Faculty Disclosure. Subhash K. Bhatia, MD, FACPsych, DLFAPA. Dr. Bhataia has listed an affiliation with:

Transcription

1 Faculty Disclosure Subhash K. Bhatia, MD, FACPsych, DLFAPA Dr. Bhataia has listed an affiliation with: Grant/Research Support Vilazidone Double Blind Placebo Control Study for PTSD, sponsored by Forest Lb Laboratories however, no conflict of interest exists for this conference. Dementia: Early Diagnosis and Treatment Strategies Subhash C Bhatia, MD.; FACPsych; DLFAPA Professor and Vice-Chairman for Clinical Affairs, Creighton University Department of Psychiatry Chief Mental Health and Behavioral Sciences Department VA Nebraska-Western Iowa Health Care System 1

2 OBJECTIVES To distinguish cognitive changes of normal aging from the pathologic changes in patients with dementia. To discuss diagnosis and treatment of prodrome of AD To discuss evidenced-based diagnostic criteria for AD. To discuss evidenced based Interventions for AD MEMORY AND NORMAL AGING Slow speed of information processing, delayed recall Benign forgetfulness: Forgetting part of an experience, may be short on details but global awareness of event is preserved Person is Aware of deficit and able to compensate by notes and/or reminders 2

3 MEMORY AND NORMAL AGING..CONTINUED Non-progressive nature of the deficit Deficit does not interfere with social and work life Experience, wisdom, higher skills in grammar and density of ideas are compensate this deficit FDG PET FINDINGS IN NORMALYOUNG AND THE OLD No Significant PET Scan differences 3

4 MILD COGNITIVE IMPAIRMENT(MCI) Amnestic type: Trouble remembering recently acquired information without effect on reasoning. This is verified by collateral source -Frequently misplacing items, forgetting appointments -Asking the same questions repeatedly, having difficulty in recalling recent events - This may progress to AD MILD COGNITIVE IMPAIRMENT(MCI) MCI is probably a prodrome to AD Morris et al. Arch Neurol. 2001;58: Approximately 50% of patients with MCI will have Alzheimer s within 4 years and 80% within 10 years 4

5 COMPARISON TO NORMAL SMALLER HIPPOCAMPUS VOLUME ON MRI IN MCI Treatment of MCI A Cholinesrase Inhibitor in comparison to Vitamin E and placebo reduce risk developing AD during 1 st year but no difference at end of 3 years Peterson et al. NEJM. June

6 POTENTIALLY REVERSIBLE CAUSES OF MEMORY LOSS D: Drugs with anticholinergic effects E: Emotions: Depression but may be an independent risk factor for AD (Ownby et al. Arch Gen Psychiatry 2006;63: ) M: Metabolic: Cardiac, pulmonary, hepatic, renal E: Endocrinopathies: Hypothyroidism N: Nutritional or Normal Pressure Hydrocephalous T: Trauma, Tumor, Toxins: Heavy Metals, Farm &Env. Toxins I: Infections: Neurosyphilis, HIV, Fungal, bladder infection A: Arterial: Vascular Causes Jerome Vesavage, MD, Stanford University 6

7 Dementia with Lewy Bodies Pathologic Aggregation of Alpha-synuclein in Neuronal Cytoplasm and Deceased Dopamine in Basal Ganglia Fluctuating Cognition with Variation in Attention and Alertness Recurrent Visual hallucinations Motor Features of Parkinsonism Severe Antipsychotic Medication Sensitivity REM Sleep Behavior Disorder Decrease tracer uptake in Striatum on SPECT No Genotypic or CSF Biomarkers as Seen in AD VASCULAR DEMENTIA Due to Disease of Small and Large Cranial Vessels Fluctuating Course Related to Cardiovascular Events Gait Disturbance, Parkinsonism, Bladder Incontinence are Early Features MRI Shows Completed or Lacunar Infarcts 7

8 Dr. Alzheimer First described d by Dr. Alois Alzheimer ( ), was a German psychiatrist and neuropathologist a colleague of Kraepelin In 1907 saw a 51-year-old female patient with memory loss, disorientation, and hallucinations Postmortem study showed Senile plaques Neurofibllary Tangles (NFTs) Alzheimer s Disease (AD) A. Multiple cognitive disturbances manifested by both 1.Memory impairment, ability to learn new information or recall previously learned information 2.One or more of the following agnosia, aphasia,apraxia, disturbance of executive functions i.e. planning, organizing, sequencing, abstracting B. Decline in Social, occupational functioning and significant decline from a previous level C. Gradual onset and progressive Course D. Not due to other medical, neurological or substance related E. Not part of delirium. Or F. Not due to another Axis I psychiatric disorder Adapted from APA DSM-IV TR 8

9 DIAGNOSIS OF AD 2011 National Institute of Aging and Alzheimer s Assoc. Workgroups Guidelines Possible AD: Meets DSM criteria without positive biomarkers Probable AD: Meets DSM criteria with positive biomarkers Definitive AD: Meets Probable AD criteria with histopathologic evidence McKhann et al. NIA-Alzheimer s Assoc. workgroups on Diagnostic Guidelines for AD. Alzheimer s Dement 2011;7(3): AD Unfortunately Afflicted These Men? 9

10 AD Biomarkers Histopathology Relate to: Inter-neuronal beta-amyloid plaque deposits Intra-neuronal neurofibllary tangles due to taupathy 10

11 CSF Biomarkers Increased CSF phosphorylated tau protein: sensitivity 44-94% and specificity % Decreased CSF β-amyloid 42 (A β -42): sensitivity 78%, specificity 81% GENETIC BIOMARKERS Early Onset (Familial) : Gene Mutations of β-app( less than 1%) -Presenilin I (Chromosome 14) -Presenilin II (Chromosome 1) -Down s Syndrome (Chromosome 21) Late Onset.Sporadic( Greater than 99% ) - Apolipoprotein E ε4 allele on chromosome 19q13.2: Not a cause for but increases risk AD: one copy approx.3.5 fold, two copies approx fold This gene is also involved in cholesterol transport protein (role of statins?) Age is a Risk Factor 11

12 Structural Imaging Biomarkers Volumetric MRI measurements: regional or whole brain shrinkage of volume Functional Imaging Biomarkers Fluorodeoxyglucose positron emission tomography (FDG PET) : Decreased Parietotemporal cerebral FDG metabolic rate Single Photon Emission Computed Tomography(SPECT): Parietotemporal hypoperfusion Adapted from Reiman et al. J Alzheimer's Dis 2011:

13 FDG PET SCANS: NORMAL AND ALZHEIMER S BRAIN M. Mega, MD, PhD, Department of Neurology, UCLA School of Medicine. Functional Imaging Biomarkers: Amyloid Imaging Using Pittsburg Compound B 13

14 Functional Imaging Biomarker: Amyloid Imaging using Florbetapir Other Findings in AD Due to degeneration of Cholinergic rich Nucleus Basalis of Meynert : Cholinergic Deficiency Inflammatory Processes: Microglia inflammatory cells seen near amyloid plaques Vascular factors: homocysteine, cholesterol (APOE-ε4 cholesterol transport protein) 14

15 COGNITIVE ASSESSMENT Quick Cognitive Assessment: MINI-COG Ask the patient to listen carefully and remember three (3) unrelated words and have the patient repeat those Have the patient draw face of the clock showing 11: 20. Give as much time needed to complete the CDT Ask the patient to repeat three (3) previously presented words Mini-cog compares well with longer screening tests for detecting dementia Kuslansky Evid Based Ment Health. 2004:7:38 15

16 MINI-COG: SCORING Give 1 point each correctly recalled word -Score Positive screen for dementia -Score 1or 2 with abnormal CDT-----Positive screen for dementia -Score 1 or 2 with normal CDT Negative screen for dementia - Score of Negative screen for dementia CDT is normal if all #s on dial are in correct sequence and position and hands correctly display requested time 2004 Geriatrics at Your Fingertips(GAYF) by American Geriatrics Society. 16

17 FOLSTEIN S MINI-MENTAL STATE EXMINATION The Progress of Alzheimer s Disease 30 Early Mild-moderate Severe Cognitive symptoms 25 MMSE score Loss of ADLs Behavioral problems 5 Nursing home placement Death Years Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer s Disease. 1996:

18 FOUR PILLARS OF DEMENTIA CARE First Pillar: Managing AD to reverse its effects or delay its progression Second Pillar: Management of Cognitive, Neuropsychiatric or Functional Symptoms to Enhance Quality of Life Third Pillar: Systematic and Evidenced- based Symptom Management Fourth Pillar: Caring for the Care Givers Lyketsos GC et al. Position Statement of American Association Geriatric Society regarding principles of care of patients resulting from Alzheimer's Disease. Am J Geriart Psychiatry. 14: , 2006 CURRENT PHARMACOTHERAPPIES MAY DELAY PROGRESSION OR MITIGATE SYMPTOMS BUT DONOT REVERSE ITS EFFECTS 18

19 MEDICATIONS FOR AD A. FDA Approved (Cognitive Enhancing interventions): I. Acetyl cholinesterase Inhibitors for mild to moderate AD Galantamine (Razadyne) Donepezil (Aricept) Rivastigmine (Exelon) Tacrine (Cognex) II. Glutamate Receptor (NMDA) Antagonist: Memantine for moderate to severe AD B. FDA Unapproved or Experimental Pharmacotherapies : Anti-inflammatory Agents Anti-oxidative agents Statins Immune System Modulators ACETYLCHOLINESTRASE INHIBITORS Drugs Galantamine- ER Rivastigmine tab/patch Donepezil Tacrine AChE : Yes Yes Yes Yes Inhibition Nicotinic i Yes No No No Receptor: Modulation BuChE: Slight Yes Slight Yes Inhibition Dose (mg) Initial 8-15mg 1.5mg bid 5mg-10 mg 10mg qid- Maximum 24 mg daily 6 mg bid Daily bedtime 40mg qid Food Clearance Yes Half Life: 7 hr 2D6,3A4 Yes for tab Half life:1.25 hr: Renal Excretion No Half life:70-80 hr:2d6,3a4 Yes, Hepatotoxic ity 19

20 Cholinesterase Inhibitors In controlled trials these cognitive enhancers cause modest improvement in cognition and function Do not alter underlying neuropathathogy for AD Make sure patient is not on any drug with anticholinergic side effects N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONIST Glutaminergic Overstimulation may be the cause of excito-toxic neuronal damage. Antiglutaminergic effect of memantine may reduce clinical deterioration in moderate-to-severe Alzheimer's disease. Starting dose 5mg daily, increase the dose by 5 mg every week with a maximum of 10 mg BID during week 4. Reisberg et al. NEJM 2003;348: In patients with moderate-to-severe AD on stable doses of Donepezil, Memantine resulted in significant better outcome than placebo on measures of cognition, ADLs, behavior and global outcome Tariot PN et al. for the Memantine Study Group. JAMA.2004:291:

21 NONPHARMACOLOGIC MANAGEMENT OF BEHAVIORAL SYMPTOMS Forgetfulness: Use memory aids, calendars, writing on white board day, date, month, appointments, label objects, keep environment simple Nighttime wakefulness: Sleep Hygiene, calming activity, calming music, calming comfortable environment. Rule out depression pain etc Wandering, Leaving Home: Look at triggers for elopement and modify them, have badges, bracelets with identification, secure doors, have safe environment Falling due to poor balance: Alert system, OT, PT, balance exercise Gitlin et al. JAMA.2012;308: NONPHARMACOLOGIC MANAGEMENT OF BEHAVIORAL SYMPTOMS Hearing Noises, Voices: Evaluate and adjust amplification of hearing aid, rule out psychosis if present consider medications Repetitive questioning: Respond with calm reassuring voice, use soft touch for reassurance, be the auxiliary cognition Aggression: Care giver education to evaluate triggers, distraction, backing away, leaving the room if patient is safe, personalizing spa like bathing experience, decrease environmental overwhelming demands/stress: environmental changes Gitlin et al. JAMA.2012;308: ; Sloane et al. J Am Geriatr Soc 2004;52: Nguyen et al. Preventing aggression in persons with dementia. Geriatrics.2008;63911):

22 Caring For Care Giver Non pharmacologic strategies are resource intensive Success of these Strategies will Depend on Health of Care giver Care Givers have higher incidence of burnout and depression Care Giver Care May Involve: Education and Support Periods of respite Home health care Hiring nighttime assistance so that care giver can sleep Treating depression Agitation/Aggression in AD: causes and management Psychopathology: Delirium, Depression, Mood Disorder or Psychosis: Medications Inability to Suppress Negative Behaviors when upset: Medications/Behavioral Interventions Adapted from Jeffery Cummings, M.D. UCLA 22

23 Medications Second Generation Antipsychotics: psychosis, aggression, hostility, violent behaviors, sleep-wake cycle disturbances Caution: Black Box Warning by FDA for over 2 fold increase in mortality in patients with dementia Antidepressants(SSRIs): Sleep-wake cycle disturbance, depression-associated agitation, anxiety, aggression, pathological crying, impulsivity Stimulants: Apathy Medications..Continued Anticonvulsants (Divalproex, gabapentin, lamotrigine etc.) Manic type behavior, agitation, aggression, sleep-wake cycle disturbance, impulsivity Anxiolytics ( Benzodiazepines, buspirone) :anxiety, tension, agitation, sleep disturbance Caution: benzodiazepine i may cause disinhibion i Adapted from Helen Lavrestky, M.D. 2004, UCLA, NPI 23

24 ANTIAMYLOID IMMUNOTHERAPIES:CLINICAL TRIALS Active Vaccine: Affitope (Affiris) Synthetic peptide mimicking unmodified N-terminus of beta-amyloid Iscomatrix (Merck); Venutide Cridificar(Wyeth) Monoclonal Antibodies Against β-amyloid: Bapineuzumab (Elan), Solanezumab (Lilly), Ponezumab (Pfizer), Gatenerumab (Roche) Bapineuzumab: associated with meningoencephlitis, vasogenic cerebral edema, microhemorrhages(trial halted) Intravenous Immunoglobulin: Octagam (Octapharma); Gammagard (Baxter Health Care) Adapted from: Delrieu et al. J Neurochem. 2012, 120: Exciting New Research Directions in AD Insulin Resistance in the Brain. This Is considered to increase β- amyloid in the brain Talbot K et al. J Clin Invest.2012;122(4): Putting Insulin in the Brain through Non Invasive Intranasal Device to improve memory Craft S et al. Arch Neurol. 2012;69(1):29-38 Mimicking APOE3 a Protective Protein to Decrease Proinflammatory cytokine interleukin 6 in the brain, reduced plaques and tangles Vitek MP et al. Neurodegener Dis 2012;10(1-4):

25 Resources: The Alzheimer s Disease Education and Research (ADEAR) Center is a service of: National Institute on Aging, part of the National Institutes of Health (NIH), part of the Department of Health and Human Services? 25