using Aβ42/40 ratio in a subset of data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).MethodFWD maps were generated in 370 subjects (126 non‐AD and 244 AD). MRI processing included ICVmapp3r for brain extraction and bias field correction, Synb0, Topup and Eddy for dMRI preprocessing and MATLAB for freewater mapping. Plasma Aβ42, Aβ40, GFAP and NFL were measured using the Simoa Human Neurology 4‐Plex E assay, and cognition was estimated using the Montreal Cognitive Assessment (MoCA). Linear regression was used to estimate the ability for FWD in the left (LcGM) and right (RcGM) cortical grey matter to predict GFAP, NFL and MoCA score in AD and nonAD based on Aβ42/40 threshold of 0.068.ResultFWD correlated with GFAP (LcGM; R = 0.4, p = 0.0013 and RcGM; R = 0.37, p = 0.0069), and MoCA total score (LcGM; R = ‐0.29, p = 0.001 and RcGM; R = ‐0.27, p = 0.001), but not with NFL across the whole group. This relationship was largely driven by the AD group wherein FWD predicted GFAP (LcGM: R = 0.12, p = 0.02, RcGM approaching significance R = 0.1, p = 0.06), and MoCA Total score (LcGM: R = ‐0.33, p<0.0001), RcGM: R = ‐0.25, p<0.0001). The nonAD group did not show this relationship. FWD did not predict NFL in the AD and nonAD group.ConclusionIn patients with Aβ42/40<0.068, suggestive of AD, FWD in cGM was more strongly related to GFAP than NFL, and predicted cognition, a pattern that was not observed in nonAD patients. Our results suggest distinct patterns of NI in AD compared with nonAD that can be detected with FWD and with a multi‐modal approach could further understanding of differences in pathophysiology across NDs.

18F]MK6240 and [18F]PI2620 autoradiography on postmortem human brain tissue in AD

AbstractBackgroundTo compare the post mortem uptake of [18F]MK6240 and [18F]PI2620 in the brain hemisphere, of A‐T‐ (CN) and A+T+ tissueMethodAutoradiography (ARG) imaging using [18F]MK6240 and [18F]PI2620 was used to assess uptake of CN and AD tissues. One study used sections of whole‐hemisphere of one CN tissue and one AD tissue. The uptake value of [18F]MK6240 was calculated from a regions of interest (ROI) drawn manually from the area of cortex gray matter (GM), cortex white matter (WM), and background (BG).Other study was 24 tissues from the prefrontal cortex (Pfc) (12CN, 12AD), hippocampus (Hip) (12 CN, 12 AD) and cerebellum (Cer) (12 CN, 12 AD) were evaluated with [18F]MK6240, and [18F]PI2620. The uptake value of [18F]MK6240 and [18F]PI2620 was calculated from ROI drawn manually from the area of pfc GM, hip GM and cer GM.ResultThe ARG showed greater [18F]MK6240 uptake in AD than in CN tissue. There were significant differences between CN and AD tissue in terms of cortex gray GM distribution and cortex WM, but no significant differences in BG. These results also, there is no correlation between the specific activity of [18F]MK6240 and the uptake value in CN and AD tissues. In a second experiment, based on our findings there was a significant difference between CN and AD groups when assessed by [18F]MK6240 as well as [18F]PI2620 in the pfc_GM and hip_GM. Furthermore, we found no difference between AD and CN tissues when assessed by [18F]MK6240 and [18F]PI2620 in cerebellum GM. Ratio values Pfc/Cer and Hip/Cer assessed by [18F]MK6240 as well as there were significant differences between CN and AD. [18F]MK6240 and [18F]PI2620 were highly correlated in AD but not in CN brain tissues.ConclusionWe also found that [18F]PI2620 and [18F]MK6240 have similar brain uptake in post‐mortem tissue.

Neuroinflammatory biomarkers in neurodegenerative disease: Insights from the ONDRI Cohort

AbstractBackgroundNeuroinflammation (NI) has been implicated in both the pathogenesis of and neuroprotection against neurodegenerative diseases (NDs)(Psenicka et al., 2021). Plasma glial fibrillary acidic protein (GFAP), and Neurofilament light (NFL) are measures of astrogliosis and neurodegeneration, respectively. Amyloid beta (Aß)42/40 ratio (Aß42 concentration to total Aß concentration) below 0.068 is associated with AD pathology (Baldeiras et al., 2018). Neuroimaging‐based inflammatory biomarkers have been proposed, including free‐water diffusion (FWD)(Pasternak et al., 2009). Here we investigated FWD as a candidate biomarker for NI in AD compared to non‐AD dementia using Aß42/40 ratio in a subset of data from the Ontario Neurodegenerative Disease Research Initiative (ONDRI).MethodFWD maps were generated in 370 subjects (126 non‐AD and 244 AD). MRI processing included ICVmapp3r for brain extraction and bias field correction, Synb0, Topup and Eddy for dMRI preprocessing and MATLAB for freewater mapping. Plasma Aß42, Aß40, GFAP and NFL were measured using the Simoa Human Neurology 4‐Plex E assay, and cognition was estimated using the Montreal Cognitive Assessment (MoCA). Linear regression was used to estimate the ability for FWD in the left (LcGM) and right (RcGM) cortical grey matter to predict GFAP, NFL and MoCA score in AD and nonAD based on Aß42/40 threshold of 0.068.ResultFWD correlated with GFAP (LcGM; R = 0.4, p = 0.0013 and RcGM; R = 0.37, p = 0.0069), and MoCA total score (LcGM; R = ‐0.29, p = 0.001 and RcGM; R = ‐0.27, p = 0.001), but not with NFL across the whole group. This relationship was largely driven by the AD group wherein FWD predicted GFAP (LcGM: R = 0.12, p = 0.02, RcGM approaching significance R = 0.1, p = 0.06), and MoCA Total score (LcGM: R = ‐0.33, p<0.0001), RcGM: R = ‐0.25, p<0.0001). The nonAD group did not show this relationship. FWD did not predict NFL in the AD and nonAD group.ConclusionIn patients with Aß42/40<0.068, suggestive of AD, FWD in cGM was more strongly related to GFAP than NFL, and predicted cognition, a pattern that was not observed in nonAD patients. Our results suggest distinct patterns of NI in AD compared with nonAD that can be detected with FWD and with a multi‐modal approach could further understanding of differences in pathophysiology across NDs.

Developing Topics.

Both 11C-Pittsburgh compound-B (PiB) and 18F-Flutemetamol (FMT) have off-target white matter (WM) signal that increases with age, but WM uptake is stronger with FMT than PiB. Although their WM patterns are comparably associated with age, the difference between them may impact visual and quantitative assessments of cortical amyloid-β uptake. Our objective was to determine whether PiB PET and FMT PET visual assessments agree with quantitative cortical amyloid-β evaluations. A cohort of cognitively unimpaired (CU) younger adults with median (range) of 39 (30, 48) years (N = 30), CU older adults with age of 67 (61, 83) years (N = 30) and older adults with AD dementia with age of 67 (54-84) years (N = 23) underwent MRI, PiB PET and FMT PET. PiB-PET and FMT PET scans were evaluated visually by two nuclear medicine specialists blinded to participant information. Disagreements were reconciled with a second, joint round of visual reads. Readers applied standard visual assessment criteria using the absence of regional gray matter (GM) and WM contrast as an indication of a positive scan. The global cortical PiB standard uptake value ratio (SUVr) was obtained referencing to cerebellar crus uptake and converted to centiloid values. Participants were classified as PiB positive/negative using a centiloid cut-off of 22. PiB and FMT visual positivity agreed with quantitative positivity on PiB-based centiloid values in 69/83 for PiB and 78/83 for FMT. There were 10 disagreements with PiB, 1 disagreement with FMT and 4 disagreements with both. Few disagreements occurred near the centiloid threshold. Interestingly, all disagreements between visual reads (amyloid-β positive) and centiloid (amyloid-β negative) in the CU younger were with PiB. FMT disagreements were always in the CU older and AD groups. Disagreements between amyloid-β positivity on visual reads and quantitative measurements (centiloid) may depend on age and tracer. PiB WM uptake is lower than FMT WM uptake, which may lead to reduced contrast between GM and WM (part of the standard criteria for visual reads), especially in younger ages. In contrast, WM uptake increases at older ages, and increased WM signal may bleed more into cortical regions, hiding subtle, near-threshold cortical uptake, especially with FMT.

Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

AbstractBackgroundThe medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.MethodOur pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.ResultThe full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.ConclusionSkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration. [1] Xie et al., Human Brain Mapping, 2020.

Discrimination early Alzheimer’s disease from mild cognitive impairment by using Easy Z‐score Imaging System for ECD SPECT

AbstractBackgroundProdromal AD progresses to dementia at a higher annual rate. Since cholinesterase inhibitor benefits early AD patients, discrimination between MCI due to AD and non‐MCI due to AD remains important.MethodWe conducted a retrospective study of MCI cases at National Cheng Kung University Hospital (NCKUH) from 2017 to 2019. Those who showed hypometabolism at posterior cingulate cortex, precuneus, or posterior parietal cortex on brain ECD SPECT and EZIS severity greater than 1.19 were categorized as MCI due to AD; in contrast, patients with EZIS severity lesser than 1.19 were categorized as non‐MCI due to AD. Clinical outcomes included deterioration of CASI, MMSE, SB scores and conversion from MCI to dementia.ResultThere was positive correlation between EZIS severity and deterioration of CASI, MMSE, SB according to multiple regression results, indicating EZIS severity could predict cognitive progression in three years follow‐up. There was no difference in dementia conversion rate between two groups either by chi‐square method or Kaplan‐Meier method, and EZIS severity was not a significant variable in binary logistic regression analysis for conversion. However, there was a trend toward greater dementia conversion rate in the EZIS‐favored MCI due to AD group, and in the second half period of follow‐up as seen on Kaplan‐Meier curves.ConclusionDuring three years of follow‐up, MCI patients with greater EZIS severity were significantly associated with worse cognitive assessment scores, and there was a trend toward greater dementia conversion rate based on cutoff value 1.19 of EZIS severity.

Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

AbstractBackgroundThe medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.MethodsOur pipeline, SkelDBM, combines skeletonization and deformation‐based morphometry to generate maps of annualized rate of atrophy on the skeleton of an MTL template (Figure 1). SkelDBM samples subjects’ atrophy maps along the skeleton of an MTL template, increasing robustness to subject‐to‐template registration errors. We evaluate SkelDBM using a subset of ADNI data studied in [1] (Table 1). Two preclinical AD groups (A+CU and tau‐positive A+CU) are compared to a control group (A‐CU) using general linear models (GLM) with age as nuisance covariate; permutation testing is used to derive statistically significant clusters.ResultsThe full A+CU vs A‐CU comparison shows significant differences in rates of change in right anterior hippocampus, right entorhinal cortex, right transentorhinal cortex, and left posterior hippocampus (Figure 2). Limiting the A+CU group to tau‐positive individuals yields more widespread differences, including most of the right anterior MTL cortex and both hippocampi. These patterns align with volumetric longitudinal data reported in [1] but provide a richer characterization of spatial atrophy patterns.ConclusionSkelDBM is sensitive to longitudinal atrophy occurring over relatively short periods (∼2 years) in preclinical AD and characterizes patterns of atrophy more comprehensively than summary volumetric measures. Summary measures are also subject to biases, since larger structures are typically associated with less measurement error and hence may show exaggerated statistical effects compared to smaller structures even when the underlying neurodegeneration rates are the same. Regional maps of longitudinal change may be more robust to this bias and may help discovery of “signature regions” associated with specific pathological drivers of neurodegeneration.[1] Xie et al., Human Brain Mapping, 2020.

Alzheimer’s disease and Parkinson’s disease dementia: Practical tips for physicians

Dementia is a progressive disorder that weakens the intellectual abilities and causes the cognitive, behavioral, and functional decline in occupational and social areas. This research is targeted to extract a profile for the dementia diagnostic and clinical characteristics by evaluating the near-term effects of Alzheimer’s disease (AD) and Parkinson’s disease dementia (PD-D). A total of 240 individuals, including 60 AD patients, 60 PD-D patients, and 120 healthy controls, were included in the study. Data of individuals treated in a local dementia outpatient clinic between 2013 and 2023 were obtained from the clinic database. AD and PD-D diagnoses were made based on the revised National Institute on Aging and Alzheimer’s Association (NIA-AA) criteria and movement disorder society (MDS) clinical diagnostic criteria, respectively. Functional, clinical, and neuropsychological evaluations of the patients were made by the same neurologist. Dementia staging and daily living activities were determined and categorized. In the patient group, functionality and instrumental activities of daily living (ADLs) scores were significantly worse than those of the control group, but there was no difference between the AD and PD-D groups. Calculation, verbal fluency, word list, early learning, and clock drawing test scores were lower in the AD group than in the PD-D group. Apathy, disinhibition, elution, irritability, abnormal motor movements, sleep, and appetite scores were significantly higher in the patient group than in the control group. While depression parameters were not significantly different between all the groups, hallucinations and anxiety parameters were significantly higher in the PD-D group than in the AD group. As an important predictor of independent living and the burden of disease, functional impairment is an important issue in patients with AD compared to those with PD-D. This study also highlights the neuropsychiatric perception disorder in terms of functional loss in AD and significant anxiety disorder for PD-D accompanied by early functional losses.

Gauge-Invariant Lagrangian Formulations for Mixed-Symmetry Higher-Spin Bosonic Fields in AdS Spaces

We deduce a non-linear commutator higher-spin (HS) symmetry algebra which encodes unitary irreducible representations of the AdS group—subject to a Young tableaux Y(s1,…,sk) with k≥2 rows—in a d-dimensional anti-de Sitter space. Auxiliary representations for a deformed non-linear HS symmetry algebra in terms of a generalized Verma module, as applied to additively convert a subsystem of second-class constraints in the HS symmetry algebra into one with first-class constraints, are found explicitly in the case of a k=2 Young tableaux. An oscillator realization over the Heisenberg algebra for the Verma module is constructed. The results generalize the method of constructing auxiliary representations for the symplectic sp(2k) algebra used for mixed-symmetry HS fields in flat spaces [Buchbinder, I.L.; et al. Nucl. Phys. B 2012, 862, 270–326]. Polynomial deformations of the su(1,1) algebra related to the Bethe ansatz are studied as a byproduct. A nilpotent BRST operator for a non-linear HS symmetry algebra of the converted constraints for Y(s1,s2) is found, with non-vanishing terms (resolving the Jacobi identities) of the third order in powers of ghost coordinates. A gauge-invariant unconstrained reducible Lagrangian formulation for a free bosonic HS field of generalized spin (s1,s2) is deduced. Following the results of [Buchbinder, I.L.; et al. Phys. Lett. B 2021, 820, 136470.; Buchbinder, I.L.; et al. arXiv 2022, arXiv:2212.07097], we develop a BRST approach to constructing general off-shell local cubic interaction vertices for irreducible massive higher-spin fields (being candidates for massive particles in the Dark Matter problem). A new reducible gauge-invariant Lagrangian formulation for an antisymmetric massive tensor field of spin (1,1) is obtained.

Segal's contractions, AdS and conformal groups

Segal's contractions, AdS and conformal groups

Clinical analysis of acute postoperative pain after total laparoscopic hysterectomy for adenomyosis and uterine fibroids – a prospective observational study

Objective To investigate the outcome of total laparoscopic hysterectomy (TLH) and postoperative pain characteristics and compare the pain severity after TLH for adenomyosis or uterine fibroids. Methods This prospective observational study collected 101 patients received TLH for adenomyosis (AD group) including 41 patients were injected goserelin (3.6 mg) 28 days before TLH, while other adenomyosis patients received TLH without preoperative treatment, and 113 patients received TLH for uterine fibroids (UF group). Pain scores were evaluated at different time sites from operation day to postoperative 72 h using the numeric rating scale. Clinical data were collected from clinical record. Results Operative time and anaesthetic time were longer in the AD group than those in the UF group (66.88 ± 8.65 vs. 64.46 ± 7.21, p = 0.04; 83.95 ± 10.05 vs. 79.77 ± 6.88, p < 0.01), severe endometriosis was quite more common in AD group (23.76% vs. 2.65%, p < 0.01). Postoperative usage of Flurbiprofen in AD group were more than that of UF group (15.48 ± 38.00 vs. 4.79 ± 18.16, p = 0.02). Total pains and abdominal visceral pains of AD group were more severe compared with UF group in motion and rest pattern at several time sites, while incision pain and shoulder pain were similar. The total postoperative pains after goserelin preoperative treatment in AD group were less than that without goserelin preoperative treatment (p < 0.05). The levels of serum NPY, PGE2 and NGF after laparoscopic hysterectomy of adenomyosis reduced with GnRH agonist pretreatment. Conclusions Acute postoperative pain for adenomyosis and uterine fibroids showed considerably different severity, postoperative total pain and abdominal visceral pains of TLH for adenomyosis were more severe compared with uterine fibroids. While patients received goserelin before laparoscopic hysterectomy of adenomyosis suffered from less severity of postoperative total pain than that without goserelin preoperative treatment.

Biomarker Screening by LCMS and Liquid Chip Technology in Acute Aortic Dissection

BACKGROUNDAortic dissection (AD) is a serious disease. Previous study, the use of peripheral blood biomarkers to diagnose AD showed strong clinical feasibility, but the possible molecular mechanism is unclear. METHODSSera from 79 healthy subjects (HC), 73 patients with well-established AD, and 74 patients with well-established acute myocardial infarction (AMI) were investigated by LC-MS to detect metabolites (AFMK, Glycerophosphocholine, Inosine, SPH). The cell factor expression in the three group were detected by Liquid Chip Technology. RESULTSThe serum content trends of 4 metabolic indexes in patients with AMI and AD group were used as the diagnostic models, and the effective diagnosis rate was 97.8%. The diagnosis rate is 89.8% in distinguishing patients with AMI from patients with AD. The expression in serum of the three groups showed that there were significant differences in the expression of 23 cytokines. By correlation analysis, it was found that miP-1, IL-7, MIP-1β, EGF and other cytokines were significantly correlated with the four metabolic molecules. CONCLUSIONSAFMK, Glycerophosphocholine, Inosine, Sphingfungin B (SPH) metabolites are potential biomarkers for AD, and the influence of related metabolic process may be related to the expression of miP-1, IL-7, MIP-1β, EGF and other cytokines.

Identification of novel diagnostic panel for mild cognitive impairment and Alzheimer’s disease: findings based on urine proteomics and machine learning

BackgroundAlzheimer’s disease is a prevalent disease with a heavy global burden. Proteomics is the systematic study of proteins and peptides to provide comprehensive descriptions. Aiming to obtain a more accurate and convenient clinical diagnosis, researchers are working for better biomarkers. Urine is more convenient which could reflect the change of disease at an earlier stage. Thus, we conducted a cross-sectional study to investigate novel diagnostic panels.MethodsWe firstly enrolled participants from China-Japan Friendship Hospital from April 2022 to November 2022, collected urine samples, and conducted an LC–MS/MS analysis. In parallel, clinical data were collected, and clinical examinations were performed. After statistical and bioinformatics analyses, significant risk factors and differential urinary proteins were determined. We attempt to investigate diagnostic panels based on machine learning including LASSO and SVM.ResultsFifty-seven AD patients, 43 MCI patients, and 62 CN subjects were enrolled. A total of 3366 proteins were identified, and 608 urine proteins were finally included in the analysis. There were 33 significantly differential proteins between the AD and CN groups and 15 significantly differential proteins between the MCI and CN groups. AD diagnostic panel included DDC, CTSC, EHD4, GSTA3, SLC44A4, GNS, GSTA1, ANXA4, PLD3, CTSH, HP, RPS3, CPVL, age, and APOE ε4 with an AUC of 0.9989 in the training test and 0.8824 in the test set while MCI diagnostic panel included TUBB, SUCLG2, PROCR, TCP1, ACE, FLOT2, EHD4, PROZ, C9, SERPINA3, age, and APOE ε4 with an AUC of 0.9985 in the training test and 0.8143 in the test set. Besides, diagnostic proteins were weakly correlated with cognitive functions.ConclusionsIn conclusion, the procedure is convenient, non-invasive, and useful for diagnosis, which could assist physicians in differentiating AD and MCI from CN.

5 Cross-cultural Diagnostic Validity of the Multilingual Naming Test (MINT) in a Sample of Older Adults.

Objective:The current study aimed to evaluate the psychometric properties and diagnostic accuracy of the 32-item version of the Multilingual Naming Test (MINT) in a sample of English and Spanish monolinguals and bilingual older adults from two ethnic groups (EA; European Americans and HA; Hispanic American) with typical and atypical aging. An IRT model was used to identify 24 MINT Items assessed across ethnicity and language testing groups (Spanish and English). We analyzed the discriminant and predictive validity of the 32-item and 24-item scales across diagnostic groups (cognitively normal [CN], mild cognitive impairment [MCI], and dementia [AD]). Diagnostic accuracy was then assessed with both versions applying ROC (Receiver Operating Characteristics) curve reporting using AUC (Area Under the Curve). We expected the MINT to distinguish between the CN and AD groups but not between CN and MCI and the MCI and AD. We conducted IRT analyses to evaluate the cross-language validity of the items from the 32-item MINT in English and Spanish through Rasch Analysis across our two ethnic groups. Finally, we tested the association between MINT scores and MRI volumetric measures of language-related areas in both cerebral hemispheres’ temporal and frontal lobes.Participants and Methods:The sample comprised 281 participants (178 females) enrolled in the 1Florida Alzheimer’s Disease Research Center (ADRC), with 175 participants self-identified as HA (51 tested in English and 124 in Spanish) and 106 EA, all of them monolingual English speakers. The participants were classified into three diagnostic groups: 1. CN (n = 94); 2. MCI (n = 148); and 3. AD (n = 39). Participants are evaluated yearly through a comprehensive neuropsychological battery, including the MINT is a standard CN task that requires patients to retrieve words upon presentation of a line drawing.Results:We obtained a ceiling effect in four items (Butterfly, Glove, Watch, and Candle). Four items were easier in English (Blind, Gauge, Porthole, and Pestle) and four in Spanish (Dustpan, Funnel, Anvil, and Mortar). In the 32-item version of the MINT, EA scored significantly higher than HA, but when removing those eight items, the ethnic difference was attenuated and no longer statistically significant (controlling for education). The ROC curves showed that both versions of the MINT had poor accuracy when identifying CN participants and were acceptable in identifying dementia participants but unacceptable for classifying MCI participants. The 32-item MINT in English and Spanish and the 24-item MINT in Spanish were significantly correlated with the bilateral MTG. However, the 24-item MINT in English was only correlated with this area’s volume in the right hemisphere. The left FG correlated with MINT scores regardless of language and MINT version. We also found some differential correlations depending on the language of administration. The bilateral hippocampi, STG, MTG and FG, and right ITG were significantly correlated only with MINT Spanish scores, while the left ITG was significant only when either version of the MINT was administered in English.Conclusions:Our results highlight the importance of analyzing cross-cultural samples when implementing neuropsychological tests.

Zinc penetration through the skin barrier in atopic dermatitis and rosacea using reflectance confocal microscopy.

Atopic dermatitis (AD) is a chronic, recurrent eczematous disorder with a complex pathophysiology caused by skin barrier abnormalities. Rosacea is a common chronic immune-mediated inflammatory disorder that results in diminished skin barrier function. Reflectance confocal microscopy (RCM) is a non-invasive method for visualizing the dynamic status of epidermal and upper dermal structures. In this study, we compared skin barrier permeability among normal, AD and rosacea groups. To assess skin barrier permeability, zinc was applied to lesional skin and the RCM reflectance intensity of zinc penetration was measured. Reflectance confocal microscopy revealed that the intensity in patients with rosacea and AD was higher than that in the normal group at depths of 8-24 μm in both the face and forearm, which were considered as the stratum corneum (SC) and tight junction (TJ) level (p < 0.0001). When comparing AD and rosacea, the intensity of rosacea was higher than that of AD at a depth of 8 μm in the face (p < 0.0001). The intensity of AD was higher than that of rosacea at a depth of 24 μm (p = 0.009). This suggests that skin barrier permeability is increased in the upper epidermis of patients with AD and rosacea. On the face, patients with rosacea had more SC weakness than did those with AD, whereas patients with AD had more TJ weakness than those with rosacea.