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Early Diagnosis of Dementia Does it really matter? Monica K. Crane, MD Associate Director, Director of Research Cole Neuroscience Center Assistant Professor of Medicine, UTMCK 10/03/12 Disclosure Statement of Financial Interest I, Monica Crane, MD…… DO have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. My presentation has been peer reviewed by ETSU, and has been found to be balanced, evidence based, and free of commercial bias. Potential Conflict of Interest Disclosure Those Relationships Are With: Eisai/Pfizer Pharmaceuticals Forest Pharmaceuticals Novartis Pharmaceuticals 1 Objectives Background –Normal Aging –Protective factors and risk factors • Early diagnosis of Alzheimer’s Disease • Clinical criteria • Why does it matter? • Dementia subtypes • Treatment Normal Aging • Intelligence: stable or • Visuospatial: mild • Attention: stable or mild • Executive function: mild (reasoning, cognitive flexibility, problem solving) • Language: stable • Memory: mild • Speed: always – Slowing of thought and action is the most reliable aging change! AD risk factors Fixed Risk Factors Modifiable Risk Factors • • • • • Lack of exercise • Smoking • High blood pressure and heart disease • High cholesterol • Poorly controlled diabetes • Low education Age Family history Genetics Mild Cognitive Impairment (MCI) 2 What were the old Alzheimer’s disease research criteria? Auguste Deter, first diagnosed AD patient, 1906. • Old criteria: DSM-IV NINCDSADRA criteria validated against neuropathological gold standards • VERY POOR specificity (23-88%) • Old definitions had good detection of a dementia syndrome (65-96%) but it was often NOT AD • There are over 20 common dementia subtypes and 50+ other rare dementia subtypes American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Text Revision. Washington, DC: American Psychiatric Press; 2000:157. Newly Proposed Criteria for probable AD • Significant abnormality in episodic memory for ≥ 6 months & at least ONE objective biomarker: – Medial temporal and medial/posterior parietal lobe atrophy – Abnormal CSF* (95% sensitive, only 29% specific) • Low amyloid B1-42 concentrations • Increased total tau and phospho-tau – FDG-PET scan: AD pattern – Florbetapir F18 (Amyvid)-PET scan: positive – Genetics (PSEN1, PSEN2, APP, trisomy 21) Dickerson. Advances in quantitative magnetic resonance imaging-based biomarkers for Alzheimer disease. Alzheimer's Research & Therapy 2010; 2:21 Meyer et al. Diagnosis-Independent Alzheimer Disease Biomarker Signature in Cognitively Normal Elderly People. Arch Neurol 2010;67:949-956. Medial temporal lobe atrophy Normal Alzheimer’s T1 MRI coronal view 3 Limbic System: Hippocampus • Stores new memories or “working memory” • NEW finding: important in our ability to envision the future and replay events that were never experienced • Important in planning and imagination Foster DJ, Wilson MA. Nature 2006;440:680-683. Foster DJ, Knierim JJ. Curr Opinion Neurobiol 2012:22:294-300. Q: What is happening to the brain in Alzheimer’s disease? A: You would see hallmark neuropathologic lesions: plaques, tangles with brain atrophy and loss of neurons and synapses. (Extracellular deposits Abnormal intraneuronal fibrillar material Florbetapir (Amyvid) binds to amyloid aggregates (β-amyloid neuritic plaque) in the brain 18 • F-florbetapir-PET scan (Neurology doi: 10.1212/WNL.0b013e3182661f74). 4 Why diagnosis early? 1. Early diagnosis Alzheimer's allows prompt treatment of reversible symptoms (such as other comorbid illnesses exacerbating the impairment). 2. Alzheimer’s is not curable but is treatable. 3. Early diagnosis gives a patient and their family more time to arm themselves with knowledge about the disease and the best way to live with the disease. Knowledge is empowering. 4. Early diagnosis and treatment can prevent hospitalization and save health care dollars! Why should I tell you and your family about the diagnosis? 1. Early diagnosis will help you and your family understand why you are having symptoms. 2. Early diagnosis gives you more time to make big life decisions: financial planning, power of attorney, living wills. 3. Early diagnosis maximizes your safety and safety of your family. Early diagnosis allows treatments for AD that help slow its progression. The big challenge for clinicians… there are many dementia types other than AD 5 Dementia Prevalence (% of each type seen in US) • Alzheimer’s Disease ~ 50-80% • Vascular dementia ~ 5-10% • Dementia with Lewy Bodies & Parkinson’s disease dementia ~10% • Frontotemporal Dementias ~10% Heterogeneity of dementia • Alzheimer’s Disease – Posterior cortical atrophy – Progressive aphasia – Amnestic variant • Vascular dementia – Large vessel (stroke) – Small vessel disease/ subcortical – CADISIL, CAA • Parkinson’s disease dementia and related disorders – Parkinson’s disease dementia and Lewy Body Dementia – Multiple System Atrophy • Frontotemporal Dementia disorders – Behavioral variant FTD – Corticobasal degeneration and Progressive supranuclear palsy – Primary Progressive Aphasia and Semantic dementia • Motor neuron diseases VASCULAR DEMENTIA 6 Vascular dementia • Large vessel disease (post-stroke) • Small vessel disease – Executive function problems – Gait disorder – Depressive symptoms – Emotional lability – Memory problems Cerebrovascular disease and “vascular depression” Striato-pallido-thalamo cortical pathways disrupted by vascular lesions. Alexopoulos GS et al. "Vascular depression" hypothesis. Arch Gen Psych 1997;54:915-922. Lewy Body Dementia • Degeneration of an area in the brain stem called the substantia nigra similar to Parkinson's disease • Degeneration of cortical areas of the brain similar to AD 7 Dementia with Lewy Bodies (DLB) versus dementia in Parkinsons disease (PDD) • . • LBD is a an umbrella term for two related clinical diagnoses: DLB and PDD • Patients with dementia before or within 1 year of Parkinson's symptoms are diagnosed with DLB. • People who have an existing diagnosis of Parkinson's for ≥ 1 year diagnosed w PDD. Lewy bodies are the pathophysiological characteristic of the disease Clinical Features of Lewy Body Dementia • • • • • • • • Fluctuating cognition Memory loss Hallucinations Symptoms that resemble Parkinson’s disease Gait changes Autonomic dysfunction Depression Poor reaction to dopamine agonists and/or antipsychotic drugs (Positive response to cholinesterase inhibitors, memantine) Frontotemporal dementias 8 “Dementia That's Neither Alzheimer's Nor Easy” Normal Alzheimer's FTD FDG-PET images of metabolic activity: healthy controls, AD, and FTD. Scale red (high FDG uptake)-yellowgreen-blue (low FDG uptake). Photo Credit: Dr. Janet Miller, Dr. Suzanna Lee, MGH/ Harvard, Radiology Rounds April 2006 FTD Prevalence FTD: Alzheimer’s disease (AD) ratio is 1:1 in those aged 45-65. Ratnavalli et al, Neurology 2002. FTD is more common that AD below age 60. Knopman et al, Neurology 2004. FTD spectrum comprises near 15% or more of the total FTD dementia cases. Boxer AL, Miller BL. Alzheimer Dis Assoc Disord. 2005. Frontotemporal dementia subtypes • Behavior variant (bvFTD): 60% of FTD cases • Semantic dementia (SD) • Progressive nonfluent aphasia (PNFA) • Progressive Supranuclear Palsy (PSP) • Corticobasal degeneration (CBD) • FTD with motor neuron disease (FTD-MND) • ALS/CTE (Chronic Traumatic Encephalopathy) Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis Assoc Disord. 2005;19 S1:S3-6 9 >50% of FTD subtypes misdiagnosed as primary psychiatric disease Woolley et al. J Clin Psychiatry. 201; 72(2): 126–133. Figure. % of patients initially misdiagnosed prior to ND diagnosis FTD International Research Criteria 1. Early behavioral disinhibition 2. Early apathy or loss of motivation 3. Loss of emotional recognition, sympathy, empathy 4. Perseverative, compulsive, ritualistic behavior 5. Hyperorality/ dietary change 6. FTD neuropsych profile 7. Frontal and/or anterior temporal atrophy on MRI or other radiologic findings 8. Presence of a known mutation Brain 2011: 134; 2456–2477 Mendez and Perryman, 2002; Mendez et al., 2007; Rascovsky et al., 2007a; Piguet et al., 2009), the International Behavioural Variant FTD Criteria Consortium (FTDC) revised guidelines for the diagnosis of bvFTD. Frontotemporal lobar degeneration (FTLD) = Neuropathology of clinical FTD Pick’s is a FTLD (pathology) not FTD (syndrome) From: LM Shaw LM, Korecka M, Clark CM, Lee VMY, Troganowski. Biomarkers of neurodeneration for diagnosis and monitoring therapeutics Nature Reviews Drug Discovery. 2007;6:295-303. 10 FTD damages 3 major networks: Dorosolateral prefrontal cortex (DLPFC) Anterior cingulate cortex (ACC) Orbitofrontal cortex (OFC) Seelar H, Rohrer LD, Pijnenburg YAL, Fox NC, can Swieten JC. Clinical, genetic and pathological heterogeneity of frontotemporal dementia: A review. J Neurol Neurosurg Psychiatry 2010. Nonpharmacologic AD prevention Good physical health = Great aging brain Regular physical exercise Positive emotions Positive relationships Limiting chronic stress “Memory and the Aging Brain.” Steven W. Anderson, PhD Thomas J. Grabowski, Jr. MD The University of Iowa. June 2003 11 Exercise protects the brain!! • Aerobic exercise training increases brain volume in aging humans Pereira AC, et al. An in vivo correlate of exercise-induces neurogenesis in the adult dentate gyrus. PNAS. 2007; 104:56385643 Lautenschlager NT et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer’s disease. JAMA, 2008;300:1077-1079. Colcombe SJ et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Bio Sci Med SCi 2006;61:1166-1170. Kramer AF et al. Exercise, cognition and the aging brain. J Appl Physiol 2006;101:1237-1242. FDA-approved Medications for Alzheimer’s Disease Cholinesterase inhibitors (ChEIs) ChEIs prevent the enzyme destruction of the neurotransmitter acetylcholine (Ach) – Acetylcholine declines in AD; loss of cholinergic input to the cortex from the basal forebrain. –Donepezil: • selective acetylcholinesterase inhibitor –Rivastigimine & Galatamine: • Inhibitor of acetylcholinesterase & butyrylcholinesterase. Whitehouse PJ, Price DL, Struble RG, Clark AW, Coyle JT, Delon MR. Alzheimer’s disease and senile dementia: loss of cholinergic neurons in the basal forebrain. Science 1982;215:1237-1239. (Zarate et al 2007; Muhonen et al 2008, Dodel et al 2008; Maeng et al 2007; Ferguson et al 2007) 12 Memantine (Noncompetitive glutamate Nmethyl-D-aspartate (NMDA)-receptor blocker) – FDA approved for moderate-severe AD. – Blocks the NMDA receptor calcium channels, inhibiting the sustained, low-level influx of excitatory calcium (Ca2+) ions into postsynaptic glutamatergic neurons. – May have a neuroprotective effect by preventing the negative consequences of persistent activation of the neuron.. Source: Atri A, et al. Long-term Course and Effectiveness of Combination Therapy in Alzheimer’s Disease. Alzheimer Dis Assoc Disord. 2008;22:209-221. Investigational drugs and vitamin therapies NEGATIVE THERAPIES DRUG MECHANISM OF ACTION AN1792 Vaccine Abeta immunotherapy Tramiprosate alzhemed - homotaurine Abeta aggregation inhibitor Latrepiridine (Dimebon) Mitochondrial stabilizer – originally antihistamine Tarenflurbil (Flurizan) Gamma-secretase modulator Semagacestat Gamma-secretase inhibitor Simvastatin Possible membrane lipid modifier Docosahexaenoic acid (DHA) Possible membrane lipid modifier or antioxidant B12, B6 , Folic Acid, Vitamin E, Omega-3 fatty acids, Ginko Biloba Multiple theories, negative longitunidal studies 13 Statins: • Elective statin use studied to see if it reduced AD progression – Hyperlipidemia promotes Aβ production and deposition in animal models of AD and cholesterol reduction reduce Aβ deposition. • Large clinical trials show no efficacy in delaying progression but NO increased AD risk. • Feb 2012: FDA warned that statins could cause “reversible memory loss.” • The evidence: USE statins for patients with heart or cerebrovascular disease (regardless of AD status) Sano M et al. A randomized, double-blind placebo controlled trial of simvastation to treat AD. Neurology 2011;77:556-563. Siegel GJ et al. Statin therapy is associated with reduced neuropathologic changes of AD. Neurology 2008;71:383 Amarenco P, Labreuche J.Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention.Lancet Neurology 2009;8:453 – 463. Vitamins versus diet/ lifestyle • Vitamin E – No difference between placebo. – High doses increase stroke risk. – Increased relative risk of prostate cancer in men. • Homocysteine lowering therapy (B-vitamins), Folic Acid B6, B12 – no benefit with supplements – The vitamins lower the homocysteine level but little else. – B12 and folic acid supplementation did not have any statistically significant effect. Miller ER 3rd et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37-46. Ford et al. Vitamins B12, B6, and folic acid for cognition in older men Neurology 2010;75 :1540-1547. Vitamins versus diet/ lifestyle • DHA – Docosahexaenoic acid is an omega3 polyunsturated fatty acid found in fish. – component of synaptic plasma membranes & affects rate of signal transduction ?neuroprotective. – NEGATIVE RCTs: no effect with supplementation. • Gingko biloba – marketed as a supplement that prevents or delays cognitive decline. – VERY LARGE RCT were negative. – A numerically greater number of subjects treated with gingko developed dementia as compared to placebo. Quinn JF et al. JAMA 2010;304:1903-1911. DeKosky ST et al. JAMA. 2008;300:2253-2262. Snitz BE et al. JAMA. 2009;302:2663-2670. 14 Insulin Resistance and AD • Risk factor for AD: Type II diabetes – Impaired nsulin signaling in AD, contributing to the neurodegenerative process. • Exendin-4 (or Exenatide) – Phase II trials: testing the effects of novel enzymeresistant analogues of the insulin-releasing incretin hormone, glucagon-like peptide 1 (GLP-1). • Intranasal Insulin – Delayed memory was improved in the MCI group receiving 20 IU of insulin (P < .05). Among insulintreated participants, no improvement in biomarkers. Craft S, Baker LD, Montine TJ, et al Arch Neurol. 2011;Sept 12. Caffeine may decrease level of beta-amyloid in AD transgenic mice • AD mice received the equivalent of 5 cups coffee/day for 2 months • End result: caffeinated AD mice performed as well as normal mice • Caffeinated mice brains showed ~50% reduction in beta amyloid • Researchers suggested that caffeine suppresses inflammatory changes in the brain that lead to an overabundance of beta amyloid. Caffeine Reverses Cognitive Impairment and Decreases Brain Amyloid-β Levels in Aged Alzheimer's Disease Mice; Gary W Arendash, Takashi Mori, Chuanhai Cao, Malgorzata Mamcarz, Melissa Runfeldt, Alexander Dickson, Kavon Rezai-Zadeh, Jun Tan, Bruce A Citron, Xiaoyang Lin, Valentina Echeverria, and Huntington Potter; J Alzheimer's Disease, 2009:17:3. 2. Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice; Chuanhai Cao, John R Cirrito, Xiaoyang Lin, Lilly Wang, Deborah K Verges, Alexander Dickson, Malgorzata Mamcarz, Chi Zhang, Takashi Mori, Gary W Arendash David M Holzman and Huntington Potter; J Alzheimer's Disease 2009; 17:3 Supplements vs. food 15 Understanding and treating dementa remains one of the greatest challenges facing all levels of health care. 16