Kantarci, Kejal

Abstract INTRODUCTION Psychotropic medication (PM) use in behavioral‐variant frontotemporal dementia (bvFTD) is higher than in other dementias. However, no information exists on whether PM use differs between sporadic and genetic bvFTD. METHODS We analyzed data from sporadic and genetic bvFTD participants with PM prescriptions in the Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects study. We estimated ordinal odds ratio (OOR) of having more PM comparing sporadic and genetic bvFTD. Finally, we explored the neuropsychiatric symptom (NPS) combinations using classification and regression trees (CART). RESULTS We included 263 with sporadic and 193 with genetic bvFTD. The OOR for sporadic bvFTD to be on PM was 1.75 (95% confidence interval: 1.21 to 2.53) for the fully adjusted model. CART revealed the most common NPS combination was apathy + personality changes in 18% of participants. DISCUSSION Participants with sporadic bvFTD were twice as likely to be on PM compared to genetic bvFTD. The reason for increased PM usage in sporadic bvFTD participants should be further investigated. Highlights We report on patients with behavioral variant frontotemporal dementia (bvFTD). We evaluated the psychotropic medication (PM) prescription at baseline in the cohort. Patients with sporadic bvFTD had more prescriptions for PM than genetic patients. The frequency of symptoms combination was different in sporadic and genetic bvFTD.

Abstract INTRODUCTION Premenopausal bilateral oophorectomy (PBO) before the age of 46 years is associated with an increased risk of dementia. We investigated the long‐term effects of PBO performed before age 50 years on amyloid beta (Aβ), tau, and neurodegeneration imaging biomarkers of Alzheimer's disease (AD). METHODS Mayo Clinic Cohort Study of Oophorectomy and Aging‐2 participants were divided into early PBO (< 46 years; n = 61), and late PBO (46–49 years; n = 51) groups and were compared to referent women who did not undergo PBO ( n = 119). RESULTS Early PBO was associated with thinner entorhinal cortex ( p = 0.014), higher tau load at higher levels of Aβ load ( Pp = 0.005), higher Aβ load ( p = 0.026), and smaller temporal lobe cortical thickness ( p = 0.022), only at older ages compared to the referent group. DISCUSSION PBO before the age of 46 years is associated with entorhinal cortex thinning, elevated tau at higher Aβ levels, along with an AD‐like pattern of atrophy at older ages. CLINICAL TRIALS REGISTRATION NCT03821857 sex‐specific effects of endocrine disruption on aging and AD. Highlights Premenopausal bilateral oophorectomy (PBO) before the ages of 46 (early PBO) years and ages 46 to 49 (late PBO) years was studied. Early PBO was associated with reduced entorhinal cortex thickness later in life. Early PBO was associated with greater amyloid beta (Aβ) load at older ages. Early PBO was associated with greater Alzheimer's disease pattern of atrophy at older ages. Early PBO was associated with higher tau load at higher Aβ levels.

AbstractINTRODUCTIONUnderstanding the relationship between amyloid beta (Aβ) positron emission tomography (PET) and Aβ cerebrospinal fluid (CSF) biomarkers will define their potential utility in Aβ treatment. Few population‐based or neuropathologic comparisons have been reported.METHODSParticipants 50+ years with Aβ PET and Aβ CSF biomarkers (phosphorylated tau [p‐tau]181/Aβ42, n = 505, and Aβ42/40, n = 54) were included from the Mayo Clinic Study on Aging. From these participants, an autopsy subgroup was identified (n = 47). The relationships of Aβ PET and Aβ CSF biomarkers were assessed cross‐sectionally in all participants and longitudinally in autopsy data.RESULTSCross‐sectionally, more participants were Aβ PET+ versus Aβ CSF− than Aβ PET− versus Aβ CSF+ with an incremental effect when using Aβ PET regions selected for early Aβ deposition. The sensitivity for the first detection of Thal phase ≥ 1 in longitudinal data was higher for Aβ PET (89%) than p‐tau181/Aβ42 (64%).DISCUSSIONAβ PET can detect earlier cortical Aβ deposition than Aβ CSF biomarkers. Aβ PET+ versus Aβ CSF− findings are several‐fold greater using regional Aβ PET analyses and in peri‐threshold‐standardized uptake value ratio participants.Highlights Amyloid beta (Aβ) positron emission tomography (PET) has greater sensitivity for Aβ deposition than Aβ cerebrospinal fluid (CSF) in early Aβ development. A population‐based sample of participants (n = 505) with PET and CSF tests was used. Cortical regions showing early Aβ on Aβ PET were also used in these analyses. Neuropathology was used to validate detection of Aβ by Aβ PET and Aβ CSF biomarkers.

In vivo proton (1H) magnetic resonance spectroscopy (MRS) is a powerful non-invasive method that can measure Alzheimer’s disease (AD)-related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by 1H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of 1H MRS metabolites with biofluid, PET, and postmortem AD biomarkers and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate the development of potential novel therapeutic approaches.

Objective Visual assessments of amyloid-β PET, used for Alzheimer’s disease (AD) diagnosis and treatment evaluation, require a careful approach when different PET ligands are utilized. Because the gray matter (GM) and white matter (WM) ligand bindings vary with age, the objective was to investigate the agreement between visual reads of 11C- and 18F-PET scans. Methods Cognitively unimpaired (CU) younger adults (N = 30; 39.5 ± 6.0 years), CU older adults (N = 30; 68.6 ± 5.9 years), and adults with AD (N = 22; 67.0 ± 8.5 years) underwent brain MRI, 11C-Pittsburgh compound-B (PiB)-PET, and 18F-flutemetamol-PET. Amyloid-β deposition was assessed visually by two nuclear medicine specialists on 11C-PiB-PET and 18F-flutemetamol-PET, and quantitatively by PET centiloids. Results Seventy-two 11C-PiB-PET and 18F-flutemetamol-PET visual reads were concordant. However, 1 18F-flutemetamol-PET and 9 11C-PiB-PET were discordant with quantitative values. In four additional cases, while 11C-PiB-PET and 18F-flutemetamol-PET visual reads were concordant, they were discordant with quantitative values. Disagreements in CU younger adults were only with 11C-PiB-PET visual reads. The remaining disagreements were with CU older adults. Conclusion Age, GM/WM binding, amyloid-β load, and disease severity may affect visual assessments of PET ligands. Increase in WM binding with age causes a loss of contrast between GM and WM on 11C-PiB-PET, particularly in CU younger adults, leading to false positivity. In CU older adults, increased WM signal may bleed more into cortical regions, hiding subtle cortical uptake, especially with 18F-flutemetamol, whereas 11C-PiB can detect true regional positivity. Understanding these differences will improve patient care and treatment evaluation in clinic and clinical trials.

AbstractINTRODUCTIONAge‐related and Alzheimer's disease (AD) dementia–related neurodegeneration impact brain health. While morphometric measures from T1‐weighted scans are established biomarkers, they may be less sensitive to earlier changes. Neurite orientation dispersion and density imaging (NODDI), offering biologically meaningful interpretation of tissue microstructure, may be an advanced brain health biomarker.METHODSWe contrasted regional gray matter NODDI and morphometric evaluations concerning their correlation with (1) age, (2) clinical diagnosis stage, and (3) tau pathology as assessed by AV1451 positron emission tomography.RESULTSOur study hypothesizes that NODDI measures are more sensitive to aging and early AD changes than morphometric measures. One NODDI output, free water fraction (FWF), showed higher sensitivity to age‐related changes, generally better effect sizes in separating mild cognitively impaired from cognitively unimpaired participants, and stronger associations with regional tau deposition than morphometric measures.DISCUSSIONThese findings underscore NODDI's utility in capturing early neurodegenerative changes and enhancing our understanding of aging and AD.Highlights Neurite orientation dispersion and density imaging can serve as an effective brain health biomarker for aging and early Alzheimer's disease (AD). Free water fraction has higher sensitivity to normal brain aging. Free water fraction has stronger associations with early AD and regional tau deposition.

[ 18 F]-Flortaucipir positron emission tomography (PET) is considered a good biomarker of Alzheimer’s disease. However, it is unknown how flortaucipir is associated with the distribution of tau across brain regions and how these associations are influenced by amyloid-β. It is also unclear whether flortaucipir can detect tau in definite primary age–related tauopathy (PART). We identified 248 individuals at Mayo Clinic who had undergone [ 18 F]-flortaucipir PET during life, had died, and had undergone an autopsy, 239 cases of which also had amyloid-β PET. We assessed nonlinear relationships between flortaucipir uptake in nine medial temporal and cortical regions, Braak tau stage, and Thal amyloid-β phase using generalized additive models. We found that flortaucipir uptake was greater with increasing tau stage in all regions. Increased uptake at low tau stages in medial temporal regions was only observed in cases with a high amyloid-β phase. Flortaucipir uptake linearly increased with the amyloid-β phase in medial temporal and cortical regions. The highest flortaucipir uptake occurred with high Alzheimer’s disease neuropathologic change (ADNC) scores, followed by low-intermediate ADNC scores, then PART, with the entorhinal cortex providing the best differentiation between groups. Flortaucipir PET had limited ability to detect PART, and imaging-defined PART did not correspond with pathologically defined PART. In summary, spatial patterns of flortaucipir mirrored the histopathological tau distribution, were influenced by the amyloid-β phase, and were useful for distinguishing different ADNC scores and PART.

AbstractINTRODUCTIONPremenopausal bilateral oophorectomy (PBO) is associated with later‐life cognition, but the underlying brain changes remain unclear. We assessed the impact of PBO and PBO age on white matter integrity.METHODSFemale participants with regional diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA) and mean diffusivity (MD) were included (22 with PBO < 40 years; 43 with PBO 40‐45 years; 39 with PBO 46‐49 years; 907 referents without PBO < 50 years). Linear regression models adjusted for age and apolipoprotein E (APOE) genotype.RESULTSFemales with PBO < 40 years, compared to referents, had lower FA and higher MD in the anterior corona radiata, genu of the corpus collosum, inferior fronto‐occipital fasciculus, superior occipital, and superior temporal white matter. Females who underwent PBO between 45 and 49 also had some changes in white matter integrity.DISCUSSIONFemales who underwent PBO < 40 years had reduced white matter integrity across multiple regions in later‐life. These results are important for females considering PBO for noncancerous conditions.Highlights Females with premenopausal bilateral oophorectomy (PBO) < 40 years had lower FA versus referents. Females with PBO < 40 years had higher MD in many regions versus referents. Adjusting for estrogen replacement therapy use did not attenuate results. Females with PBO 45‐49 years also had some white matter changes versus referents.

AbstractINTRODUCTIONFemale‐specific reproductive factors and exogeneous estrogen use are associated with cognition in later life. However, the underlying mechanisms are not understood. The present study aimed to investigate the effect of reproductive factors on neuroimaging biomarkers of Alzheimer's disease (AD) and cerebrovascular pathologies.METHODSWe evaluated 389 females (median age of 71.7 years) enrolled in the Mayo Clinic Study of Aging with reproductive history data and longitudinal magnetic resonance imaging (MRI) scans. We used linear mixed effect models to examine the associations between reproductive factors and changes in neuroimaging measures.RESULTSEver hormonal contraception (HC) use was longitudinally associated with higher fractional anisotropy across the corpus callosum, lower white matter hyperintensity (WMH) volume, and greater cortical thickness in an AD meta‐region of interest (ROI). The initiation of menopausal hormone therapy (MHT) > 5 years post menopause was associated with higher WMH volume.DISCUSSIONHC use and initiation of MHT >5 years post menopause were generally associated with neuroimaging biomarkers of cerebrovascular pathologies.Highlights Hormonal contraception use was associated with better brain white matter (WM) integrity. Initiation of menopausal hormone therapy >5 years post menopause was associated with worsening brain WM integrity. Hormonal contraception use was associated with greater cortical thickness. Ages at menarche and menopause and number of pregnancies were not associated with imaging measures. There were few associations between reproductive factors or exogenous estrogens and amyloid or tau PET.