Treatment: Lewy body disease and more Present and Future Bruce L. - PowerPoint PPT Presentation

Neurodegenerative Causes Alzheimer’s disease frontotemporal dementia Treatment: Lewy body disease and more Present and Future Bruce L. Miller, MD A.W. and Mary Margaret Clausen Distinguished Professor in Neurology Director, Memory and Aging Center Co-Director, Global Brain Health Institute Joint Appointment in Psychiatry Dementia cognitive decline that interferes with everyday functioning memory, executive, behavioral, and/or motor symptoms Neuropathologic Inclusions AD & PD Spread Along Circuits AD Aβ-42 & tau  Tau-positive neurofibrillary FTD tau or lesions in AD TDP-43 (left, green) PSP, CBD tau  α-synuclein-positive lesions (Lewy bodies & PD, DLB, MSA α-synuclein neurites) in PD & DLB CJD PrP sc Goedert et al Trends Neurosci 2010 1

Functional Connectivity Dorsal Midbrain Selective Vulnerability Brainstem Tegmental Network & Tau PET in PSP Nuclei/Tauopathies Functional Connectivity Tau PET  Locus Coeruleus  Dorsal Raphe Nuclei  Substantia Nigra  Gigantocellular Nuclei  Pedunculopontine Nuclei 0 2.5 Eser et al Grinberg Lab JNEN 2018 Gardner et al. Ann Neurol 2013, Rabinovici 2015 24-Hour Sleep Patterns in Adults Neurodegeneration Fiction & Facts Fiction Fact Healthy Older Adult Degenerative disorders begin Most start with psychiatric 1. 1. PSP: change in cognition or movement prodrome key to early intervention Hyperarousal Psychiatric symptoms lack They are key to understanding 2. 2. day & night scientific relevance to dementia neurodegeneration Mood disorders are a reaction Mood changes reflects 3. 3. to the illness anatomy/chemistry of disease CBS: Psychiatric symptoms in They are the roadmap for 4. 4. neurodegeneration irrelevant understanding mood, emotion Decreased to typical psychiatric disorders psychosis, compulsions, etc. arousal Walsh... Neylan 2017 Sleep 2

Psychiatric Syndromes, Particularly Late in Life, Psychiatric Changes in Dementia Increase Risk for Dementia  13,535 patients, Kaiser Permanente 14% midlife depressive symptoms (45–60) - 9% late life symptoms (60–75) -  Midlife symptoms increased risk of dementia by 20%  Late life symptoms increased risk by 70% Barnes, Yaffe et al, Arch Gen Psychiatry, 2012 Shdo, et al., submitted Hypothesis Psychiatric Disorders in PD  Early changes in brainstem reticular core  108 patients seen by psychiatrist (Seritan) from 2015–18 (Braak stages 1–3): serotonergic,  Age: 63.7 ± 8.9 years noradrenergic, and cholinergic systems disrupted  anxiety, depressive symptoms  Sex: 72 (66.7%) male  PD diagnosis age: 52.8 ± 11 years N (%)  Amygdala sensitive to brainstem projection Patients with anxiety disorders 72 (66.7) changes  anxiety, depressive symptoms • Preceding PD diagnosis 40 (55.5) appear earlier than motor dysfunction Patients with depressive disorders 94 (87.0) • Preceding PD diagnosis 49 (52.1) Patients with anxiety & depressive disorders 63 (58.3) Braak et al., 2003 Seritan et al., accepted 3

Chronic Invasive Brain Recordings to Study Median Onset Ages For MDD, GAD, and Anxiety and Depression in PD Patients Panic Disorder, Compared to General Population Median Onset Ages More 1) Patient selection: symptoms severe - Patients with PD - with anxiety/depression - Needing DBS to control motor signs Minimal General population Sign test 2) Patients are implanted with a 3) Brain signals are chronically permanent ECoG strip over the N Min Median Max median onset age p-value Recorded in different mood states PFC attached to an Activa PC+S and paired with mood assessment MDD 39 8 46 74 29 < .0001 using visual analogue scales on p=0.008 an IPad app (Moodify) GAD 15 31 50 74 32 .0002 Panic disorder 13 20 59 71 24 .0005 50 uV 20 60 40 1s N = number of patients with exact onset ages for this psychiatric disorder; Min = minimum age; worse 5) PFC beta power (20-30Hz) correlates 4) Each PFC recording is analyzed in the Max = maximum age; GAD = generalized anxiety disorder; MDD = major depressive disorder. With the severity of anxiety and depression frequency domain and correlate with symptoms Seritan et al., accepted De Hemptinne & Starr Beta Power in the Prefrontal Cortex Correlates Early Changes in Emotion Accompany AD with Anxiety and Depression in PD Patients Emotional symptoms occur frequently  In MCI (35–85%) and AD (75%) - p=0.008 Anxiety and depression are most common - With comorbid emotional symptoms there is:  Worse function, higher risk of dementia conversion - More rapid decline - Recording contacts Increased salience network  connectivity in AD (Zhou, 2010)  Relates to agitation, irritability, - More beta power in the prefrontal cortex is associated aberrant motor behavior (Balthazar, 2013) - with more severe anxiety/depression 4

BLSA Increasing Emotional Reactivity in Antidepressant Use Associated with Lower Preclinical AD & Insula Hyperconnectivity Amyloid-β in Humans  Retrospective analysis of PET scans  Older adults with antidepressant treatment (trazodone) in the past 5 years showed less amyloid-β accumulation  Longer treatment time correlated with lower amyloid-β burden R Fredericks et al., Alz Dement 2018 Cirrito et al, PNAS, 2011 Loss of Empathy Relationship Turmoil and Empathy in FTD  R temporal pole  Marital dissolution and infidelity significantly greater in the  R medial OFC bvFTD group than nfvPPA, svPPA, CBS, PSP and AD  R caudate  R medial frontal  Across all patients, empathy loss associated marital dissolution  bvFTD patients who experienced marital dissolution or infidelity Only right hemisphere had significantly lower empathy scores than those who did not mediates these empathy changes Takeda & Perry et al, submitted Rankin et al. Brain 2006 5

Caregiver Health Study Caregiver 162 caregivers or study  162 patients or healthy controls  Psychopathology partners 35 Alzheimer’s disease - Patient 32 Behavioral variant FTD - Brain 15 Nonfluent variant FTD - 83% spouses  23 Semantic variant FTD - 63 years old  17 Corticobasal Syndrome Caregiver - 56% female  17 Progressive Supranuclear Palsy - Global Health 23 Healthy Controls 88% White American  - Measures: Covariates: Structural MRI  Measures:  caregiver age and sex MMSE (cognitive functioning)  SCL-90 (Psychopathology)  patient diagnosis, disease severity, cognitive functioning, head size  CDR (disease severity)  SF-36 (Global Health)  MRI scanner field strength  NPI (Neuropsychiatric Inventory)  Hua, Wells, Haase, Chen, Rosen, Miller, Levenson (accepted) Hua, Wells, Haase, Chen, Rosen, Miller, Levenson (accepted) Dementia and Geriatric Cognitive Disorders Dementia and Geriatric Cognitive Disorders Consistent Neural Correlates of Lifestyle Moderates Clinical Manifestation Worse Caregiver Health of Genetic FTD MAPT, GRN, C9orf72 *Adj. baseline frontotemporal volumes, age, Hua, Wells, Haase, Chen, Rosen, Miller, Levenson (accepted) Casaletto, 2018 Dementia and Geriatric Cognitive Disorders sex, education, FTLD-CDR sum of boxes 6

How? What are “modifiable factors”? Retraining Speech Production and Fluency in nfvPPA Physical activity Stress Treatment was repeated rehearsal of scripts via    structured treatment with a clinician as well as Cognitive stimulation/Education Social engagement   home practice Diet Head trauma   Significant improvement in production of correct,  Vascular disease Poor sleep   intelligible scripted words for trained topics, smoking Pollution -  reduction in grammatical errors for trained topics, and overall increase in intelligibility for trained as hypertension - well as untrained topics at post-treatment diabetes - Follow-up testing revealed maintenance of gains  obesity - for trained scripts up to 1 year post-treatment Henry et al. 2018 Physical Activity is Associated Mental Stimulation & “Brain Training” with Better Brain Aging  ACTIVE Study: 10-year benefits of processing speed & Any type (almost), ≥moderate intensity, ≥45 minutes, any frequency  reasoning trainings Increased memory structures  Increased Connection Better integrity of brain connections  Thinking Speed  UCSF Gazzaley Lab: Restore brain activity Less inflammation  Associated with “super cognitive aging” to young adult levels   Conversely…Watching TV >3hrs/day in mid-life  poorer cognition 25 years later - Northey et al., 2017; Erickson et al., 2011; Bott et al., 2017 Rebok et al., 2014; Anguera et al., 2013; Hoang et al , 2016 7