Kantarci, Kejal

ABSTRACT Background and Purpose Neurodegeneration of the substantia nigra in Lewy body disease is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. Our objective was to measure iron deposition in the substantia nigra in patients with probable dementia with Lewy bodies (pDLB) and patients who are at risk for pDLB by quantitative susceptibility mapping (QSM). Methods Participants included pDLB ( n = 36), mild cognitive impairment with at least one core feature of DLB (MCI‐LB; n = 15), idiopathic rapid eye movement sleep behavior disorder (iRBD; n = 11), and an age‐and gender‐matched clinically unimpaired control group ( n = 102). QSM was derived from multi‐echo 3D gradient recalled echo MRI at 3T, and groups were compared on mean susceptibility values of the substantia nigra and its relation to parkinsonism severity. Results Patients with pDLB had higher susceptibility in the substantia nigra compared to controls ( p < 0.001) and MCI‐LB ( p = 0.043). The susceptibility of substantia nigra showed an increasing trend from controls to iRBD and MCI‐LB, and to pDLB ( p < 0.001). Parkinsonism severity was not associated with the mean susceptibility in the substantia nigra in the patient groups. Conclusions Our data suggested that QSM is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in pDLB. The trend of increasing susceptibility from controls to iRBD and MCI‐LB, and to pDLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses, independent of parkinsonism severity.

Background and Purpose: Cerebral microbleeds (CMBs) are represented by small areas of hemosiderin deposition, detected on brain magnetic resonance imaging (MRI), and found in ≈23% of the cognitively normal population over age of 60 years. CMBs predict risk of hemorrhagic and ischemic stroke. They correlate with increased cardiovascular mortality. In this article, we sought to determine in a population-based study whether antithrombotic medications correlate with CMBs and, if present, whether the association was direct or mediated by another variable. Methods: The study consisted of 1253 participants from the population-based Mayo Clinic Study of Aging who underwent T2* gradient-recalled echo magnetic resonance imaging. We tested the relationship between antithrombotic medications and CMB presence and location, using multivariable logistic-regression models. Ordinal logistic models tested the relationship between antithrombotics and CMB frequency. Using structural equation models, we assessed the effect of antithrombotic medications on presence/absence of CMBs and count of CMBs in the CMB-positive group, after considering the effects of age, sex, vascular risk factors, amyloid load by positron emission tomography, and apoE. Results: Two hundred ninety-five participants (26.3%) had CMBs. Among 678 participants taking only antiplatelet medications, 185 (27.3%) had CMBs. Among 95 participants taking only an anticoagulant, 43 (45.3%) had CMBs. Among 44 participants taking an anticoagulant and antiplatelet therapy, 21 (48.8%) had CMBs. Anticoagulants correlated with the presence and frequency of CMBs, whereas antiplatelet agents were not. Structural equation models showed that predictors for presence/absence of CMBs included older age at magnetic resonance imaging, male sex, and anticoagulant use. Predictors of CMB count in the CMB-positive group were male sex and amyloid load. Conclusions: Anticoagulant use correlated with presence of CMBs in the general population. Amyloid positron emission tomography correlated with the count of CMBs in the CMB-positive group.

Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective: To determine whether CMBs on antemortem MRI correlate with CAA. Methods: We reviewed 54 consecutive participants with antemortem T2*GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By a clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal/cortical components correlated with number of lobar CMBs. Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA.

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers. Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women. Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1–42 (Aβ1–42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs. Results: Only the number of microvesicles positive for Aβ1–42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045). Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17β-estradiol may reduce the accumulation of cortical amyloid-β. However, how menopausal hormone therapies modify the associations of amyloid-β accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-β deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42–58; 5–36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17β-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-β deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = −0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = −0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-β accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-β accumulation.

AbstractBeing a woman is one of the strongest risk factors for multiple sclerosis. The natural reproductive period from menarche to natural menopause corresponds to the active inflammatory disease period in multiple sclerosis. The fifth decade marks both the peri-menopausal transition in the reproductive aging and a transition from the relapsing-remitting to the progressive phase in multiple sclerosis. A short reproductive period with premature/early menopause and/or low number of pregnancies may be associated with an earlier onset of the progressive multiple sclerosis phase. A cross-sectional study of survey-based reproductive history in a multiple sclerosis clinical series enriched for patients with progressive disease, and a case–control study of multiple sclerosis and age/sex matched controls from a population-based cohort were conducted. Menarche age, number of complete/incomplete pregnancies, menopause type and menopause age were compared between 137 cases and 396 control females. Onset of relapsing-remitting phase of multiple sclerosis, progressive disease onset and reaching severe disability (expanded disability status scale 6) were studied as multiple sclerosis-related outcomes (n = 233). Menarche age was similar between multiple sclerosis and control females (P = 0.306). Females with multiple sclerosis had fewer full-term pregnancies than the controls (P &lt; 0.001). Non-natural menopause was more common in multiple sclerosis (40.7%) than in controls (30.1%) (P = 0.030). Age at natural menopause was similar between multiple sclerosis (median, interquartile range: 50 years, 48–52) and controls (median, interquartile range: 51 years, 49–53) (P = 0.476). Nulliparous females had earlier age at progressive multiple sclerosis onset (mean ± standard deviation: 41.9 ± 12.5 years) than females with ≥1 full-term pregnancies (mean ± standard deviation: 47.1 ± 9.7 years) (P = 0.069) with a pregnancy-dose effect [para 0 (mean ± standard deviation: 41.9 ± 12.5 years), para 1–3 (mean ± standard deviation: 46.4 ± 9.2 years), para ≥4 (mean ± standard deviation: 52.6 ± 12.9 years) (P = 0.005)]. Menopause age was associated with progressive multiple sclerosis onset age (R2 = 0.359, P &lt; 0.001). Duration from onset of relapses to onset of progressive multiple sclerosis was shorter for females with premature/early menopause (n = 26; mean ± standard deviation: 12.9 ± 9.0 years) than for females with normal menopause age (n = 39; mean ± standard deviation: 17.8 ± 10.3 years) but was longer than for males (mean ±standard deviation: 10.0 ± 9.4 years) (P = 0.005). There was a pregnancy-dose effect of age at expanded disability status scale 6 (para 0: 43.0 ± 13.2 years, para 1–3: 51.7 ± 11.3 years, para ≥4: 53.5 ± 4.9 years) (P = 0.013). Age at menopause was associated with age at expanded disability status scale 6 (R2 = 0.229, P &lt; 0.003). Premature/early menopause or nulliparity was associated with earlier onset of progressive multiple sclerosis with a ‘dose effect’ of pregnancies on delaying progressive multiple sclerosis and severe disability. Although causality remains uncertain, our results suggest a beneficial impact of oestrogen in delaying progressive multiple sclerosis. If confirmed in prospective studies, our findings have implications for counselling women with multiple sclerosis about pregnancy, surgical menopause and menopausal hormone therapy.

AbstractBackgroundWhile β‐amyloid and tau PET imaging are widely studied in cognitive aging and Alzheimer’s disease (AD), little is known about findings in aging multiple sclerosis (MS) patients. As aging is an essential factor in developing neurodegeneration in MS, β‐amyloid and tau biomarkers may be utilized to understand the influence of AD pathophysiology on cognitive aging in MS.MethodWe studied patients with MS (n=16) and controls (n=80) matched for age, sex and APOE ε4 status from the population‐based Mayo Clinic Study of Aging who underwent Pittsburgh compound‐B (PiB) PET imaging. Twelve of the 16 patients with MS and 60 matching controls also underwent flortaucipir (AV1451) tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVr) from previously determined AD signature regions and from the entire cortex were calculated for group comparisons and testing for associations with age.ResultAD signature PiB SUVr (p=0.044), total cortical PiB SUVr (p=0.048) and the frequency of abnormal PiB SUVrs (p=0.040) were lower in patients with MS than controls. Although AD signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (p=0.041) in patients with MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls (Figure 1). The AD signature PiB SUVr increased more with increasing AD signature AV1451 SUVr in controls than in patients with MS (p=0.03) (Figure 2).ConclusionIn patients with MS, cortical β‐amyloid deposition was lower than age‐matched controls, while cortical tau deposition was not different between the groups. This suggests that some aspect of MS pathobiology retards the accumulation of β‐amyloid, but not the accumulation of tau.

AbstractBackgroundFamilial frontotemporal dementia (f‐FTLD) is typically caused by mutations in one of three genes: microtubule‐associated protein tau (MAPT), progranulin (GRN), and a repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene. Accurate characterization of the natural history of each mutation is important for clinical prognostication and clinical trial design, and it could shed light on disease biology. Such models have not been thoroughly developed using participants that represent all disease stages, with longitudinal data. We characterized the trajectory of atrophy in each gene by using longitudinal voxel‐wise analyses of gray matter volume, and we assessed whether functional independence declined in tandem.MethodF‐FTLD participants (n=100) with a known mutation (MAPT+ (n=28), GRN+ (n=33), C9orf72+ (n=39)) were grouped according to disease stage (CDR®+NACC FTLD module). We included participants with at least two structural MRIs at a given disease stage: presymptomatic (CDR®+NACC‐FTLD=0, n=57), mild/questionable (CDR®+NACC‐FTLD=0.5, n=15), and symptomatic (CDR®+NACC‐FTLD ≥1, n=28). We fitted longitudinal linear mixed effects models to extract mean atrophy rates in each lobe compared to longitudinal imaging from family members without mutations (n=60). All results presented below were significant at p<.001.ResultUsing the left frontal lobe as an exemplar, in the presymptomatic stage, MAPT mutation carriers showed the greatest rate of atrophy compared to controls (88 mm3/year more volume loss than controls), followed by GRN+ (65 mm3/year) and then C9orf72+ (49 mm3/year). In the mild/questionable stage, MAPT+ showed a greater divergence from controls (374 mm3/year) than did GRN+ (107 mm3/year) or C9orf72+ (223 mm3/year). In the symptomatic stage, MAPT+ again lost volume at the fastest rate (2,099 mm3/year), followed by GRN+ (1,360 mm3/year). C9orf72 expansion carriers showed a much slower rate of volume loss (115 mm3/year). Similar patterns were observed for other brain regions. In contrast to the imaging results, C9orf72+ exhibited similar rates of functional decline compared to GRN+ and MAPT+ at all levels of disease severity.ConclusionThe primary f‐FTLD genes show divergent atrophy trajectories as a function of disease stage, with C9orf72 expansion carriers exhibiting a slow degeneration throughout the disease course, possibly due to unique pathophysiological mechanisms.

AbstractBackgroundMultiple imaging modalities have been individually shown to be useful in diagnosing Dementia with Lewy Bodies (DLB). Reduced striatonigral uptake on ioflupane‐SPECT reflects striatonigral dopamine dysfunction observed in DLB, while other imaging modalities assess different aspects of DLB, which potentially work complementarily when used together. We assessed how well ioflupane‐SPECT differentiates DLB from Alzheimer’s Disease Dementia (ADem) and whether adding another imaging modality to ioflupane‐SPECT would provide additional value.MethodIoflupane‐SPECT, MRI, FDG‐PET, and PiB‐PET were assessed on 35 DLB and 14 ADem patients (including 12 patients with eventual autopsy confirmation). Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with ioflupane‐SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake. Hippocampal volume was calculated with structural MRI, cingulate island sign (CIS) ratio with FDG‐PET, and global cortical PiB retention with PiB‐PET.ResultLower DaTQUANT z‐scores of putamen were observed in DLB patients compared to ADem patients (c‐statistic 0.896, p<0.001). Ioflupane‐SPECT showed higher c‐statistic in differentiating DLB from ADem than hippocampal volume on MRI (c‐statistic 0.718, p=0.034), CIS on FDG‐PET (c‐statistic 0.869, p=0.003), or global cortical PiB retention on PiB‐PET (c‐statistic 0.869, p=0.002), but some overlap between two diagnostic groups was still observed with the single imaging modality. Among these imaging modalities, ioflupane‐SPECT was the only modality correlated with the Unified Parkinson Disease Rating Scale (UPDRS) part III, while only PiB‐PET correlated with Montreal Cognitive Assessment (MoCA) test score. Adding another imaging modality to ioflupane‐SPECT enhanced c‐statistics (+MRI c‐statistic 0.931, p<0.001; +FDG‐PET c‐statistic 0.957, p=0.005; +PiB‐PET c‐statistic 0.955, p=0.007), and ioflupane‐SPECT in combination with both FDG‐PET and PiB‐PET showed the highest c‐statistic of 0.974 (p=0.043).ConclusionIoflupane‐SPECT is an excellent imaging modality to identify DLB by detecting striatonigral dopamine dysfunction which is strongly associated with motor impairment in DLB. Correlative neuroimaging with MRI, FDG‐PET, or PiB‐PET may add small incremental value in differentiation of DLB and ADem. Supported by NIH grants (AG016574, AG006786, AG015866, NS100620, AG062677), grant from GE Healthcare, the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, the Deal Family Foundation, and the Little Family Foundation.