Firat Kara

University of Antwerp, Bio-imaging, Post-Doc

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Dr. Firat Kara is an assistant professor of Radiology at the Mayo Clinic, Rochester, Minnesota. Dr. Kara received his Ph.D. degree from Leiden University and completed his postdoc in the Bioimaging Lab at Antwerp University. His research focuses on imaging and epidemiology of neurodegenerative diseases such as Alzheimer’s disease. In particular he studies how sex related physiological alterations effect progression of Alzheimer’s disease. In addition he studies how tau and amyloid pathologies are associated with brain metabolites, as measures by magnetic resonance spectroscopy.
Address: Breda, North Brabant, Netherlands

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Eric S . Kim (UBC)

University of British Columbia

Issel Anne Lim, PhD

Johns Hopkins University

John Sutton

Macquarie University

Keith Laws

University of Hertfordshire

Tomasz Komendzinski

Nicolaus Copernicus University

Fabio Gualtieri

Ludwig-Maximilians-Universität München

Gedeon Deák

University of California, San Diego

Stephen Mayhew

University of Birmingham

Bálint Forgács

Eötvös Loránd University Budapest

Giorgio Seano

Institut Curie

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Papers by Firat Kara

Premenopausal bilateral oophorectomy and brain white matter brain integrity in later‐life

Alzheimer's & dementia, Jun 20, 2024

Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study

medRxiv (Cold Spring Harbor Laboratory), Jun 30, 2024

Imaging in Neurology Research II: Exploring Plasticity and Cognitive Networks by In Vivo MRI

Springer eBooks, 2017

The aim of this chapter is to introduce several models of neuroplasticity and to illustrate how b... more

Plug-and-play Advanced Magnetic Resonance Spectroscopy

We developed an automated advanced-single-voxel MRS acquisition protocol at 3T to facilitate acqu... more We developed an automated advanced-single-voxel MRS acquisition protocol at 3T to facilitate acquisition of high-quality spectroscopic data without local MRS expertise. Voxel-based B0 and B1 calibrations were incorporated into the consensus-recommended semi-LASER sequence and combined with automated voxel prescription. Automated B0 and B1 calibrations saved ~4.5min per voxel vs. manual calibrations. All spectra acquired with the automated protocol by rotating MR technologists were usable, while only 83% of those collected with the manual protocol were usable and spectral quality was more variable. The protocol allows automated acquisition of high-quality MRS data with high success rate on a clinical 3T platform.

Association of tamoxifen and raloxifene therapy with cognitive performance, odds of mild cognitive impairment, and neuroimaging markers of neurodegeneration

Alzheimers & Dementia, Jun 1, 2023

BackgroundTamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone rec... more BackgroundTamoxifen is used as a selective estrogen receptor modifier (SERM) to treat hormone receptor‐positive breast cancer. Raloxifene, another SERM, has been used for the treatment of osteoporosis in post‐menopausal women. The aim of this cross‐sectional study was to examine whether a history of tamoxifen or raloxifene use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or structural neurodegenerative MRI markers.MethodThe study included women with and without a personal history of breast cancer enrolled in the Mayo Clinic Study of Aging (MCSA). A history of breast cancer and use of SERMs before the MCSA enrollment visit was abstracted using the Rochester Epidemiology Project medical‐linkage system. Participants had a diagnosis of MCI (prevalent) at the time of enrollment into the MCSA. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive measures z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), hippocampal volume, and Alzheimer’s disease signature cortical thickness.ResultAmong the women aged ≥ 50 at enrollment in the MCSA, 151 had a history of breast cancer, and 2235 had no prior history of any cancer. Of the 151 women with a history of breast cancer, 42 (28%) had taken tamoxifen and 109 (72%) had not at enrollment in the MCSA; 54 had neuroimaging data (tamoxifen = 16; no tamoxifen = 38). Among the women without prior history of cancer at enrollment in the MCSA, 76 (3%) had taken raloxifene and 2159 (97%) had not; 755 had neuroimaging data (raloxifene = 25; no raloxifene = 730). No significant associations between tamoxifen with global or domain‐specific cognition or odds of MCI were observed among women with a history of breast cancer after adjusting for confounders (Table 1). Likewise raloxifene was not significantly associated with global or domain‐specific cognition or odds of MCI in women without a history of cancer after adjusting for confounders (Table 2). We did not find significant associations between SERMs and any neuroimaging outcome (Table 3).ConclusionOur results suggest use of tamoxifen or raloxifene is not significantly associated with cognition in postmenopausal women.

Standardization of Small Animal Imaging—Current Status and Future Prospects

Molecular Imaging and Biology, Oct 2, 2017

The benefit of small animal imaging is directly linked to the validity and reliability of the col... more The benefit of small animal imaging is directly linked to the validity and reliability of the collected data. If the data (regardless of the modality used) are not reproducible and/or reliable, then the outcome of the data is rather questionable. Therefore, standardization of the use of small animal imaging equipment, as well as of animal handling in general, is of paramount importance. In a recent paper, guidance for efficient small animal imaging quality control was offered and discussed, among others, the use of phantoms in setting up a quality control program (Osborne et al. 2016). The same phantoms can be used to standardize image quality parameters for multicenter studies or multi-scanners within center studies. In animal experiments, the additional complexity due to animal handling needs to be addressed to ensure standardized imaging procedures. In this review, we will address the current status of standardization in preclinical imaging, as well as potential benefits from increased levels of standardization.

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In Vivo Preclinical Molecular Imaging of Repeated Exposure to an N-methyl-d-aspartate Antagonist and a Glutaminase Inhibitor as Potential Glutamatergic Modulators

Journal of Pharmacology and Experimental Therapeutics, Dec 14, 2018

Glutamate is the principal excitatory neurotransmitter in the brain and is at the base of a wide ... more Glutamate is the principal excitatory neurotransmitter in the brain and is at the base of a wide variety of neuropathologies, including epilepsy, autism, Fragile X, and obsessive compulsive disorder. Glutamate has also become the target for novel drugs in treatment and in fundamental research settings. However, much remains unknown on the working mechanisms of these drugs and the effects of chronic administration on the glutamatergic system. This study investigated the chronic effects of two glutamate-modulating drugs with imaging techniques to further clarify their working mechanisms for future research opportunities. Animals were exposed to saline (1 ml/kg), (5S,10R)-(1)-5-Methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine (MK-801) (0.3 mg/kg), or ebselen (10 mg/kg) for 7 consecutive days. At the sixth injection, animals underwent a positron emission tomography (PET)/ computed tomography (CT) with (3-(6-methyl-pyridin-2ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime) (ABP-688) to visualize the metabotropic G protein-coupled glutamate receptor 5 (mGluR5). After the seventh injection, animals underwent a magnetic resonance spectroscopy (MRS) scan to visualize glutamate and glutamine content. Afterward, results were verified by mGluR5 immunohistochemistry (IHC). PET/CT analysis revealed that animals receiving chronic MK-801 or ebselen had a significant (P , 0.05) higher binding potential (2.90 6 0.47 and 2.87 6 0.46, respectively) when compared with saline (1.97 6 0.39) in the caudate putamen. This was confirmed by mGluR5 IHC, with 60.83% 6 6.30% of the area being highlighted for ebselen and 57.14% 6 9.23% for MK-801 versus 50.21% 6 5.71% for the saline group. MRS displayed significant changes on the glutamine level when comparing chronic ebselen (2.20 6 0.40 mmol/g) to control (2.72 6 0.34 mmol/g). Therefore, although no direct effects on glutamate were visualized, the changes in glutamine suggest changes in the total glutamate-glutamine pool. This highlights the potential of both drugs to modulate glutamatergic pathologies.

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In Vivo Longitudinal Monitoring of Changes in the Corpus Callosum Integrity During Disease Progression in a Mouse Model of Alzheimer’s Disease

Current Alzheimer Research, Nov 18, 2015

The corpus callosum is the largest commissural fiber connecting left and right hemisphere of the ... more The corpus callosum is the largest commissural fiber connecting left and right hemisphere of the brain. Emerging evidence suggests that a variety of abnormalities detected in the microstructure of this white matter fiber can be an early event in Alzheimer's disease (AD) pathology. However, little is known about tissue characteristics of these abnormalities and how these abnormalities evolve during AD progression. In this study, we measured in vivo magnetic resonance transverse relaxation times (T2) to longitudinally monitor changes in tissue integrity and abnormalities related to myelination and demyelination processes in corpus callosum of AD mouse models. The most striking finding of our study was a significant elongation of T2 values in the corpus callosum at 10, 14, 16 and 18 months of age compared to age-matched wild-type mice. In contrast, the gray matter regions surrounding the corpus callosum, such as the cortex and hippocampus, showed a significant T2 decrease compared to wild-type mice. Histological analyses clearly revealed demyelination, gliosis and amyloid-plaque deposition in the corpus callosum. Our results suggest that demyelinating and inflammatory pathology may result in prolonged relaxation time during AD progression. To our knowledge, this is the first in vivo T2 study assessing the microstructural changes with age in the corpus callosum of the Tg2576 mouse model and it demonstrates the application of T2 measurement to noninvasively detect tissue integrity of the corpus callosum, which can be an early event in disease progression.

Neurochemical levels measured by 1 H MR spectroscopy are associated with amyloid‐β and tau deposition in cognitively unimpaired older adults

Alzheimers & Dementia, Dec 1, 2021

Proton MR Spectroscopy (1H MRS) provides non‐invasive measurements of alterations in brain bioche... more Proton MR Spectroscopy (1H MRS) provides non‐invasive measurements of alterations in brain biochemistry associated with neuronal and glial abnormalities in neurodegeneration. 1H MRS with along with automated voxel placement (AVP) improves the precision of 1H MRS metabolite measurements. Our objective was to investigate the association of 1H MRS metabolites obtained by the advanced sLASER single voxel 1H MRS protocol with early tau deposition as measured by AV‐1451 PET and Aβ deposition as measured by 11C‐Pittsburgh compound B (PiB) PET in cognitively unimpaired older adults.

rnaset2 mutant zebrafish model familial cystic leukoencephalopathy and reveal a role for RNase T2 in degrading ribosomal RNA

Proceedings of the National Academy of Sciences of the United States of America, Jan 3, 2011

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Long-term ovarian hormone deprivation alters functional connectivity, brain neurochemical profile and white matter integrity in the Tg2576 amyloid mouse model of Alzheimer's disease

Neurobiology of Aging

Premenopausal bilateral ovariectomy is considered to be one of the risk factors of Alzheimer'... more Premenopausal bilateral ovariectomy is considered to be one of the risk factors of Alzheimer's disease (AD). However, the underlying mechanisms remain unclear. Here, we aimed to investigate long-term neurological consequences of ovariectomy in a rodent AD model, TG2576 (TG), and wild-type mice (WT) that underwent an ovariectomy or sham-operation, using in vivo MRI biomarkers. An increase in osmoregulation and energy metabolism biomarkers in the hypothalamus, a decrease in white matter integrity, and a decrease in the resting-state functional connectivity was observed in ovariectomized TG mice compared to sham-operated TG mice. In addition, we observed an increase in functional connectivity in ovariectomized WT mice compared to sham-operated WT mice. Furthermore, genotype (TG vs. WT) effects on imaging markers and GFAP immunoreactivity levels were observed, but there was no effect of interaction (Genotype × Surgery) on amyloid-beta-and GFAP immunoreactivity levels. Taken together, our results indicated that both genotype and ovariectomy alters imaging biomarkers associated with AD.

Association of raloxifene and tamoxifen therapy with cognitive performance, odds of mild cognitive impairment, and brain MRI markers of neurodegeneration

Cancer Medicine

The aim of this cross‐sectional study was to examine whether a history of selective estrogen rece... more The aim of this cross‐sectional study was to examine whether a history of selective estrogen receptor modifiers (SERMs), tamoxifen and raloxifene, use was associated with cognitive performance, odds of mild cognitive impairment (MCI), or magnetic resonance imaging (MRI) markers of neurodegeneration associated with Alzheimer's disease. We included women with prior history of breast cancer or no prior history of any cancer at enrollment in the Mayo Clinic Study of Aging (MCSA). This information was abstracted using the Rochester Epidemiology Project medical‐linkage system. Logistic regression was used to examine associations of SERMs with odds of MCI. Linear regression models were used to examine associations of SERMs with cognitive z‐scores (Memory, Executive Function, Language, Visuospatial Skills, Global Cognition), and MRI markers. Among 2840 women aged 50 and older in the MCSA, 151 had a history of breast cancer, and 42 (28%) of these had a history of tamoxifen treatment. A t...

Neurochemical levels measured by 1 H MR spectroscopy are associated with amyloid‐β and tau deposition in cognitively unimpaired older adults

Alzheimer's & Dementia, 2021

Higher systolic and diastolic blood pressures are associated with loss of white matter integrity in postmenopausal women of the KEEPS Continuation Study

Alzheimer's & Dementia, 2021

BackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. ... more BackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.MethodWomen (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.ResultThe median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/&lt;120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).ConclusionHigher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

Plug‐and‐play advanced magnetic resonance spectroscopy

Magnetic Resonance in Medicine, 2022

PurposeAdvanced MRS protocols improve data quality and reproducibility relative to vendor‐provide... more PurposeAdvanced MRS protocols improve data quality and reproducibility relative to vendor‐provided protocols; however, they are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high‐quality spectroscopic data without local MRS expertise.MethodsFirst, a B0 shimming protocol was selected for automation by comparing 3 widely used B0 algorithms (2 vendor protocols and FAST(EST)MAP). Next, voxel‐based B0 and B1 calibrations were incorporated into the consensus‐recommended semi‐LASER sequence and combined with an automated VOI prescription tool, a recently developed method for automated voxel prescription. The efficiency of collecting single‐voxel data from a clinical cohort (N = 40) with the automated protocol (calibration time and fraction of usable datasets) was compared with the nonautomated semi‐LASER protocol (N = 35...

1H MR spectroscopy biomarkers of neuronal and synaptic function are associated with tau deposition in cognitively unimpaired older adults

Neurobiology of Aging, 2022

Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological cha... more Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.

Waist‐hip ratio as a moderator of the effects of hormone therapy on cognitive function in recently menopausal women

Alzheimer's & Dementia, 2021

BackgroundResearch on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive ... more BackgroundResearch on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive decline or Alzheimer’s disease has been inconsistent. The Women’s Health Initiative Memory Study (WHIMS) revealed elevated incident cognitive impairment for women starting MHT after age >65 with oral conjugated equine estrogens (o‐CEE) treatment, especially among women with diabetes. Subsequently, the Cognitive and Affective substudy of the Kronos Early Estrogen Prevention Study (KEEPS‐Cog) found that MHT initiated soon after menopause caused neither cognitive benefit nor harm. Waist‐to‐hip ratio (WHR) is a measure of central adiposity and a surrogate marker for insulin resistance/prediabetes. To explore effects of MHT in insulin‐resistant states, in younger women, we analyzed WHR as a predictor of cognitive response to MHT in KEEPS‐Cog.MethodsKEEPS‐Cog randomized women less than 36‐months postmenopause to oCEE, transdermal 17‐β‐estradiol (tE2) or placebo for 48 months. Cognitive test...

15.1 28.60 ± 0.38 28.38 ± 0.10 26.06 ± 0.28 26.28 ± 0.23 26.28 ± 0.53 26.55 ± 0.27 Age-related ch... more 15.1 28.60 ± 0.38 28.38 ± 0.10 26.06 ± 0.28 26.28 ± 0.23 26.28 ± 0.53 26.55 ± 0.27 Age-related changes in regional brain T1 and T2 relaxation times in the healthy mouse at 17.6 T Firat Kara, Fu Chen, Itamar Ronen, Huub J. M. de Groot, Jorg Matysik, and A Alia Leiden Institute of Chemistry, Leiden University, Leiden, Netherlands, Department of Radiology, Leiden University Medical Center, Leiden, Netherlands, Institut fuer Analytische Chemie, Universitaet Leipzig, Leipzig, Germany

Monitoring Alzheimer's disease in transgenic mice with ultra high field magnetic resonance imaging

While aging remains one of the most significant risk factors for development of Alzheimer disease... more While aging remains one of the most significant risk factors for development of Alzheimer disease (AD), increasing evidence strongly points to the potential roles of cerebrovascular and white matter abnormalities in the disease development. A better understanding of the manner in which these abnormalities contribute to disease progression can be achieved by in vivo characterization of AD related pathologies. To this end, MR based techniques serve as effective non-invasive tools to longitudinally monitor changes in AD brain. In this thesis, a variety of MR based techniques were optimized and employed to longitudinally monitor the AD progression in transgenic mouse models of the disease at 9.4T and 17.6T. In Chapter 2, age-dependent blood flow alterations were examined in a Tg2576 mouse model of Alzheimer's disease using MR angiography at 17.6T. AD is linked to abnormalities in the vascular system. In Chapter 3, in vivo T2 changes were longitudinally monitored in the corpus callos...

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Preservation of white matter integrity on DTI 3 years after early menopausal hormone therapies

Alzheimer's & Dementia

BackgroundThe critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopau... more BackgroundThe critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopausal hormone therapy begins shortly after menopause, it may have beneficial effects on brain structure and cognitive health. We investigated white matter integrity with diffusion tensor MRI (DTI) 3 years after the end of mHT trial in recently menopausal women who were randomized shortly after menopause.MethodParticipants of this study were enrolled in the Kronos Early Estrogen Prevention Study (aged 42–56 years; 5–36 months past menopause). Participants received the following treatments: 0.45 mg/d oral conjugated equine estrogen (oCEE, n=19); 50 μg/d transdermal 17β‐estradiol (tE2, n=22); or placebo (n=33) for 4 years. Oral progesterone (200 mg/d) was given to hormone therapy groups for 12 days each month. DTI was performed 3 years after the end of 4 years of hormone therapy (n=75), which corresponded to 7 years after randomization. Voxel‐based analysis was performed on DTI to evaluate fr...

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Premenopausal bilateral oophorectomy and brain white matter brain integrity in later‐life

Alzheimer's & dementia, Jun 20, 2024

Long-term cognitive effects of menopausal hormone therapy: Findings from the KEEPS Continuation Study

medRxiv (Cold Spring Harbor Laboratory), Jun 30, 2024

Imaging in Neurology Research II: Exploring Plasticity and Cognitive Networks by In Vivo MRI

Springer eBooks, 2017

The aim of this chapter is to introduce several models of neuroplasticity and to illustrate how b... more

Plug-and-play Advanced Magnetic Resonance Spectroscopy