Effects of Alzheimer and Lewy Body Disease Pathologies on Brain Metabolism.

OBJECTIVE: This study aimed to determine the pattern of 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) related to postmortem Lewy body disease (LBD) pathology in clinical Alzheimer disease (AD). METHODS: FDG-PET scans were analyzed in 62 autopsy-confirmed patients and 110 controls in the Alzheimer's Disease Neuroimaging Initiative. Based on neuropathologic evaluations on Braak stage for neurofibrillary tangle, Consortium to Establish a Registry for AD score for neuritic plaque, and Lewy-related pathology, subjects were classified into AD(-)/LBD(-), AD(-)/LBD(+), AD(+)/LBD(-), and AD(+)/LBD(+) groups. The association between postmortem LBD and AD pathologies and antemortem brain metabolism was evaluated. RESULTS: AD and LBD pathologies had significant interaction effects to decrease metabolism in the cerebellar vermis, bilateral caudate, putamen, basal frontal cortex, and anterior cingulate cortex in addition to the left side of the entorhinal cortex and amygdala, and significant interaction effects to increase metabolism in the bilateral parietal and occipital cortices. LBD pathology was associated with hypermetabolism in the cerebellar vermis, bilateral putamen, anterior cingulate cortex, and basal frontal cortex, corresponding to the Lewy body-related hypermetabolic patterns. AD pathology was associated with hypometabolism in the bilateral hippocampus, entorhinal cortex, and posterior cingulate cortex regardless of LBD pathology, whereas LBD pathology was associated with hypermetabolism in the bilateral putamen and anterior cingulate cortex regardless of AD pathology. INTERPRETATION: Postmortem LBD and AD pathologies had significant interaction effects on the antemortem brain metabolism in clinical AD patients. Specific metabolic patterns related to AD and LBD pathologies could be elucidated when simultaneously considering the two pathologies. ANN NEUROL 2022;91:853-863.

Effects of amyloid beta and dopaminergic depletion on perfusion and clinical symptoms.

INTRODUCTION: Although mixed pathologies are common in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), the effects of amyloid beta and dopaminergic depletion on brain perfusion and clinical symptoms have not been elucidated. METHODS: In 99 cognitive impairment patients due to AD and/or DLB and 32 controls, 18F-florbetaben (FBB) and dual-phase dopamine transporter (DAT) positron emission tomography (PET) were performed to measure the FBB standardized uptake value ratio (SUVR), striatal DAT uptakes, and brain perfusion. RESULTS: Higher FBB-SUVR and lower ventral striatal DAT uptake were intercorrelated and, respectively, associated with left entorhinal/temporo-parietal-centered hypoperfusion and vermis/hippocampal-centered hyperperfusion, whereas regional perfusion mediated clinical symptoms and cognition. DISCUSSION: Amyloid beta deposition and striatal dopaminergic depletion contribute to regional perfusion changes, clinical symptoms, and cognition in the spectrum of normal aging and cognitive impairment due to AD and/or LBD. HIGHLIGHTS: Amyloid beta (Aß) deposition was associated with ventral striatal dopaminergic depletion. Aß deposition and dopaminergic depletion correlated with perfusion. Aß deposition correlated with hypoperfusion centered in the left entorhinal cortex. Dopaminergic depletion correlated with hyperperfusion centered in the vermis. Perfusion mediated the Aß deposition/dopaminergic depletion's effects on cognition.

Hematological Changes Associated with Theileria orientalis Infection in Korean Indigenous Cattle.

Tick-borne pathogens can cause serious problems in grazing cattle. However, little information is available on tick-mediated diseases in cattle grazing on mountains. Thus, this study aimed to understand the potential problems related to tick-borne diseases in grazing cattle through the investigation of prevalent tick-transmitted infections, and their associated hematological changes, in terms of season and grazing type in Korean indigenous cattle (=Hanwoo). Hanwoo cattle from 3 regions of the Republic of Korea (=Korea) were either maintained indoors or placed on grassy mountains from spring to fall of 2014 and 2015. Cattle that grazed in mountainous areas showed a greater prevalence of tick-borne infections with an increased Theileria orientalis infection rate (54.7%) compared to that in non-grazing cattle (16.3%) (P<0.001). Accordingly, the red blood cell (RBC) count and hematocrit (HCT) values of grazing cattle were significantly lower than those of non-grazing cattle throughout the season (P<0.05). Moreover, RBC, hemoglobin (Hb), and HCT of T. orientalis-positive group were significantly lower than those of T. orientalis-negative group (P<0.05). T. orientalis is a widespread tick-borne pathogen in Korea. Grazing of cattle in mountainous areas is closely associated with an increase in T. orientalis infection (RR=3.4, P<0.001), and with consequent decreases in RBC count and HCT. Thus, these findings suggest that the Hanwoo cattle in mountainous areas of Korea are at a high risk of infection by T. orientalis, which can lead to hematological alterations. This study highlights the necessity of preventive strategies that target T. orientalis infection.

Predictors associated with the rate of progression of nigrostriatal degeneration in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. METHODS: In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. RESULTS: More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. DISCUSSION: Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis.

Substantia nigral dopamine transporter uptake in dementia with Lewy bodies.

Nigrostriatal dopaminergic degeneration is a pathological hallmark of dementia with Lewy bodies (DLB). To identify the subregional dopamine transporter (DAT) uptake patterns that improve the diagnostic accuracy of DLB, we analyzed N-(3-[18F] fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl)-nortropane (FP-CIT) PET in 51 patients with DLB, in 36 patients with mild cognitive impairment with Lewy body (MCI-LB), and in 40 healthy controls (HCs). In addition to a high affinity for DAT, FP-CIT show a modest affinity to serotonin or norepinephrine transporters. Specific binding ratios (SBRs) of the nigrostriatal subregions were transformed to age-adjusted z-scores (zSBR) based on HCs. The diagnostic accuracy of subregional zSBRs were tested using receiver operating characteristic (ROC) curve analyses separately for MCI-LB and DLB versus HCs. Then, the effect of subregional zSBRs on the presence of clinical features and gray matter (GM) density were evaluated in all patients with MCI-LB or DLB as a group. ROC curve analyses showed that the diagnostic accuracy of DLB based on the zSBR of substantia nigra (area under the curve [AUC], 0.90) or those for MCI-LB (AUC, 0.87) were significantly higher than that based on the zSBR of posterior putamen for DLB (AUC, 0.72) or MCI-LB (AUC, 0.65). Lower zSBRs in nigrostriatal regions were associated with visual hallucination, severe parkinsonism, and cognitive dysfunction, while lower zSBR of substantia nigra was associated with widespread GM atrophy in DLB and MCI-LB patients. Taken together, our results suggest that evaluation of nigral DAT uptake may increase the diagnostic accuracy of DLB and MCI-LB than other striatal regions.

Air pollution is associated with faster cognitive decline in Alzheimer's disease.

OBJECTIVE: Although chronic exposure to air pollution is associated with an increased risk of dementia in normal elderlies, the effect of chronic exposure to air pollution on the rates of cognitive decline in Alzheimer's disease (AD) has not been elucidated. METHODS: In this longitudinal study, a total of 269 patients with mild cognitive impairment or early dementia due to AD with the evidence of brain ß-amyloid deposition were followed-up for a mean period of 4 years. Five-year normalized hourly cumulative exposure value of each air pollutant, such as carbon monoxide (CO), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), and particulate matter (PM2.5 and PM10 ), was computed based on nationwide air pollution database. The effects of chronic exposure to air pollution on longitudinal cognitive decline rate were evaluated using linear mixed models. RESULTS: Higher chronic exposure to SO2 was associated with a faster decline in memory score, whereas chronic exposure to CO, NO2 , and PM10 were not associated with the rate of cognitive decline. Higher chronic exposure to PM2.5 was associated with a faster decline in visuospatial score in apolipoprotein E ε4 carriers. These effects remained significant even after adjusting for potential confounders. INTERPRETATION: Our findings suggest that chronic exposure to SO2 and PM2.5 is associated with faster clinical progression in AD.

Therapeutic Potential of Chungsangboha-tang for the Treatment of Asthma: A Review of Preclinical and Clinical Studies.

In traditional Korean medicine, Chungsangboha-tang (CSBHT) and its modified forms are used to treat various respiratory disorders, including asthma. This study aimed to identify research trends, clarify the effectiveness of CSBHT and related prescriptions, and lay a foundation for future research. We conducted a literature review using PubMed, Embase, Google Scholar, Oriental Medicine Advanced Searching Integrated System, National Digital Science Links, Korean Medical Database, Wanfang Data, and Chinese National Knowledge Infrastructure databases. We analyzed 25 studies, including 5 in vitro studies, 6 animal studies, and 14 human studies. Many studies evaluated the efficacy of CSBHT and its related prescriptions, including experimental studies on its effectiveness in asthma. The main mechanism of action involves the anti-inflammatory effect caused by the regulation of various immune cells, cytokines, and chemokines. In addition, clinical trials on asthma reported the benefits of CSBHT and its related prescriptions. However, there has been no randomized controlled study of clinical trials on the clinical effectiveness of CSBHT in asthma. Therefore, large-scale randomized controlled studies should be conducted in the future.

Effects of Alzheimer's genetic risk scores and CSF biomarkers in de novo Parkinson's Disease.

Coexisting Alzheimer's disease (AD) pathology is common in Parkinson's disease (PD). However, the implications of genetic risk scores (GRS) for AD have not been elucidated in PD. In 413 de novo PD and 195 healthy controls from the Parkinson's Progression Marker Initiative database, the effects of GRS for AD (GRS-AD) and PD (GRS-PD) on the risk of PD and longitudinal CSF biomarkers and clinical outcomes were explored. Higher GRS-PD and lower baseline CSF α-synuclein were associated with an increased risk of PD. In the PD group, GRS-AD was correlated positively with CSF p-tau/Aß and negatively with CSF α-synuclein. Higher GRS-PD was associated with faster CSF p-tau/Aß increase, and GRS-AD and GRS-PD were interactively associated with CSF α-synuclein. In the PD group, higher GRS-AD was associated with poor visuospatial function, and baseline CSF p-tau/Aß was associated with faster cognitive decline. Higher GRS-PD was associated with better semantic fluency and frontal-related cognition and motor function given the same levels of CSF biomarkers and dopamine transporter uptake. Taken together, our results suggest that higher GRS-AD and CSF p-tau/Aß, reflecting AD-related pathophysiology, may be associated with cognitive decline in PD patients.

Implication of Small Vessel Disease MRI Markers in Alzheimer's Disease and Lewy Body Disease.

BACKGROUND: Small vessel disease (SVD) magnetic resonance imaging (MRI) markers including deep and periventricular white matter hyperintensities (PWMH), lacunes, and microbleeds are frequently observed in Alzheimer's disease (AD) and Lewy body disease (LBD), but their implication has not been clearly elucidated. OBJECTIVE: To investigate the implication of SVD MRI markers in cognitively impaired patients with AD and/or LBD. METHODS: We consecutively recruited 57 patients with pure AD-related cognitive impairment (ADCI), 49 with pure LBD-related cognitive impairment (LBCI), 45 with mixed ADCI/LBCI, and 34 controls. All participants underwent neuropsychological tests, brain MRI, and amyloid positron emission tomography. SVD MRI markers including the severity of deep and PWMH and the number of lacunes and microbleeds were visually rated. The relationships among vascular risk factors, SVD MRI markers, ADCI, LBCI, and cognitive scores were investigated after controlling for appropriate covariates. RESULTS: LBCI was associated with more severe PWMH, which was conversely associated with an increased risk of LBCI independently of vascular risk factors and ADCI. PWMH was associated with attention and visuospatial dysfunction independently of vascular risk factors, ADCI, and LBCI. Both ADCI and LBCI were associated with more lobar microbleeds, but not with deep microbleeds. CONCLUSION: Our findings suggest that PWMH could reflect degenerative process related with LBD, and both AD and LBD independently increase lobar microbleeds.

Effects of baseline serum uric acid and apolipoprotein E4 on longitudinal cognition and cerebral metabolism.

Serum uric acid, a natural antioxidant, may have a protective effect on the progression of Alzheimer's disease (AD). To investigate the effect of serum uric acid on longitudinal cognitive and brain metabolic changes, we utilized data on baseline serum uric acid levels, APOE genotyping, and longitudinal cognitive scores from the Alzheimer's Disease Neuroimaging Initiative for 1,343 participants with normal cognition (NC), mild cognitive impairment (MCI), or dementia. In 979 participants, brain metabolism was measured using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) images. Higher serum uric acid levels exhibited a detrimental effect on NC, whereas a protective trend was observed in individuals with cognitive impairment. Interestingly, higher uric acid levels were associated with a slower decline in cognitive scores and brain metabolism in females with MCI, and this effect was found in APOE4 carriers, but not in non-carriers. Longitudinal AD-like patterns of brain metabolism on FDG-PET images also appeared to mediate the effects of baseline uric acid levels on longitudinal cognitive decline. In summary, higher serum uric acid may interact with APOE4 to alleviate longitudinal metabolic changes and cognitive decline in female MCI patients.

Implication of metabolic and dopamine transporter PET in dementia with Lewy bodies.

To evaluate the implication of 18F-fluorodeoxyglucose (FDG)- and dopamine transporter (DAT)-positron emission tomography (PET) in the diagnosis and clinical symptoms of dementia with Lewy bodies (DLB), 55 DLB patients and 49 controls underwent neuropsychological evaluation and FDG-, DAT-, and 18F-Florbetaben (FBB) PET. DAT- and FDG-uptake and FDG/DAT ratio were measured in the anterior and posterior striatum. The first principal component (PC1) of FDG subject residual profiles was identified for each subject. Receiver operating characteristic curve analyses for the diagnosis of DLB were performed using FDG- and DAT-PET biomarkers as predictors, and general linear models for motor severity and cognitive scores were performed adding FBB standardized uptake value ratio as a predictor. Increased metabolism in the bilateral putamen, vermis, and somato-motor cortices, which characterized PC1, was observed in the DLB group, compared to the control group. A combination of posterior putamen FDG/DAT ratio and PC1 showed the highest diagnostic accuracy (91.8% sensitivity and 96.4% specificity), which was significantly greater than that obtained by DAT uptake alone. Striatal DAT uptake and PC1 independently contributed to motor severity and language, memory, frontal/executive, and general cognitive dysfunction in DLB patients, while only PC1 contributed to attention and visuospatial dysfunction.

Erratum.

[This corrects the article DOI: 10.1002/dad2.12177.].

Interaction of CSF α-synuclein and amyloid beta in cognition and cortical atrophy.

INTRODUCTION: Lewy body-related pathology is commonly observed at autopsy in individuals with dementia, but in vivo biomarkers for α-synucleinopathy are lacking. METHODS: Baseline cerebrospinal fluid (CSF) biomarkers, polygenic risk score (PRS) for Parkinson's disease (PRS-PD) and Alzheimer's disease (PRS-AD), longitudinal cognitive scores, and magnetic resonance imaging were measured in 217 participants from the Alzheimer's Disease Neuroimaging Initiative. Linear mixed models were used to find the relationship of CSF biomarkers and the PRS with cognition and cortical atrophy. RESULTS: Higher PRS-PD and PRS-AD were associated with lower CSF α-synuclein and amyloid beta (Aß), respectively. Lower CSF α-synuclein and the interaction of CSF α-synuclein and Aß were associated with lower cognitive scores and global cortical atrophy most prominently in the occipital cortex. DISCUSSION: Lower CSF α-synuclein could be a biomarker for α-synucleinopathy, and the simultaneous evaluation of CSF biomarkers for AD and CSF α-synuclein could reveal the independent and interactive effects on cognition and cortical atrophy.

Effects of Lewy body disease and Alzheimer disease on brain atrophy and cognitive dysfunction.

OBJECTIVES: To investigate the independent and interaction effects of Alzheimer disease (AD) and Lewy body disease (LBD) on cognition and brain atrophy. METHODS: We consecutively recruited 38 controls and 108 patients with AD-related cognitive impairment (ADCI) and/or LBD-related cognitive impairment (LBCI) from university-based dementia and movement clinics. Diagnoses of ADCI and LBCI were supported by 18F-florbetaben PET and 18F-N-(3-fluoropropyl)-2ß-carbon ethoxy-3ß-(4-iodophenyl) nortropane-PET, respectively. There were 38 controls, 26 patients with pure ADCI (18 mild cognitive impairment [MCI] and 8 dementia), 28 patients with pure LBCI (13 MCI and 15 dementia), and 54 patients with mixed ADCI and LBCI (17 MCI and 37 dementia). We performed group-wise comparisons for neuropsychological z scores and regional cortical thickness. We also evaluated the effects of ADCI and LBCI using general linear models. RESULTS: Compared to the controls, patients in the pure ADCI group and pure LBCI group had focused cortical thinning in the bilateral entorhinal/right anterior temporal cortices and bilateral anteromedial temporal/basal frontal cortices, respectively, while the mixed disease group had additional cortical thinning in the widespread association cortices. The independent effects of ADCI and LBCI on regional cortical thinning overlapped in the widespread association cortices, especially at the bilateral temporoparietal junction and parietal cortices. ADCI and LBCI had independent detrimental effects on the copying item of the Rey-Osterrieth Complex Figure Test. CONCLUSIONS: Concomitant ADCI and LBCI are associated with the accentuation of neurodegeneration to widespread association cortices, and both diseases contribute to visuospatial dysfunction.