DEMENTIA (Major Neurocognitive Disorder) SUSAN BEHNAWA, M.D. DIVISION OF GERIATRIC MEDICINE AND GERONTOLOGY UC IRVINE HEALTH SCHOOL OF MEDICINE

DEMENTIA (Major Neurocognitive Disorder) SUSAN BEHNAWA, M.D. DIVISION OF GERIATRIC MEDICINE AND GERONTOLOGY UC IRVINE HEALTH SCHOOL OF MEDICINE

Objectives Review the epidemiology and social impact of Dementia Discuss the definition of Dementia Recognize the clinical presentation of Dementia Outline the diagnostic approach to patients Differentiate Mild Cognitive Impairment vs. Dementia Characterize the Major Dementia Syndromes Review Treatment and Management Approaches Discuss possible Prevention Strategies

Types of Dementia Alzheimer s Disease (AD) is the most common type, accounting for ~2/3 of all cases and affecting 6-8% of those 65 years old Disease prevalence doubles every 5 years after age 60 yrs, 45%+ who are 85 yrs old have AD DLB now thought to be 2 nd MCC dementia FTD smaller percentage with younger age of onset Neurodegenerative diseases such as Huntington disease, Parkinson disease, head injury, alcoholism account for other

Epidemiology and Social Impact of AD An estimated 5.4 million Americans have Alzheimer's disease. By mid-century, the number of people living with Alzheimer's disease in the United States is projected to grow to 13.8 million, fueled in large part by the aging baby boom generation. Today, someone in the country develops Alzheimer's disease every 66 seconds. By 2050, one new case of Alzheimer's is expected to develop every 33 seconds, resulting in nearly 1 million new cases per year. In 2013, official death certificates recorded 84,767 deaths from Alzheimer's disease, making it the sixth leading cause of death in the United States and the fifth leading cause of death in Americans age 65 years. Between 2000 and 2013, deaths resulting from stroke, heart disease, and prostate cancer decreased 23%, 14%, and 11%, respectively, whereas deaths from Alzheimer's disease increased 71% (actual number of deaths likely much larger) In 2016, an estimated 700,000 Americans age 65 years will die with Alzheimer's disease, and many of them will die because of the complications caused by Alzheimer's disease.

Epidemiology and Social Impact of AD In 2015, more than 15 million family members and other unpaid caregivers provided an estimated 18.1 billion hours of care to people with Alzheimer's and other dementias, a contribution valued at more than $221 billion. Average per-person Medicare payments for services to beneficiaries age 65 years with Alzheimer's disease/other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2016 for health care, long-term care and hospice services for people age 65 years with dementia are estimated to be $236 billion. The costs of Alzheimer's care may place a substantial financial burden on families, who often have to take money out of their retirement savings, cut back on buying food, and reduce their own trips to the doctor. In addition, many family members incorrectly believe that Medicare pays for nursing home care and other types of long-term care.

DSM-V Criteria: Major Neurocognitive Disorder (previously known as Dementia) 2013 Evidence from history and clinical assessment that indicates significant cognitive impairment in at least one of the following cognitive domains: Learning and Memory Language Executive Function Complex Attention Perceptual-Motor Function Social Cognition Impairment is acquired and represents a significant decline from previous level of functioning Cognitive deficits must interfere with independence in everyday activities In neurodegenerative dementias (i.e. Alzheimer s), the onset is insidious and progressive Disturbances are not occurring exclusively during the course of delirium Disturbances are not better accounted for by another mental disorder (e.g. Major Depressive Disorder, Schizophrenia)

Cognitive Domains Complex Attention Sustained, divided, and selective attention as well as processing speed Executive Functioning Planning, decision making, working memory error detection and correction, inhibition, and mental flexibility Learning and Memory All memory registers (e.g. short-term, semantic, autobiographical) and implicit learning Language Expressive and Receptive Language Perceptual-Motor Includes visual perception, visuo-constructional abilities, perceptual-motor, praxis, and gnosis Social Cognition Recognition of emotions and theory of mind

Normal Aging vs. Dementia Normal Cognitive Decline of aging is primarily mild changes in memory and rate of information processing; these are not progressive and do not affect daily function New learning is slower but still occurs, is usually well compensated with memory supports (e.g. lists) Self-reported memory loss does not appear to correlate with subsequent development of dementia; Informant-reported memory loss is much better predictor of current presence and future development of dementia In community-dwelling, cognitively normal individuals ages 62 to 100 years, learning or acquisition performance declined uniformly with increasing age. In contrast, delayed recall or forgetting remained relatively stable. Aging is associated with decline in learning of new information but not in memory retention. Patients with dementia may have difficulty with one or more of the following: Retaining new information (eg, trouble remembering events) Handling complex tasks (eg, balancing a checkbook) Reasoning (eg, unable to cope with unexpected events) Spatial ability and orientation (eg, getting lost in familiar places) Language (eg, word finding) Behavior

Normal Memory Changes vs Dementia TYPICAL AGING Complains about memory loss but able to provide detailed examples of forgetfulness Occasionally searches for words May have to pause to remember directions but doesn t get lost in familiar places Remembers recent important events; conversations are not impaired Interpersonal social skills are at the same level Able to function independently despite occasional memory lapses Losing things from time to time SYMPTOMS OF DEMENTIA May complain of memory loss only if asked; unable to recall specific instances Frequent word-finding pauses, substitutions Gets lost in familiar places; takes excessive time to return home Notable decline in memory for recent events and ability to converse Loss of interest in social activities; may behave in socially inappropriate ways Difficulty performing simple tasks; forgetting how to do things that have been done many times before Misplacing items and not being able to retrace steps to find them

Clinical Evaluation for Suspected Dementia Informant interview, patient interview, and office-based clinical assessment are most important Current condition, medical history, medications, substance use, living arrangements Onset and nature of symptoms Cognitive performance will be influenced by number of years of formal education Some tests are affected by language performance or cultural differences Improve accuracy by performing serial assessments to determine presence of a decline and using a medical interpreter when needed Assess ADLs and iadls Routine labs: CBC, Na, Ca, Bun/Cr, FBG, RPR, TSH, B12 If indicated: LFTs, Folic Acid, Homocysteine, MMA, UA, Utox, CSF, HIV, EKG, CXR In general, the diagnosis of dementia is clinical

Cognition Screening Instruments Mini-Cog Visuospatial, Executive Function, Recall St. Louis University Mental Status Exam Orientation, Recall, Calculation, Naming, Attention, Executive Function Montreal Cognitive Assessment Orientation, Recall, Attention, Naming, Repetition, Verbal Fluency, Abstraction, Executive Function, Visuospatial Folstein Mini-Mental Status Exam* Orientation, Registration, Attention, Recall, Naming, Repetition, 3-step Command, Language, Visuospatial (*licensed version of MMSE should be purchased from Psychological Assessment Resources (PAR) for $1.23 per test) Functional Activities Questionnaire Informant Based, Executive Functioning, ADLs, Attention, Concentration, Memory, Home Safety

Brain Imaging Studies Helpful in the following situations: Onset <65 yrs of age, sudden onset or rapidly progressing symptoms, evidence of focal or asymmetrical neurologic deficits; clinical picture suggestive of NPH (onset within last year, gait disorder, unexplained incontinence is present); hx of recent fall or trauma Non-contrast CT head scan adequate to exclude intracranial bleeding, space-occupying lesions, and hydrocephalus; will see characteristic parietal and temporal deficits in AD or the widespread irregular deficits in vascular dementia MRI is often performed if vascular dementia is suspected, but white matter changes in T2 weighted MRI should not be overinterpreted Functional brain imaging studies such as PET may be useful when the diagnosis remains uncertain FDA has approved PET scanning with florbetapir, which binds brain amyloid, but few insurers provide payment, and guideless from NIA and AA still recommend limited use by specialists CSF analysis of beta-amyloid and phosphorylated tau has limited availability and interpretation is challenging

Delirium Disturbance of consciousness with reduced ability to focus, sustain, or shift attention A change in cognition or a perceptual disturbance not better explained by a preexisting, established, or evolving dementia Disturbance develops over a short period of time (usually hours to days) Disturbance tends to fluctuate during the course of the day Evidence suggesting cognitive disturbance caused by the direct physiological consequences of a medical condition Causes of Delirium D - drug use E - electrolyte and physiologic abnormalities L - lack of drugs (withdrawal, e.g. Etoh) I - infection R - reduced sensory input I - intracranial problems (stroke, bleeding, meningitis, post-ictal) U - urinary retention and fecal impaction M - myocardial problems (e.g. MI, arrhythmia, CHF) *Almost any acute illness may cause delirium*

Depression Depression and dementia may occur in the same patient. Patients with depression are more likely to complain about memory loss than those with dementia Patients with depression may have signs of psychomotor slowing and give poor effort on testing ("I just can t do this"), while those with dementia often try hard but respond with incorrect answers. People with history of depression/affective disorder may become demented Prevalence of older adults with depression ~ 10% People with dementia frequently become depressed - Perhaps as many as 25% of patients will experience depression during their course Apathy and affective (sad or anxious) presentations may also occur that may present differently than textbook depression Cognitive behavioral therapy limited with dementia SSRI s a good choice for medication, especially Celexa (Citalopram), Lexapro (Escitalopram), or Zoloft (Sertraline) Start low dose, and realize that will take longer to respond, watch for side effects, especially anorexia Avoid tricyclics due to anticholinergic effects Trazadone or Mirtazapine if sleep disturbances prominent

15 questions, may be self-administered 5 or more positive responses suggestive of clinically significant depression More severe cognitive impairment may limit effectiveness of screen If cognitive impairment mild, and depression severe, consider treating depression before making AD diagnosis

Neurocognitive Disorder (Dementia) Mild Neurocognitive Disorders (similar to MCI): Measurable decline in one or more cognitive domains causing the individual to use compensatory strategies in their management of iadls Major Neurocognitive Disorders: Measurable decline in one or more cognitive domains to a degree impairing his or her ability to manage iadls or ADLs independently. Subcategorized according to presumed etiology Primary Diagnosis would be Major or Mild NCD, followed by etiological subtype DSM-V has also added specifiers Behavioral Disturbances (with or without) Degree of severity in Major NCDs (Mild, Moderate, Severe) Possible versus Probable (when designating a specific dementia)

Mild Cognitive Impairment (MCI) Individuals who have a subjective complaint of cognitive decline in at least one domain (complex attention, executive function, learning and memory, language, perceptual-motor or social cognition) to a degree that is noticeable and measurable, but not to a degree that causes impairment in independent living. MCI as a diagnostic entity allows for identification and possible early treatment of individuals who may convert to AD (9-14/1,000 person-years) For individuals with MCI whose single domain of impairment is memory (amnestic MCI versus nonamnestic MCI), the rate of conversion to AD is predictably higher but not wholly predictive of AD or other dementias Nearly half of individuals with amnestic MCI maintain a stable degree of impairment or return to a state of normal cognition over 3-5 years DSM-V terminology oof 'mild neurocognitive disorder (mncd)' defined by a noticeable decrement in cognitive functioning that goes beyond normal changes seen in aging. It is a disorder that may progress to dementia - importantly, it may not. Presently, our understanding of mncd is derived from research on mild cognitive impairment (MCI).

Cognitive Impairment as a Spectrum

Alzheimer s Disease Most common; major risk factors are family history, genetic factors, head injury Gradual Onset, Progressive Decline in cognitive functioning Memory impairment is typically the core feature present in the earliest stages Pathology is associated with parietal and temporal regions of the brain Motor and sensory functions are spared until middle or late stages Autopsy findings of Beta-Amyloid plaques and Neurofibrillary Tangles (Tau protein) Difficulty learning and retaining new information early, later compromised ability to learn and retrieve information and pts are unable to access older, more distant memories Aphasia, apraxia, disorientation, visuospatial dysfunction, impaired judgement, and executive dysfunction are also present Probability of AD is amplified by presence of a biomarker in addition to clear decline in memory and learning Auguste Deter ( May 1850 -April 1906). Nationality: German. Her maiden name is unknown. She married Karl Deter in the 1880s or so and together they had one daughter. Auguste had a normal life. However, during the late 1890s, she started showing symptoms of dementia. After many years, she became completely mindless, muttering to herself. She was the first person diagnosed with Alzheimer's Disease (named after Dr. Alois Alzheimer).

Biomarkers in Alzheimer s Disease Biomarkers of brain amyloid-beta (Aβ) protein deposition: low cerebrospinal fluid Aβ42 and positive PET amyloid imaging 3 major biomarkers of downstream neuronal degeneration or injury are: elevated CSF tau, [both total tau and phosphorylated tau (p-tau)]; decreased 18fluorodeoxyglucose (FDG) uptake on PET in temporo parietal cortex; disproportionate atrophy on structural magnetic resonance imaging in medial, basal, and lateral temporal lobe, and medial parietal cortex

Vascular Dementia Cognitive deficits most often associated with vascular damage (micro or macro) in nature Risk factors: HTN, DM, Age, CVA, EtOH, CV RFs May see focal neurologic deficits that accompany cognitive loss Abrupt onset, fluctuating course, stepwise decline Cognitive/Neurologic impairments correlate anatomically with area of ischemia More likely than AD to have depression, affective changes, disturbance of gait, and confusion Relatively high mixed etiology found in AD Temporal association of CV events, genetic predispositions, and/or neuroimaging date increase probability of a diagnosis of vascular dementia

Dementia with Lewy Bodies Both dementia and at least one of the following core features must be present: Recurrent and detailed visual hallucinations Parkinsonian signs Fluctuating changes in alertness/attention Poor visuospatial abilities are often out of proportion to other cognitive deficits Additional suggestive features may include autonomic dysfunction, sleep disorder, severe neuroleptic sensitivity, and psychiatric misidentification syndromes This diagnosis may overlap with AD and the dementia associated with Parkinson disease but having at least 2 core features raises the probability of dementia with Lewy bodies If Parkinson disease has been diagnosed or has been present for 1 yr before cognitive symptoms are seen, the diagnosis is more c/w Parkinson disease dementia If parkinsonian symptoms are present at the same time as cognitive symptoms, dementia with Lewy bodies should be considered

Frontotemporal Dementia Often seen in patients with onset of cognitive symptoms at a younger age Shrinking of the frontal and temporal regions; most common in men Executive and language dysfunction and significant behavioral changes Disinhibition and Hyperorality before significant memory decline Often have a profound effect on patient s social functioning Memory deficits are not as pronounced in the early stage Language impairment in FTD may progress much faster than other domains FTD probability increased by presence of known genetic marker and/or evidence of disproportionate frontal and/or temporal lobe involvement from neuroimaging

Treatment and Management of Dementia Goal is to enhance QOL and maximize functional performance Emphasis on non-pharmacological treatment Behavioral symptoms challenge both family members and professional caregivers Pharmacological treatment for behavioral problems recommended only after nonpharmacological treatments prove ineffective, or when there is an emergent need such as extreme patient distress or risk of physical violence Schedule regular appointments with PCP 3-6 months, screen for behavioral disturbance and proper sleep hygiene, caregiver well-being Family and Caregiver Education and support Environmental modification with attention to safety

Pharmacological Considerations Decreased renal clearance and hepatic impairment Drug interactions and adverse effects likely Anticholinergic side effects are a particular problem for patients with dementia because they can worsen cognitive impairment and lead to delirium Any nonessential medications with CNS adverse effects should be considered carefully

Cholinesterase Inhibitors Primary medications available for stabilizing cognitive function in Alzheimer s Dementia Currently approved by the FDA: Donepezil, Rivastigmine, and Galantamine By slowing the breakdown of the NT Acetylcholine, these medications are thought to facilitate memory function because of the association of acetylcholine and memory In clinical trials, these meds demonstrate a modest delay in cognitive decline compared with placebo Onset of behavioral problems and decline in ADLs is modestly delayed compared to placebo Widespread treatment in vascular dementia not currently recommended because of limited cognitive benefit and lack of sufficient data ChIs may be helpful in managing attention and behavioral disturbances/hallucinations associated in Dementia with Lewy Bodies

Cholinesterase Inhibitors Rivastigmine is approved by the FDA for use in Parkinson disease No role for ChIs in treating Frontotemporal Dementia; evidence suggests they may worsen agitation Effects are modest in all disorders Patients and Family should be counseled to have realistic expectations Discontinuation of the medication should be considered after a reasonable time period if decline continues at the rate expected without treatment In long-term therapy with initial positive responses to treatment but continued advancement of cognitive decline, unclear what effect discontinuation will have on cognition When cognitive decline persists despite maximum treatment with ChIs, tapering the medication over time may be considered Abrupt discontinuation is not recommended

Cholinesterase Inhibitors Dosed once daily, either in oral form (Donepezil and Galantamine) or as a 24-hr patch (Rivastigmine) Follow slow titration curve to maximize tolerable dosage while avoiding adverse effects Nausea, Diarrhea, Insomnia, Headaches, Dizziness, Orthostasis, Nightmares, Bradycardia

Aricept (Donepezil) Approved for mild-moderate-severe AD Begin 5 mg daily for four weeks Titrate up to 10 mg daily 23 mg dose available for severe dementia Common side effects: Upset stomach or poor appetite Sleep disturbances Syncope/Orthostasis/ Bradycardia

Exelon (Rivastigmine) Approved for mild to moderate AD and Parkinsons Dementia Pills Begin 1.5 mg orally twice a day Titrate up by 1.5 mg dose to target of 6 mg bid Titrate every 2 weeks to target Patches may have less GI side effects Begin 4.6 mg patch, change daily Titrate up in four weeks to 9.5 mg patch, then 13.3mg Common side effects same, with addition of rash from patches

Razadyne (Galantamine ) Approved for mild to moderate dementia DO NOT USE FOR MCI (Black Box Warning Increased Death) Available in short acting or long acting forms Goal daily doses are the same (16-24 mg) Begin 8 mg per day (either 4mg BID, or 8mgER once daily) 4 weeks between dosage titration

Memantine NMDA Antagonist Thought to have neuroprotective effects by reducing glutamate-mediated excitotoxicity Clinical trials support the efficacy of memantine in moderate to severe stages of AD Trials have yet to establish efficacy in other dementias Most common adverse effects are constipation, dizziness, and headache Can be used safely as a single agent and in conjunction with ChIs for moderate to severe AD

Namenda (Memantine) Namenda Titration Pack: Begin 5mg daily for one week, then 5 mg twice daily for one week, then 10mg in the morning and 5mg in the evening for one week, then 10mg twice daily Target dose is 10 mg bid but once/day may be adequate (long half life - hrs). (May need to dose adjust for renal failure). Very well tolerated. May reduce GI side effects of cholinesterase inhibitors (can start before or with).

Other Cognitive Enhancers Antioxidants Gingko Biloba Vitamin E B vitamins Omega 3 fatty acids Medium chain triglycerides Other OTC supplements

Antidepressants Consider for AD patients with Depressive symptoms, including depressed mood, appetite loss, insomnia, fatigue, irritability, agitations SSRIs can be helpful in managing disinhibitions and compulsive behaviors associated with FTDs However SSRIs and SNRIs can possibly exacerbate risk of fall, especially those with greater anticholinergic tone (e.g. Paroxetine)

Behavioral and Psychological Symptoms of Dementia (BPSD) Very common problem, ranging from sundowning, to anger, to oppositional behavior, to wandering. Hallucinations, Delusions, Affective syndrome, Depression, Anxiety, Irritability, Agitation, Behavioral Syndrome, Euphoria, Disinhibition, Apathy, Aberrant Motor behaviors, Sleep disturbances Prevalence 60-80% depending on setting Incidence over any patient s course >80% Frequent cause of hospitalization, nursing home placement, caregiver burden (and burnout) No easy answers Caregiver education Safe environments Activities focused on giving patients satisfaction, adapted to current capabilities When considering medications, ask: Are you treating the patient or the caregiver?

Psychoactive Medications Paranoia, agitation, and irritability are best managed by non-pharmacologic strategies Reduce overstimulation, distraction, redirection, physical activity 1 st and 2 nd generation antipsychotics help control behavioral and psychological sx of dementia All antipsychotics increase risk of all-cause mortality in setting of dementia ALL carry risk of death/black box warning. Consider written informed consent. Frequently attempt to taper Avoid use of BZDs and meds with anticholinergic effects Antidepressants with sedating effects (Mirtazapine, Trazodone) can be considered in management of insomnia

Sleep Disturbance in Dementia Day/night reversal hard on caregivers Overall sleep and quality of sleep impaired Treat the patient, support the caregiver Daytime activity Melatonin 1-3mg before bedtime Trazadone, Remeron sometimes helpful Avoid benzo s, z-drugs

Concomitant Medical Problems Err on the side of safety. DM: hypoglycemia more dangerous than modestly elevated glucose HTN: orthostatic hypotension and risks of falls are substantial Medications that impair food intake increase risks Meds that impair cognition to be avoided Often necessary to compromise with once daily regimens to improve compliance Nutrition and SafetyConditions Especially important to focus on prognosis and goals of care

Caregiver Burnout The Caregiver Burden Inventory (CBI) 22 items, with 5 possible responses per item Never, Rarely, Sometimes, Quite Frequently, Nearly Always Composite numeric score and five subscale scores (0-4) Scores of 36 or higher indicative of significant burden May be used as self-report or via interview A strategy for self-report during an office visit

Supporting the Caregiver During the past month have you often been bothered by feeling down, depressed, or hopeless? During the past month have you often been bothered by little interest or pleasure in doing things? If concerned about significant depression, considering asking about thoughts of self-harm, or harm directed at care reciever. A delicate issue if not the provider for caregiver. Just asking about burden is helpful. Validate the caregiving experience/role. People want to know if they are doing enough or what they are supposed to be doing? Community support resources Alzheimer s Association support groups

Dementia is a Terminal Disease POLST Form Timely discussions with patients and families Recognition of decline and poor prognosis Adequate diagnosis and treatment of pain Restricted use of feeding tubes: No improved survival, No improved nutritional status, No improved functional status, No prevention of aspiration Careful hand feeding is much more beneficial, for patient and caregiver, and safer. Late stage: people become bedfast, have swallowing difficulties, lose the ability to communicate basic information and needs, have increased risk for infections and death Referral to Hospice in a timely manner