Diagnosis and treatment of dementia

Diagnosis and treatment of dementia Nathaniel Chin, MD, Assistant Professor (CHS) of Medicine Division of Geriatrics, UW School of Medicine and Public Health Director of Medical Services, Wisconsin Alzheimer s Disease Research Center Medical Director, Wisconsin Registry for Alzheimer s Prevention (WRAP) Study Madison, Wisconsin

Learning Objectives Overview of neurodegenerative diseases Clinical evaluation of memory complaint Discuss staging and disease course

Disclosures None

Misunderstanding in the community Confusion due to terminology I don t have dementia, I have Alzheimer s disease I have Alzheimer s, but at least I don t have dementia I don t have Alzheimer s, I was diagnosed with MCI

NIA & AA Diagnostic Criteria for Dementia Problems with thinking and daily function Cognitive symptoms that: Represent a decline from previous level Affect at least 2 thinking abilities on cognitive testing Interfere with usual functional abilities Are not explained by other medical or psychiatric illness Dementia due to AD Memory is the primary complaint & ruled out other causes Gradually progressive and with a documented decline Genetic testing or biomarkers

Dementia is a syndrome not a disease Rule out: Underlying medical disease Psychiatric disease Medications Progressive decline Alzheimer s Disease Vascular cognitive impairment Lewy Body dementia HIV, Alcohol, CJD Frontotemporal Dementia Parkinson s disease dementia Mixed pathologies

There are many causes of dementia Alzheimer s disease Vascular cognitive impairment Frontotemporal dementia Parkinson's disease Other Lewy Body dementia Frontotemporal dementia Lewy body disease Alzheimer's disease alone Parkinson disease dementia Vascular Mixed pathology Mixed pathology

Vascular Cognitive Impairment

Changes in definition Vascular Dementia NINDS AIREN (1993) 1. Memory impairment + at least one other domain 2. IADL impairment 3. Evidence of CVD 4. Causal relationship between dementia & CVD (onset within 3 months of stroke and/or acute onset) Vascular Dementia AHA/ASA (2011) 1. Evidence of stroke or subclinical vascular injury 2. 2 cognitive domains + IADL impairment PROBABLE VAD: IMAGING EVIDENCE TEMPORAL RELATIONSHIP OR RELATIONSHIP IN SEVERITY/PATTERN OF IMPAIRMENT AND PRESENCE OF DIFFUSE, SUBCORTICAL CVD NO GRADUALLY PROGRESSIVE DEFICITS BEFORE OR AFTER STROKE Major vascular neurocognitive disorder DSM 5 (2013) 1. Major neurocognitive disorder criteria met 2. Onset of deficits temporally related to cerebrovascular event OR Evidence for decline prominent in complex attention (including processing speed) and frontalexecutive dysfunction 3. Evidence of CVD from history, physical exam, and/or neuroimaging sufficient to account for neurocognitive deficits PROBABLE VAD: AT LEAST ONE OF 3 FEATURES Both clinical and genetic evidence of CVD is present

Vascular Cognitive Impairment subtypes Vascular impairment of cognition classification consensus study (VICCCS; Skroot, 2017) Proposed mechanisms of cause: Cerebral amyloid angiopathy Mixed dementia White matter hyperintensities Microbleeds/microhemorrhages Microinfarcts Arteritis/vasculitis

Lewy body disease

Dementia with Lewy Bodies (DLB) 4 th consensus report of the DLB consortium (McKeith et al, 2017) CORE CLINICAL FEATURES Fluctuating cognition with pronounced variations in attention and alertness. Recurrent visual hallucinations that are typically well formed and detailed. REM sleep behavior disorder, which may precede cognitive decline. One or more spontaneous cardinal features of parkinsonism: these are bradykinesia (defined as slowness of movement and decrement in amplitude or speed), rest tremor, or rigidity. SUPPORTING CLINICAL FEATURES Severe sensitivity to antipsychotic agents Postural instability; repeated falls; syncope or other transient episodes of unresponsiveness Severe autonomic dysfunction, e.g., constipation, orthostatic hypotension, urinary incontinence Hypersomnia; hyposmia Hallucinations in other modalities; systematized delusions; apathy, anxiety, and depression *(1) Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET. (2) Abnormal (low uptake) 123iodine MIBG myocardial scintigraphy. (3) Polysomnographic confirmation of REM sleep without atonia. Probable DLB: 2 or more core clinical features 1 core clinical feature + 1 indicative biomarker* Possible DLB: 1 core clinical feature or 1 indicative biomarker* is present

Parkinson s disease dementia Development of Parkinson s motor symptoms first Motor symptoms precede cognitive symptoms by at least 1 year but often it is 6 8 years Population based studies 37% of patients whose PD began after 70yo had dementia 9% of patients whose PD began before 70yo Prevalence of dementia was 42% 4 years after PD diagnosis and 78% 8 years after diagnosis Possible association with APOE4 Galvin JE et al. "Current Issues in LBD Diagnosis, Treatment and Research" May 2008.

Frontotemporal disease

Frontotemporal dementia Normal Behavioral variant FTD (bvftd) Primary progressive aphasia (PPA) Rascovsky K et al. Brain. 2011 Sep, 134(pt9): 2456 77. Epub 2011 Aug 2.

Behavioral variant FTD Early behavioral disinhibition, apathy, loss of empathy Early perseverative, stereotyped, compulsive/ritualistic behavior Hyperorality and/or dietary changes Neuropsychological profile: deficits in executive tasks, but relative sparing of memory and visuospatial skills Rascovsky K et al. Brain. 2011 Sep, 134(pt9): 2456 77. Epub 2011 Aug 2.

Primary progressive aphasia Difficulty with language is most prominent clinical feature Language deficits are principal cause for impaired function Aphasia should be most prominent deficit at symptom onset Mesulam MM. Ann Neurol 2001;49:425 432.

Alzheimer s disease is not dementia AD can cause MCI and dementia MCI and dementia can be caused by other diseases AD is an abnormal process in the brain Amyloid builds up and plaques form Deposits of excess amyloid Amyloid not cleared from the brain Neurofibrillary tangles develop within cells Exposure of tau protein, become hyperphosphorylated Inflammation Develops after amyloid and tangles May be involved in development of amyloid

Mixed pathologies are more common than single pathology In persons with probable AD, vascular disease is present in approximately 90% and other degenerative diseases in about 65% N=1078 autopsied subjects from the Religious Orders Study and Memory & Aging Project (Rush) Kapasi, DeCarli, Schneider, 2017; Acta Neuropathologica

To provide help the patient has to be seen and diagnosed Less than 50% of persons with AD are diagnosed Reasons to be evaluated Rule out reversible causes Take advantage of early treatments Participate in support programs Participate in research, public awareness & advocacy Advanced care planning Prince M et al. Alzheimer s Disease International World Alzheimer Report 2011. The benefits of early diagnosis and intervention, King s College London, UK.

Other benefits of early diagnosis Identify MCI in addition to dementia More research is focusing on MCI Lifestyle interventions that may modify disease course

Risk factors for Alzheimer s disease Age Family history of AD Apolipoprotein E4 (APOE4) genetic risk Low educational level Head trauma with loss of consciousness Vascular risk factors Inflammation Insulin resistance & metabolic risk factors Depression

Vascular risk factors associated with Alzheimer s Elevated blood pressure in midlife Obesity Diabetes Obstructive sleep apnea Physical inactivity Smoking

Addressing modifiable risk factors may impact disease course Physical activity Diet Stress reduction Sleep Cognitive activity Social activity Hearing/Vision Smoking cessation

Finnish Geriatric (FINGER) study to Prevent Cognitive Impairment 2 year study 1260 adults ages 60 77 yrs Multi domain intervention: Diet Exercise Cognitive training Vascular risk monitoring Improved cognitive performance Ngandu et al. Lancet 2015; 385: 2255 63

Cardiorespiratory fitness strengthens our brain

Among individuals with higher amyloid, higher physical fitness was associated with better memory performance Shultz et al., 2015, Journal of the International Neuropsychological Society

The MIND diet keeps your brain younger Brain healthy food groups: Green leafy vegetables Other vegetables Nuts Berries Beans Whole grains Fish Poultry Olive oil Unhealthy groups are: Red meats Butter and stick margarine Cheese Pastries and sweets Fried or fast food Morris, M. C., Tangney, C. C., Wang, Y., Sacks, F. M., Barnes, L. L., Bennett, D. A., & Aggarwal, N. T. (2015). MIND diet slows cognitive decline with aging. Alzheimer's & dementia, 11(9), 1015 1022.

MIND diet associated with reduced development of Alzheimer s disease 2 nd Tertile Hazard Ratio = 0.65 Highest Tertile Hazard Ratio = 0.47 Mediterranean Diet Hazard Ratio = 0.46 DASH Diet = 0.61 Alzheimers Dement. 2015 Sep;11(9):1007 14

Stress can affect our brain and its function High cortisol associated with Worse memory and visual perception Lower total brain volume, occipital and frontal gray matter volume Microstructural change in areas connecting parts of the brain More evident in women No relationship to APOE4

Perceived stress can affect our brain function Increasing levels of perceived stress associated with Lower initial cognitive testing scores Faster rate of cognitive decline Present in both black and white adults 65+ 30% greater risk of MCI Alzheimer Dis Assoc Disord. 2016 Apr Jun;30(2):93 8.

Sleep & AD 3 subjective sleep measures Worse sleep quality Sleep related problems Daytime somnolence Worse subjective sleep measures associated with greater AD pathology CSF AB, t tau, p tau

Sleep & AD Less adequate sleep, more sleep problems, and greater somnolence on questionnaires associated with greater amyloid burden on PET scan Amyloid burden not related to sleep amount, trouble falling asleep, and Epworth Sleepiness scale

Evaluation of suspected dementia

What can be done in a non memory clinic? Ask the patient if they re worried about their memory Then ask a family member Be on the look out for functional changes (IADLs primarily) Missing appointments Making mistakes on medications Multiple ER or urgent care visits Driving accidents Unkempt on exam Weight loss in elderly (are they eating?) Perform a cognitive screener

Cognitive screening tests are helpful but do not provide the diagnosis Perform when patient, family member, or provider are worried about memory/thinking changes Takes time: 10 15 minutes Can be done by a medical assistant, RN, APP, PhD, MD Recommended screeners Mini Cog SLUMS MOCA

Initial work up Assess reversible causes Medications Mood Sleep apnea Thyroid Obtain memory labs or confirm labs within the past 12 months Complete metabolic panel: Na, Cr/BUN, Ca, LFTs Complete blood count, including MCV TSH, HgbA1c, Lipid panel Vitamin B1, B6, B12, Vitamin D, Folate Obtain or confirm structural brain imaging Image obtained during the time period of cognitive symptoms MRI provides best picture but CT is adequate in most cases

The hippocampus shrinks in AD Scheltens et al. Lancet Neurol 2002;1:13 20.

Metabolism decreases on FDG PET Less glucose use Scheltens et al. Lancet Neurol 2002;1:13 20.

Making the diagnosis takes time Detailed interview with patient and family Cognitive, functional, behavioral/psychiatric history Physical exam Full neurological exam Cognitive testing RBANS, Cognistat = 1 hour Lab testing if needed HIV, RPR, Vitamin levels Brain scans if needed CT or MRI Advanced brain scans FDG PET DAT scan Education and feedback Referral to appropriate resources Advanced care planning

What are the reversible forms of cognitive impairment? Non reversible = neurodegeneration AD, FTD, LBD, PDD, VCI Reversible = treat the underlying problem and cognition improves Medication induced Hypothyroidism/Hyperthyroidism Vitamin deficiency: Vit B1, B6, B12, D, Folate Chronic infection: Syphilis, Lyme disease Sleep apnea Mood disorders: depression, anxiety, bipolar, schizophrenia Delirium

Once diagnosed Things to get done immediately HC POA Financial POA Advanced directive Eventually Advanced Care Planning Discuss health values Discuss living environments Safety issues Support services

Stages of Dementia No two cases of dementia are the same May have symptoms from several stages at one time Typical course duration is 8 10 years from diagnosis Most have symptoms years prior to diagnosis 3 stage model & 7 stage model Confusing terminology Not comprehensive Do not discuss abilities that remain

3 Stage Model Often used for dementia due to Alzheimer s disease Mild dementia Early stage Moderate dementia Middle stage Severe dementia Late stage

7Stage Model Stage 1: No cognitive impairment Stage 2: Very mild cognitive decline Mild cognitive changes Stage 3: Mild cognitive impairment Cognitive impairment on testing Stage 4: Moderate cognitive decline Early stage dementia Stage 5: Moderately severe cognitive decline Mid stage dementia Impaired ADLs Stage 6: Severe cognitive decline Moderately severe dementia or middle stage Assistance for all ADLs Stage 7: Very severe cognitive decline Late stage dementia

Stage 1 Mild dementia Early Stage Cognition Mild memory loss of recent events Forgets what was just done, loses items Word finding difficulties Trouble remembering names Trouble planning or organizing Function Can still care for self, but takes longer to do perform ADLs or IADLs Psychological function and behavior Mood or personality changes Irritable, less initiative (apathy)

Stage 2 Moderate dementia Middle Stage Cognition Moderate memory loss & confusion Forgetful of events and/or personal history Difficulty expressing thoughts Cannot calculate, judge, plan Disoriented to time, place, date Function Needs more assistance with daily tasks & hygiene Urinary and stool incontinence Psychological function and behavior Sleep pattern disruption Irritable, moody, focused on self Withdrawn, wandering at times

Stage 3 Severe dementia Late Stage Cognition Severe memory and cognitive impairment Appears to not understand surroundings Cannot recognize family or self Minimal to no speech Function Bedridden requiring 24 hour assistance Physical impairments: coordination, walk, sit up, transfer, swallowing, smile Psychological function and behavior May have delusions, paranoia, hallucinations

FAST Scale http://www.setma.com/your Life Your Health/Hospice Palliative Scales Part I

Develop community allies Refer patients to: Alzheimer s Association Alzheimer s and Dementia Alliance of WI Aging and Disability Resource Center Provide information on home health services

Optimize care by working with the caregiver Establish routines Sleep wake cycles Timing of medications, location of medications Routine daily tasks Utilize calendars, sticky notes, white board Address safety Involve Physical Therapy for falling, weakness, ambulation Involve Occupational Therapy for ADLS/IADLs, home environment Involve Speech Therapy for communication and swallow issues

We must address the caregiver Compared with non caregiver controls matched by age, gender, race and marital status, caregivers of persons with AD or related disorders require 46% more physician visits 71% more prescribed medications Higher diastolic blood pressure Hyper coagulable state Higher plasma norepinephrine 60% rate stress as high or very high 40% suffer from depression Haley WE, Levine EG, Brown SL et al. Am J Geriatr Soc. 1987(May); 35(5): 405 411 Shaw et al. J Psychosom Res 2003; 54:293 302 VonKanel et al. Am J of Cardiol 2001(June);87:1405 1408 Grant I; Psychosom Med 1999; 51:420 423

FDA approved treatments for AD treat symptoms and not the disease Acetylcholinesterase inhibitors Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Razadyne) N methyl D aspartate (NMDA) Receptor Antagonists Memantine (Namenda)

The benefits of cholinesterase inhibitors can be meaningful improved cognition: but difficult to detect clinically small treatment effects improved global performance improved ADLs and possibly QOL decreased caregiver burden delayed nursing home placement Cummings Am J Geri Psychiatry 2003; Schneider Lancet 2004

The side effects of cholinesterase inhibitors can be meaningful and costly Most common side effects GI: nausea, vomiting, diarrhea CNS: insomnia, abnormal dreams Cardiac: bradycardia, syncope Other: muscle cramps, fatigue, weight loss Start low, go slow; meals may help with GI side effects May worsen frontotemporal dementia

NMDA antagonist: memantine Glutamate, the main excitatory neurotransmitter in the brain, acts at NMDA receptors Memantine blocks NMDA receptors and so may reduce the negative effects of glutamate (excitotoxicity and cell death)

The benefits of memantine can be meaningful later in the course of disease FDA approved for moderate-to-severe Alzheimer s disease Has been shown to slow the progression of cognitive changes May delay nursing home placement Provides an alternative for patients who cannot tolerate cholinesterase inhibitors Very few side effects relative to placebo Tariot et al JAMA 2004; Lopez et al J Neurol Neurosurg Psychiatry 2009

The treatment of other dementias look similar Cholinesterase inhibitors can be used in: Lewy body disease Parkinson disease dementia (rivastigmine) Vascular cognitive impairment (galantamine) Selective serotonin reuptake inhibitors (SSRIs) are used in: Frontotemporal dementia

Other related treatments Antidepressants Selective serotonin reuptake inhibitors (SSRIs) Anxiolytics No benzodiazepines SSRI Buspirone, wellbutrin, gabapentin Sleep aides Trazodone & mirtazapine Psychotropics (not FDA approved for dementia) First utilize DICE approach Quetiapine, risperidone, olanzapine Avoid haldol in lewy body dementia

Research studies Diagnostic studies Imaging techniques PET scan for amyloid, tau, synapses MRI scans CSF studies Different markers Blood based biomarkers Intervention trials Drug trials Lifestyle interventions Disclosure of amyloid status

Resources NIA Alzheimer s Disease Education & Referral (ADEAR) Center http://www.nia.nih.gov/alzheimers/ Alzheimer s Association http://www.alz.org/ Alzheimer s & Dementia Alliance http://www.alzwisc.org/ Wisconsin Department of Health Services https://www.dhs.wisconsin.gov/dementia/family caregiver training.htm Wisconsin Alzheimer s Institute http://www.wai.wisc.edu/ Wisconsin Alzheimer s Research Center (ADRC) http://www.adrc.wisc.edu/

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