Lowe, Val J.

AbstractAlterations of cerebral glucose metabolism can be detected in patients with isolated rapid eye movement sleep behaviour disorder, a prodromal feature of neurodegenerative diseases with α-synuclein pathology. However, metabolic characteristics that determine clinical progression in isolated rapid eye movement sleep behaviour disorder and their association with other biomarkers need to be elucidated. We investigated the pattern of cerebral glucose metabolism on 18F-fluorodeoxyglucose PET in patients with isolated rapid eye movement sleep behaviour disorder, differentiating between those who clinically progressed and those who remained stable over time. Second, we studied the association between 18F-fluorodeoxyglucose PET and lower dopamine transporter availability in the putamen, another hallmark of synucleinopathies. Patients with isolated rapid eye movement sleep behaviour disorder from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine (n = 22) and age-and sex-matched clinically unimpaired controls (clinically unimpaired; n = 44) from the Mayo Clinic Study of Aging were included. All participants underwent 18F-fluorodeoxyglucose PET and dopamine transporter imaging with iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane on single-photon emission computerized tomography. A subset of patients with isolated rapid eye movement sleep behaviour disorder with follow-up evaluations (n = 17) was classified as isolated rapid eye movement sleep behaviour disorder progressors (n = 7) if they developed mild cognitive impairment or Parkinson’s disease; or isolated rapid eye movement sleep behaviour disorder stables (n = 10) if they remained with a diagnosis of isolated rapid eye movement sleep behaviour disorder with no cognitive impairment. Glucose metabolic abnormalities in isolated rapid eye movement sleep behaviour disorder were determined by comparing atlas-based regional 18F-fluorodeoxyglucose PET uptake between isolated rapid eye movement sleep behaviour disorder and clinically unimpaired. Associations between 18F-fluorodeoxyglucose PET and dopamine transporter availability in the putamen were analyzed with Pearson’s correlation within the nigrostriatal pathway structures and with voxel-based analysis in the cortex. Patients with isolated rapid eye movement sleep behaviour disorder had lower glucose metabolism in the substantia nigra, retrosplenial cortex, angular cortex, and thalamus, and higher metabolism in the amygdala and entorhinal cortex compared with clinically unimpaired. Patients with isolated rapid eye movement sleep behaviour disorder who clinically progressed over time were characterized by higher glucose metabolism in the amygdala and entorhinal cortex, and lower glucose metabolism in the cerebellum compared with clinically unimpaired. Lower dopamine transporter availability in the putamen was associated with higher glucose metabolism in the pallidum within the nigrostriatal pathway; and with higher 18F-fluorodeoxyglucose uptake in the amygdala, insula, and temporal pole on a voxel-based analysis, although these associations did not survive after correcting for multiple comparisons. Our findings suggest that cerebral glucose metabolism in isolated rapid eye movement sleep behaviour disorder is characterized by hypometabolism in regions frequently affected during the prodromal stage of synucleinopathies, potentially reflecting synaptic dysfunction. Hypermetabolism is also seen in isolated rapid eye movement sleep behaviour disorder, suggesting that synaptic metabolic disruptions may be leading to a lack of inhibition, compensatory mechanisms, or microglial activation, especially in regions associated with nigrostriatal degeneration.

Abstract Dysexecutive Alzheimer’s disease (dAD) manifests as a progressive dysexecutive syndrome without prominent behavioral features, and previous studies suggest clinico-radiological heterogeneity within this syndrome. We uncovered this heterogeneity using unsupervised machine learning in 52 dAD patients with multimodal imaging and cognitive data. A spectral decomposition of covariance between FDG-PET images yielded six latent factors (“eigenbrains”) accounting for 48% of variance in patterns of hypometabolism. These eigenbrains differentially related to age at onset, clinical severity, and cognitive performance. A hierarchical clustering on the eigenvalues of these eigenbrains yielded four dAD subtypes, i.e. “left-dominant,” “right-dominant,” “bi-parietal-dominant,” and “heteromodal-diffuse.” Patterns of FDG-PET hypometabolism overlapped with those of tau-PET distribution and MRI neurodegeneration for each subtype, whereas patterns of amyloid deposition were similar across subtypes. Subtypes differed in age at onset and clinical severity where the heteromodal-diffuse exhibited a worse clinical picture, and the bi-parietal had a milder clinical presentation. We propose a conceptual framework of executive components based on the clinico-radiological associations observed in dAD. We demonstrate that patients with dAD, despite sharing core clinical features, are diagnosed with variability in their clinical and neuroimaging profiles. Our findings support the use of data-driven approaches to delineate brain–behavior relationships relevant to clinical practice and disease physiology.

Abstract Objectives Sex differences permeate many aspects of dementia with Lewy bodies (DLB), including epidemiology, pathogenesis, disease progression, and symptom manifestation. However, less is known about potential sex differences in patterns of neurodegeneration in DLB. Here, we test whether grey matter networks also differ between female and male DLB patients. To assess the specificity of these sex differences to DLB, we additionally investigate sex differences in healthy controls (HCs). Methods A total of 119 (68.7 ± 8.4 years) male and 45 female (69.9 ± 9.1 years) DLB patients from three European centres and the Mayo Clinic were included in this study. Additionally, we included 119 male and 45 female age-matched HCs from the Mayo Clinic. Grey matter volumes of 58 cortical, subcortical, cerebellar, and pontine brain regions derived from structural magnetic resonance images were corrected for age, intracranial volume, and centre. Sex-specific grey matter networks for DLB patients and HCs were constructed by correlating each pair of brain regions. Network properties of the correlation matrices were compared between sexes and groups. Additional analyses were conducted on W-scored data to identify DLB-specific findings. Results Networks of male HCs and male DLB patients were characterised by a lower nodal strength compared to their respective female counterparts. In comparison to female HCs, the grey matter networks of male HCs showed a higher global efficiency, modularity, and a lower number of modules. None of the global and nodal network measures showed significant sex differences in DLB. Conclusions The disappearance of sex differences in the structural grey matter networks of DLB patients compared to HCs may indicate a sex-dependent network vulnerability to the alpha-synuclein pathology in DLB. Future studies might investigate whether the differences in structural network measures are associated with differences in cognitive scores and clinical symptoms between the sexes.

Abstract Background and objectives. Sex is an important contributing factor to neuroimaging phenotypes in brain disorders. However, little is known about the contribution of sex differences to the neurodegeneration in dementia with Lewy bodies (DLB). We investigated sex differences in probable DLB patients by using both visual rating scales of lobar atrophy and automated estimations of regional atrophy. Methods. We included 442 probable DLB patients from the European-DLB consortium and the Mayo Clinic who have magnetic resonance imaging (MRI) data available. We assessed sex differences and the sex-by-age interaction in two largely independent samples through visual rating scales of lobar atrophy (n = 333; mean age 73 ± 8 years, 62% males) and automated regional estimations of gray matter (GM) volume and mean cortical thickness (CTh) (n = 165; mean age 69 ± 9 years, 72% males). We used binary logistic regression and ANOVA for statistical analysis. Results. We found a statistically significantly higher likelihood of frontal atrophy measured by the global cortical atrophy-frontal subscale (GCA-F) in males (40% of males had an abnormal GCA-F score versus 29% of females, P-value = 0.006). Using automated estimations, we found smaller GM volumes in 6 cortical regions in males compared with females, as well as smaller GM volume in the entorhinal cortex and thinner olfactory cortices in females, compared with males. The sex-by-age interaction showed statistically significant results in 6 cortical volumes and 7 mean CTh estimations (P-value ≤ 0.05), accentuated in the right middle frontal gyrus (FDR-adjusted P-value = 0.047). These cross-sectional interactions indicated that while females have statistically significantly less atrophy than males at younger ages, differences become non-significant at older ages, with females showing the same level of atrophy than males around the age of 75. Conclusions. This study demonstrates sex differences on brain atrophy in probable DLB. While male DLB patients have a more widespread pattern of cortical atrophy at younger ages, these sex differences tend to disappear with increasing age. Longitudinal studies will help establish these cross-sectional findings and inform on sex and age considerations to the use of MRI in clinical routine, as the field moves towards precision medicine.

Introduction FDG PET/CT was prospectively studied in 287 cN0 head and neck cancer patients in ACRIN 6685, and additional analysis of neck FDG uptake upon recurrence-free survival (RFS) and overall survival (OS) was performed. Patients and Methods Two hundred eight had analyzable data. Survival analysis was performed to compare RFS and OS based on neck FDG visual assessment (VA) and SUVmax. For SUVmax, the optimal thresholds were calculated using conditional inference trees on a randomly selected 70% training data set and validated using the remaining 30% of data. Kaplan-Meier curves with log-rank tests were generated for the patient groups based on VA and optimal SUVmax thresholds, and the hazards ratios (HRs) and 95% confidence intervals (CIs) were also calculated. Hypothesis testing was set at a significance level of 0.05. Results A total of 73.9% of bilateral cN0 and 50.0% of unilateral cN0 were alive at the end of the study with the remaining being dead or lost to follow-up. Overall survival median follow-up time was 24.0 months (interquartile range, 15.8–25.3; range, 0–37.0). A total of 63.3% of bilateral cN0 and 42.5% of unilateral cN0 patients remained disease free during the study. Recurrence-free survival median follow-up time was 23.9 months (interquartile range, 12.4–25.2; range, 0–35.6). Visual assessment of necks by our panel of radiologists was significantly associated with RFS (HR [95% CI], 2.30 [1.10–4.79]; P = 0.02), but not with OS (HR [95% CI], 1.64 [0.86–3.14]; P = 0.13). The optimal SUVmax thresholds were 2.5 for RFS and 5.0 for OS. For SUVmax assessment, applying the optimal thresholds to the 30% test data yielded HRs (95% CIs) of 2.09 (0.61–7.14; P = 0.23) for RFS and 3.42 (1.03–11.41; P = 0.03) for OS. The SUVmax threshold of 5.0 was significantly associated with RFS (HR [95% CI], 5.92 [1.79–19.57]; P < 0.001). Conclusions Neck FDG uptake by VA is significant for RFS. An SUVmax threshold of 5.0 is significantly associated with OS and RFS.

AbstractBackgroundAmyloidosis‐driven tau deposition has been a significant focus of imaging research in Alzheimer’s disease (AD). However, the 3R/4R tau seen in AD can be observed in the transentorhinal/entorhinal regions (Braak I/II) in the absence of amyloidosis. The underlying drivers of this phenomenon are not well understood. Our goal was to examine amyloid‐independent pathways of longitudinal Tau‐PET SUVR progression in the entorhinal cortex (ERC) using a broad range of risk and protective factors.MethodWe identified 449 participants from the population‐based sample of Mayo Clinic Study of Aging >50 years old with baseline amyloid PET and at least two serial tau PET scans (mean number of scans=2.3; mean follow‐up time=3.2 years). Using an amyloid SUVR cut‐point of 1.48, we categorized participants into A+ (n=167; mean age=77.5 years; 56% male; baseline ERC tau=1.20; 83% cognitively unimpaired) and A‐ (n=282; mean age=67.5; 56% male; baseline ERC tau=1.07; 92% cognitively unimpaired). We used an ERC tau SUVR cut‐point of 1.21 to determine T+. We fit mixed effects and growth curve models with age, sex, baseline amyloid, risk factors (midlife activities, sleep, stress, education/occupation, cardiovascular metabolic conditions) as predictors and longitudinal ERC tau as the outcome. We fit separate models in A‐, A+, and all participants.ResultsFor models of all participants and A+ participants, the only predictors of higher rates of ERC tau deposition were increasing age and amyloid SUVR (p<0.05). In the A‐ models (figure below), amyloid SUVR and age were predictors of baseline, but not longitudinal ERC tau. However, a greater number of cardiovascular metabolic conditions predicted a higher rate of ERC tau accumulation (0.007 (0.002), p<0.05). Only 13% of the 23 A‐T+ participants were APOE4 carriers (compared to 31% in the overall sample), suggesting the role of non‐APOE4 pathways to tau deposition.ConclusionOur results support previous evidence that significant amyloidosis is causal to higher rates of tau deposition. However, in those without significant amyloidosis, cardiovascular metabolic conditions predicted higher rates of ERC tau accumulation. Further work is warranted to investigate the mechanisms through which genetics, comorbidities, and lifestyle may play a role in early tau deposition.

AbstractBackgroundβ‐amyloid plaques, a pathological hallmark of Alzheimer’s disease, are common in dementia with Lewy bodies (DLB). However, little is known about when β‐amyloid levels increase throughout the Lewy body disease (LBD) continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD), to a stage of mild cognitive impairment‐Lewy bodies (MCI‐LB), and finally DLB. Our objective was to investigate β‐amyloid deposition throughout the LBD continuum, as well as the influence of sex and APOE ε4 status, as potential factors contributing to Alzheimer’s disease pathological changes.MethodPatients with iRBD (n=24), MCI‐LB (n=62), and DLB (n=82) from the Mayo Clinic Alzheimer’s Disease Research Center and Center for Sleep Medicine were included. β‐amyloid levels were measured by Pittsburgh compound B (PiB) PET and global cortical standard uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared to each other and to cognitively unimpaired individuals (CU; n=100) balanced on age and sex from the Mayo Clinic Study of Aging (MCSA). Clinical groups were compared using ANCOVA after adjusting by age.ResultMCI‐LB and DLB patients had significantly higher global cortical PiB SUVR than CU participants, while PiB SUVR in iRBD patients was comparable to that of CU participants (Figure 1). DLB patients also had significantly higher global cortical PiB SUVR compared to iRBD patients (p=0.004). In MCI‐LB and DLB, global cortical PiB SUVR was higher in APOE ε4 carriers compared to APOE ε4 non‐carriers (p<0.001), and women had higher global cortical PiB SUVR compared to men (p=0.024).ConclusionIn this cross‐sectional study, β‐amyloid pathology gradually increased throughout the clinically defined LBD continuum. Whereas β‐amyloid levels are comparable to cognitively unimpaired individuals in iRBD, a significant elevation in β‐amyloid levels coincides with cognitive impairment observed in MCI‐LB and DLB. Specifically, women and APOE ε4 carriers tend to have higher β‐amyloid levels than men and APOE ε4 non‐carriers. These findings have important implications for targeting patients within the LBD continuum, who may benefit from amyloid modifying therapies.

AbstractBackgroundPosterior Cortical Atrophy (PCA) is one of the atypical Alzheimer’s Disease (AD) variants, characterized by predominant visuospatial and visuoperceptual deficits, with dorsal and ventral subtypes recognized clinically and radiographically. A third primary occipital (caudal) variant has been suggested. The objective of this study was to determine its demographics, clinical manifestations, and biomarker findings.MethodFifty‐two PCA patients with positive amyloid PET scans were investigated. Patients underwent neuropsychological assessment, 3T MRI imaging and FDG‐, amyloid‐ and tau‐PET scans. Regional FDG‐PET values were normalized to the pons and represented as z‐scores relative to a control population. Patients were divided into “primary occipital” and “other PCA” subgroups according to FDG‐PET defined criteria, with primary occipital defined as patients in which the z‐scores for occipital subregions were at least one standard deviation lower (i.e., more abnormal) than the z scores in all other brain regions. Global amyloid‐PET, temporoparietal FDG‐PET and temporal tau‐PET regions‐of‐interest (ROI) were calculated. Student’s T test and Fisher’s exact analyses were used to investigate differences in demographics, clinical findings, and imaging biomarkers across the two groups.ResultNine patients were classified as primary occipital; primary occipital patients were older (64.8±6.9 versus 59.3±6.8, p=0.034) and had more years of education (17.7±1.7 versus 15.1±2.6, p=0.007) compared to the other PCA patients. Clinical evaluation revealed worse performance for the primary occipital group on the Ishihara test for color perception (p<0.001), while the other PCA patients performed worse on the Western Aphasia Battery (WAB) praxis scale (p=0.005). Overall neuropsychiatric symptom burden as defined by the NPI‐Q was lower in the primary occipital group (p<0.001). The FDG‐PET meta‐ROI (weighted median uptake in angular gyrus, posterior cingulate, and inferior temporal ROIs, normalized to the pons and vermis) was higher in the primary occipital subtype (p=0.006), but no differences were observed in amyloid and tau‐PET.ConclusionClinical and biomarker findings suggest primary occipital PCA is characterized by an older age at onset, more color perception dysfunction, less severe ideomotor apraxia and less hypometabolism in temporal‐parietal meta‐ROI compared to more established phenotypes.

AbstractBackgroundStudies of aging and dementia often acquire brain MRI and PET images, then de‐identify and share these widely with other researchers. It is known that research participants can potentially be re‐identified from brain MRI and CT using face recognition, but this has not been tested with PET imaging.MethodWe generated face reconstruction images of 182 volunteers using their existing amyloid (PiB), tau (FTP), and FDG PET scans from clinical GE PET/CT scanners, and we measured how often commercial automatic face recognition (Microsoft Azure) correctly matched these reconstructions with photographs of their faces. We additionally compared these match rates with face reconstructions from CT (from PET/CT) and MRI. When testing face recognition from PET scans, CT was used only during PET reconstruction, not for face recognition. We also validated our updated mri_reface software, originally developed to de‐identify (“de‐face”) faces in MRI, with new support for PET images. We measured face recognition rates before and after applying mri_reface to PET, CT, and MRI. In addition, we measured effects of de‐facing on biomarker measurements (global and regional SUVR) using 244 ADNI Florbetapir (FBP) amyloid PET scans with two automated pipelines: FreeSurfer 6.0 (PETSurfer) and an in‐house SPM12‐based pipeline.ResultRates of successful face recognition with PET ranged from 32‐41% (Table 1) across tracers. These were lower than MRI (98%) and CT (78%) but still concerning for participant privacy. Using mri_reface reduced face recognition to 0‐3.5% for PET, 5% for CT, and 8% for MRI. mri_reface had little effect on global amyloid SUVR measurements from ADNI PET images (Figure 1). ICC values between original and de‐faced images were 1.00 with biases and median absolute differences < 0.5%, across both pipelines. Effects on individual regions all had ICC values > 0.98 with biases and median absolute differences < 2%.ConclusionFace reconstructions from PET images have sufficient quality for potential re‐identification using publicly available face recognition technology. Research studies should consider using face de‐identification (de‐facing) software on PET images in addition to CT and structural MRI. Our free, automatic mri_reface software greatly reduced the potential for face recognition without substantially affecting SUVR measurements.