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Professor of Psychiatry and Behavioral Sciences Division of Geriatric Psychiatry and Neuropsychiatry Johns Hopkins Unive

Molecular Imaging of the Depression-Dementia Continuum Gwenn S. Smith, Ph.D. Professor of Psychiatry and Behavioral Sciences Division of Geriatric Psychiatry and Neuropsychiatry Johns Hopkins University School of Medicine. The Depression- Dementia Conundrum (Meyers and Bruce, 1998).

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Professor of Psychiatry and Behavioral Sciences Division of Geriatric Psychiatry and Neuropsychiatry Johns Hopkins Unive

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  1. Molecular Imaging of the Depression-Dementia Continuum Gwenn S. Smith, Ph.D. Professor of Psychiatry and Behavioral Sciences Division of Geriatric Psychiatry and Neuropsychiatry Johns Hopkins University School of Medicine

  2. The Depression- Dementia Conundrum (Meyers and Bruce, 1998) • Are these two potentially co-occurring disorders affecting the phenomenology or pathogenesis of each other? • Is depression: • a psychological reaction to cognitive decline • a neurobiological prodrome • a non-cognitive manifestation of neuronal loss • Despite adequate treatment: • 25% of patients show stable response, the rest show “brittle” response or fail to respond (Dew et al., 1997)

  3. Increased Glucose Metabolism in Cortico-Cortico Circuits in Geriatric Depressed Patients versus Controls Voxel-wise comparison of quantitative glucose metabolism data, p < 0.001

  4. Regions of the Brain with Reduced Rates of Glucose Metabolism in Eleven E4 Homozygotes and Their Relation to Brain Regions with Reduced Glucose Metabolism in Thirty-seven Patients with Probable Alzheimer's Disease. Reiman EM. Caselli RJ. Yun LS. Chen K. Bandy D. Minoshima S. Thibodeau SN. Osborne D. Preclinical evidence of Alzheimer‘s disease in persons homozygous for the E 4 allele for apolipoprotein E. New England Journal of Medicine. 334(12):752-8, 1996

  5. The Acute Cerebral Glucose Metabolic Response to Citalopram is Correlated with 12 week Citalopram Treatment Outcome Reductions in metabolism after acute citalopram (40mg, IV) are associated with improvement of depressive symptoms (Smith, G., Workman, C., AJGP, in press)

  6. Cerebral MetabolicNetworks of Improved Mood/Anxiety after Citalopram Treatment Subcortical-limbic-frontal network (Anterior Cingulate Gyrus (BA 32 seed associated with subcortical [bilateral substantia nigra, left pulvinar], and frontal regions [bilateral superior frontal gyri (BA 6), bilateral middle frontal (BA 46), bilateral orbitofrontal (BA 10/11, BA 47)], bilateral amygdala, the right insula (BA 13))

  7. Cerebral Metabolic Networks of Improved Cognition after Citalopram Treatment Medial temporal-parietal-frontal network (Parahippocampal Gyrus seed associated with frontal [bilateral superior (BA 6), left ACC (BA 24), bilateral medial (BA 10), orbitofrontal (BA 11), parietal [left precuneus (BA 7)], occipital [bilateral cuneus (BA 18) and bilateral lateral occipital gyri (BA 19)], and temporal regions [bilateral STG (BA 22), bilateral MTG (BA 21), and bilateral ITG (BA 20)]) was associated with cognitive improvement (verbal memory and verbal fluency) Diaconescu et al., 2010

  8. Decreased Serotonin Transporter Binding in Geriatric Depression Voxel-wise comparison of geriatric depressed patients to age matched controls. Widespread reductions of [11C]-DASB BPNDs are observed in cortical (anterior and posterior cingulate gyrus, precuneus, middle temporal gyrus), subcortical (thalamus, midbrain) and limbic (parahippocampal gyrus, amygdala) regions.

  9. Serotonin Transporter Occupancy is Correlated with Depressive Symptom Improvement (HDRS) x y zStructurez score 15 -16 35 Right Cingulate Gyrus 4.08 -3 6 27 Left Cingulate Gyrus (BA 24) 3.36 -31 49 -11 Left Middle Frontal Gyrus 3.58 -54 33 3 Left Inferior Frontal Gyrus 3.46 61 2 1 Right Superior Temporal Gyrus (BA 22) 3.32 39 -72 25 Right Middle Temporal Gyrus 3.47 3 -59 49 Right Precuneus (BA 07) 3.68 -39 -50 43 Left Inferior Parietal Lobule 3.48 36 -23 -25 Right Parahippocampal Gyrus 3.26 -19 -8 -16 Left Parahippocampal Gyrus 3.62 12 -98 12 Right Cuneus (BA 18) 3.19

  10. APPswe/PS1 Δ E9 mouse model Liu, Savonenko, Price, Lee et al.,2008

  11. Parametric [11C]PIB Images in Depressed MCI 75yrs; MCI Late-onset Depr 74yrs; MCI (Depr. age 49) 67yrs; MCI Early-onset Depr 67yrs; MCI Late-onset Depr 74yrs; MCI (Depr. age 55) M Butters et al. 2008

  12. Basal cerebral metabolism may modulate the cognitive effects of Abeta in mild cognitive impairment: an example of brain reserve Cohen AD, Price JC, Weissfeld LA, James J, Rosario BL, Bi W, Nebes RD, Saxton JA, Snitz BE, Aizenstein HA, Wolk DA, Dekosky ST, Mathis CA, Klunk WE. J Neurosci. 2009 ;29(47):14770-8.

  13. Sample Characteristics Gender Age MMSE HAM-D Controls 2F/3M 64.8 ± 5.3 29.6 ± 1.3 0.63  1 Patients 4F/2M 63.5 ± 4.6 29.5 ± 1.2 17.3 ± .2 3.0 ± 1.9 All 6 patients met criteria for response (50% reduction in HDRS score/HDRS score<10) and 5/6 for remission (HDRS score<6)

  14. Greater Aβ deposition ([11C]-PiB) in Geriatric Depression SFG MFG ACG PCu STG Con 1.10 ± 0.1 1.11 ± 0.1 1.15 ± 0.1 1.15 ± 0.1 1.06 ± 0.1 Dep 1.49 ± 0.4 1.42 ± 0.3 1.44 ± 0.2 1.50 ± 0.4 1.38 ± 0.3 ________________________ _DVRs; (p < 0.05) In the patients, voxel-wise analyses confirmed greater Aβ in these areas and the insula (bilateral), left orbito-frontal gyrus and left parahippocampal gyrus. Greater Aβ was correlated with less improvement in verbal memory after citalopram treatment in the anterior cingulate (BA 24, bilateral), left superior and middle frontal cortex, and parahippocampal gyrus (bilateral).

  15. Greater Aβ deposition ([11C]-PiB) in Geriatric Depression

  16. Covariance Pattern of SERT and Aβ Discriminates Geriatric Depressed Patients from Controls mmPLS Subject Score SERT: [11C]-DASB Aβ: [11C]-PiB Red: NC>PT Blue: PT>NC SERT covariance pattern with Aβ: posterior cingulate, precuneus (bilateral, p=.003) and the left hippocampus/ parahippocampal gyrus (p=.0003). Aβ ovariance pattern with SERT: posterior cingulate/precuneus (bilateral, p=.002), left anterior cingulate/medial frontal region (p=.005) and left medial orbitofrontal region (p=0.007). [mmPLS=multimodality partial least squares] (Smith, GS, Marano, C., Workman, CI, Zhou, Y, Chen, K, Reiman, E., Wong, DF, Lyketsos, CG, 2010)

  17. Working Hypotheses Aβ Decreased SERT Increased Glutamate (7T MRS) Glucose hypermetabolism

  18. “…the emerging picture is one wherein Aβ is related to both structural and functional downstream alterations that mediate neural failure or compensation and in the aggregate define the cognitive state” (Jagust , 2009)

  19. . Association of preoperative depression and survival after resection of malignant brain astrocytoma Fig. 1. Estimated Kaplan-Meier survival after primary resection of GBM (WHO grade IV) in patients with pre-operative medicated depression versus patients without pre-operative depression (median survival, 7 vs 11 months). We found that regardless of the patient's functional status prior to surgery (KPS score), WHO grade III vs. grade IV tumor, patient's age, or clinical presentation, those with depression had over a 40% increase in the relative risk of mortality versus the nondepressed cohort. This association was independent of degree of resection or postoperative treatment regimen.

  20. CONCLUSIONS • Cortical glucose hypermetabolism is observed in geriatric depression • 2) Citalopram metabolic decreases were observed in specific networks: subcortical-limbic-frontal network associated with improved affect medial temporal-parietal-frontal network associated with improved cognition • 3) SERT is decreased in geriatric depressed patients; SERT occupancy correlated with depressive symptom improvement in regions of the “affective network” • Aβ observed in regions of the “cognitive network” and is correlated with less citalopram improvement in verbal memory. • 5) The spatial covariance pattern for SERT and Aβ discriminates patients from controls to a greater extent than either measure separately.

  21. Collaborators Department of Psychiatry and Behavioral Sciences (Geriatric Psychiatry and Neuropsychiatry) Christopher Marano, MD Clifford Workman, BSc Cynthia Munro, PhD J-M Sheppard Leoutsakos, PhD Constantine Lyketsos, MD MHS Peter Rabins, MD, MPH Department of Medicine (Geriatric Medicine) Esther Oh, MD Department of Neurology (Cognitive Neuroscience) Marilyn Albert, PhD Department of Pathology (Neuropathology) Alenna Savonenko, MD, PhD Donald Price, MD Memory and Alzheimer’s Treatment Clinic Bayview General Clinical Research Center (CRU) FM Kirby Center of the Kennedy Krieger Institute

  22. Collaborators Department of Radiology Section of High Resolution Brain PET Imaging Yun Zhou, PhD Oliver Rousset, PhD Arman Rahmim, PhD James Brasic, MD Hiroto Kuwabara, MD,PhD Maria Guevara MD Blanca Bisuna, MD Babar Husain, MD Vanessa Harvey, MD Willian Willis, BA Steven Condouris, BA Daniel Holt, BS Robert Dannals, PhD Dean F. Wong, MD, PhD Neuroradiology Martin Pomper, MD, PhD Christopher Endres, PhD Micharl Kraut, MD, PhD National Institute on Aging Susan Resnick, PhD SUPPORT BY THE NIMH GERIATRICS RESEARCH BRANCH Jovier Evans, PhD, George Niederehe, Ph.D

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