Advances in the Medical Management of Patients with Memory Complaints

Advances in the Medical Management of Patients with Memory Complaints Gregory A. Jicha, M.D., Ph.D. Professor of Neurology McCowan Endowed Chair in Alzheimer Research Sanders-Brown Center on Aging University of Kentucky College of Medicine Lexington, KY Departments of Neurology & Neurosurgery Kentucky Neuroscience Institute Financial Disclosure Consultant Lilly Contract research Alltech, Axovant, Esai, Lilly, Toyama, Transtech NIH Funding NIA R01 AG038651, NIA R01 AG042419, NIA P30 AG028383, NIA NICHHD R01 HD064993, NINR R01 NR014189, NIA U19AG010483, NIH UL1TR000117 Educational Need/Practice Gap Practice Gap Less than 50% of persons with AD are diagnosed We have the knowledge and ability to make this 100% Less than 50% of those diagnosed are treated for AD We have the knowledge and ability to make this 100% The situation is even worse for other causes of dementia We need to do much better than this Practice Need The field is in dynamic change in regards to diagnosis and management These changes are poorly understood by those that do not specialize in this area of care Practice parameters need to be updated, but until then, programs like this are essential Last updates for AAN practice parameters: 2001-Early Detection of Dementia and Mild Cognitive Impairment 2001-Diagnosis of Dementia 2001-Management of Dementia Objectives Upon completion of this educational activity, learners will be able to: 1. Review up to date criteria for the diagnosis of dementia by DSM-5 criteria 2. Describe diagnostic criteria for 4 major types of dementia 3. Discuss biomarker findings including: cognitive testing, structural & molecular imaging, and CSF in the context of the differential diagnosis of dementia 4. Explain how to develop a rationale plan for treatment of dementia and associated symptoms Expected Outcome Increased ability to recognize and diagnosis different causes of dementia even at the stage of mild cognitive impairment Development of a concise diagnostic algorithm that takes into account practical aspects of daily clinic flow Expand symptomatic targets for intervention and rationale therapeutic approaches to care of the patient with dementia Case #1 78 year old man referred for consultation of memory loss, accompanied by wife of 56 years Pt denies memory changes or functional decline Wife has noticed decline in his abilities to shop for a few items without a list, and notes intermittent repeating of questions She agrees that he is experiencing no functional decline and is still actively driving (without concerns on her part), managing finances (assembling tax information), and engaged socially (local rotary club & Church activities) He is also noted to be less warm, more distanced emotionally, has behavioral change (telling grandson, age 10 dirty limericks), and has some early paranoid thoughts that his wife is having an affair They note imbalance in gait with some intermittent shuffling PMHx notable for: HTN, HLD, DM, CABG x 3 1

What is your pre diagnostic differential? 1) Normal as there is no impact on his daily function 2) Mild cognitive impairment (MCI) no particular type specified 3) Alzheimer s disease 4) Dementia with Lewy Bodies 5) Vascular dementia 6) Frontotemporal dementia How does one get from here? First step: Determine where on the cognitive spectrum a person may be? Decline in cognition To here? Decline in function Normal mild MCI moderate MCI severe MCI mild dementia moderate dementia severe dementia? Diagnostic Algorithm: cognitive continuum Normal MCI or Impaired Dementia Neuropsych testing Decline in cognition Decline in function Mild Memory complaint may be made by informant or participant (either or both) Neuropsych testing determines objective evidence for impairment 1.5 s.d. below mean for new subjects or 1.0 s.d. below baseline for longitudinal participants Functional decline is measured on FAQ (CDR?) Major AAN Practice parameter: Medical w/u for reversible causes of dementia or MCI Labs: TSH, B12, folate, RPR if at risk Brain imaging Jicha et al., Dement Geriatr Cogn Disord 2008;26:187 192 Medical w/u is negative So, it s MCI! But what type? 1) Alzheimer s disease 2) Dementia with Lewy Bodies 3) Vascular dementia 4) Frontotempora l dementia 5) Other 2

Alzheimer s disease (NINDS-ADRDA) Dementia by DSM-III-R/V criteria Deficits in two or more areas of cognition Progressive worsening of memory and cognitive dysfunction Onset age 40-90 Absence of other systemic/brain disorders Dementia with Lewy bodies (3 rd Int. Workshop on DLB) Dementia by DSM-III-R/V criteria Deficits in cognition may not be memory (usually attention/spatial) Parkinsonism Early hallucinations Fluctuations Supportive: Depression REM sleep behavior disorder Vascular dementia (NINDS-AIREN) Dementia by DSM-III-R/V criteria Cerebrovascular disease present: a) focal neurologic signs (stroke) history of stroke not necessary b) CT or MRI evidence of stroke Onset of dementia within 3 months of stroke, or abrupt deterioration of cognitive function or stepwise course Frontotemporal dementia (NIH work group on FTD) Prominent behavioral disorder Loss of interpersonal skills Emotional blunting Perseveration or impersistance or Language involvement Comprehension or fluency Cognition typically preserved Can be assoc with MND/ALS Biomarkers of disease? FDG PET CSF Biomarker use If available, these can be powerful tools to guide accurate biologic etiology Diagnostic category Amyloid (PET or CSF) Neuronal Injury (MRI, tau PET, CSF) MCI due to AD (clinical) MCI AD MCI AD MCI AD MCI AD Biomarker probability Not needed Not needed Not determined Positive Negative or not done Intermediate Negative or not done Positive Intermediate Positive Positive High likelihood Negative Negative Low likelihood 3 rd Party payors including Medicare will cover? 1. MRI scans 2. FDG PET for diagnosis of any dementia 3. CSF for amyloid and tau 4. Amyloid PET 5. Tau PET Diagnosis using MRI: Visual Rating System (VRS) MRI Characteristics T2 weighted 3D Echo sequence such as MP RAGE or similar in the CONAL PLANE ENTHINAL CTEX RATING = 0 NO ATROPHY Stage 0 NMAL THICKNESS NO WIDENING OF COLLATERAL SULCUS Scheltens et al. J. Neurol 1995 3

RATING = 1 MINIMAL ATROPHY ENTHINAL CTEX 1. SLIGHT DECREASE IN THICKNESS 2. MINIMAL COLLATERAL SULCUS WIDENING 3. BOTH Stage 1 ENTHINAL CTEX RATING = 2 MILD ATROPHY 1. MILD DECREASE IN THICKNESS 2.MILD WIDENING OF COLLATERAL SULCUS 3. BOTH Stage 2 ENTHINAL CTEX RATING = 3 MODERATE ATROPHY 1.MODERATE DECREASE IN THICKNESS (EVEN IN THE ABSENCE OF WIDENING OF COLLATERAL SULCUS) 2.BOTH MODERATE DECREASE IN THICKNESS AND WIDENING OF COLLATERAL SULCUS Stage 3 ENTHINAL CTEX RATING = 4 SEVERE ATROPHY 1.SEVERE DECREASE IN THICKNESS (EVEN IN THE ABSENCE OF WIDENING OF COLLATERAL SULCUS) 2. BOTH SEVERE DECREASE IN THICKNESS AND WIDENING OF COLLATERAL SULCUS Stage 4 RATING = 0 NO ATROPHY 1. NO WIDENING OF LOTS LOTS: Lateral Occipitotemporal Quick review RATING = 1 MINIMAL ATROPHY RATING = 2 MILD ATROPHY 1. MINIMAL WIDENING OF LOTS 1. MILD WIDENING OF LOTS Let s put it in practice! Mr. ER is a 78 yo male evaluated for the first time in 2005. He presented with mild cognitive deficits predominantly in short term memory and word finding difficulties. He also had mild symptoms of depression that required the use of an antidepressant. RATING = 3 MODERATE ATROPHY 1. MODERATE WIDENING OF LOTS RATING = 4 SEVERE ATROPHY 1. SEVERE WIDENING OF LOTS MMSE BNCG D Recall FAQ PSMS 1/12/2005 27 53/60 10/15 2/36 0/24 4

MRI in 2005 CT scan and cognition in 2011 MMSE BNCG DR FAQ PSMS 1/12/2005 27 53/60 10/15 2/36 0/24 9/27/2011 17 30/60 0/15 31/36 15/24 January 2005 February 2011 Now what s your diagnosis? 1) Alzheimer s disease 2) Dementia with Lewy Bodies 3) Vascular dementia 4) Frontotemporal dementia 5) Other Algorithm for Dx Memory complaint or other impetus for consult Neuro exam with bedside cognitive evaluation Medical w/u (Imaging & lab testing per AAN) Establish diagnosis of dementia Define type of dementia Neuropsych evaluation if bedside testing normal Treat Medically reversible causes of decline if found (folate, B12, TSH, CT/MRI) Use additional biomarkers as needed to confirm diagnosis Treat type of dementia & related symptoms Empiric Approach to Treatment Assess symptoms in hierarchical fashion and target main symptom Drugs to use Choose only one target Cognitive issues Behavioral issues Psychiatric issues Motor issues identified as major identified as major identified as major identified as major problem problem problem problem Attempt Attempt SSRI, Attempt SSRI, Attempt carbidopalevodopa, dopamine cholinesterase antipsychotic, or antipsychotic, inhibitor or mood stabilizing benzodiazepine or agonist, or riluzole memantine anti epileptic other agent Evaluate effectiveness and re prioritize symptom hierarchy every 3 mos AChEI effective in AD, DLB, & VaD, 50/50 in FTD? Memantine effective in AD & DLB, possible in VaD, in question in FTD SSRIs & other antidepressants effective across the board Select based on side effect profile Benzodiazepines can help at times but at a cost? Anti hypertensives antagonists like prazosin may help, but watch BP Stimulants of active interest, but as of yet have not shown benefit and may have some risk Antipsychotics 2.6 to 4.5% increase ( 1.7) in pneumonia and CVD events 5

Back to our patient The primary issue at hand is his delusional thoughts about his wife having an affair Try an AChEI? Try memantine? Try an SSRI? Try a Benzo? Try Prazosin? Try a stimulant? Try an anti psychotic? You put him on an AChEI He responds with improvement in cognition and resolution of his delusions. Holmes: Neurology, Volume 63(2).July 27, 2004.214 219 What else should you do? Where do you turn for help managing the behavioral, psychiatric, and caregiving issues? What about diseasemodifying therapies? Long term Effects of Donepezil on Cognition: ADAS Cog Mean Change From Baseline Increased benefit in mod severe AD adding memantine to AchEI 6 Improve 0 6 12 n Decline in ADAS Cog score based on the natural history of untreated patients with moderate Alzheimer s disease* Decline 18 0 6 12 14 26 38 50 62 74 85 98 Cumulative Weeks From Baseline of the Double blind Study Rogers SL, Friedhoff, LT. Eur Neuropsychopharmacol. 1998;8:67 75; *Stern RG, et al. Am J Psychiatry. 1994;151:390 396. Tariot PN. Etal., JAMA. 291(3):317 24, 2004 Jan 21. The debate over combination therapy? Do new higher dose formulations help? Exelon patch (rivastigmine) Aricept XR (donepezil) Namenda XR (memantine) 2007 2010 2013 Howard et al., N Engl J Med. 2012 Mar 8;366(10):893 903 Modifications of existing drugs can lead to longer patent protection, but do they really help? Remember, these drugs help symptoms but do not change course of disease If they do not add benefit, why invest the time or money? 6

Aricept 23mg? Namenda XR 28mg? Namenda 10mg 5.7 point difference in SIB Placebo vs Namenda Namenda XR 28mg 2.6 point difference in SIB AChEI vs Namenda/AChEI Farlow et al., Clin Ther. 2010 Jul;32(7):1234 51 Data derived from FDA package inserts Exelon patch 13.3mg? Significant slowing of decline on ADLs 9.5mg vs 13.3mg Extending patent life Let s assume that 3 million of the over 5 million persons with AD are taking an AD drug A brand name AD drug typically costs $450/mos Minimal effect on cognition 9.5mg vs 13.3mg Total costs over 12 months at $450/mos = $5,400/year Cummings et al., Dement Geriatr Cogn Disord. 2012;33(5):341 53 Market $ for an AD drug/year = $16,200,000,000 There are 81 countries in the world with smaller GNP than this! Notable countries include: Georgia, Jamaica, North Korea, Iceland, Greenland, Armenia, and much of the entire continent of Africa, among others Comprehensive care throughout the continuum of decline Reach out to the Alz Assoc for support groups and resources Refer to the senior center for resources Refer to day care programs Utilize non pharmacologic interventions as a 1 st line Call us at SBCoA (859) 323 5550 We may be able to help you identify the resources in your area! If it s a tricky case or nothing you do seems to help? Refer on to a specialist Done everything and the family wants more? Consider clinical trial opportunities 7

Final word on driving issues in dementia At least texting isn t a major problem here Non memory domain involvement may be more an issue than STM alone Managing driving cessation with respect is key Often direct confrontation is the only way Factors that may add to unsafe driving practices In addition to cognitive loss: Vision loss Hearing loss Loss of sensation in feet Slow reaction time Medications AAN Practice parameter on driving in dementia If driving is an issue, how you may be able to help? Directly state the issues Order a formal driving evaluation Preferably through a rehab facility rather than DMV assessment (up to 76% pass even though actuarial stats demonstrate poor driving safety) Support family intervention Be the bad guy/gal Write a Rx You may no longer drive because you have Alzheimer s disease Follow state laws on reporting unsafe driving All states have laws for persons with lapses of consciousness (seizures, syncope etc) Reporting laws vary between states In KY there is no mandate to report, but a letter to DMV frequently solves the matter Other states may have reporting requirements States whose licensing laws specifically mention Alzheimer s disease include CA and PA. laws refer to individuals with cognitive impairment FL, GA, IW, KS, KY, NE, NV, ND, RI, SC, UT, VA, & DC reference the need to monitor people with mental disease or impairment. Alzheimer s KNI: fighting back every way we can! AD LEARN study Functional loss Memory loss Brain shrinkage (MRI) Brain malfunction (PET) Cell death (tau) Amyloid plaques Normal TIME 8