Dementia – A How to Approach for Clinicians

Ho-Yann Jong, M.D.October 26, 2017

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Learning Objectives• Review the clinical features of Alzheimer’s disease, Lewy body

disease, frontotemporal disorders, and cognitive disorder due to vascular disease

• Understand how to work up patients presenting with cognitive complaints in primary care setting

• Understand when to refer to neurology and cognitive specialist

• Review of non-pharmacological interventions and FDA-approved medications for cognitive disorders

Overview: Definitions

• Major neurocognitive disorder– Replaces the term “dementia” in DSM-V.– Significant cognitive decline from prior level of functioning in ≥ 1 cognitive

domains (attention, executive function, learning/memory, language, perceptual-motor, social) such that it interferes with independence in at least complex daily activities.

– Significant objective impairment in cognition on standard testing.– Not due to delirium or another medical/mental condition.

• Mild neurocognitive disorder– Replaces the term “mild cognitive impairment” in DSM-V.– Cognitive decline does NOT interfere with independence of daily activities. – Modest degree of objective impairment in cognition on standard testing. – Not due to delirium or another medical/mental condition.

DSM-5: http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm17

Overview: Common Etiologies

• Degenerative: – Alzheimer’s disease (most common)– Lewy body disease– Frontotemporal disorder(s)

• Vascular:– Multi-infarct– Subcortical

Alzheimer’s Disease• Most common cause of dementia• Age: Biggest risk factor

– Incidence: • 1.3% per year (age > 65)• Doubles every 5 years after age 65

– Early-Onset: Younger than age 65 – Do NOT mix up “early-onset” with “early/mild-

stage”• Death within 3-9 years (on average) after diagnosis

– 6th leading cause of death in the U.S. (2014)• Prevalence: 4.7 million in the U.S (age 65 or older) in

2010– 13.8 million in the U.S. by 2050

Querfurth and LaFerla 2010; Herbert et al 2013; National Center for Health Statistics; Image source: Wikipedia.

Auguste Deter: First AD patient diagnosed by Dr. Alois Alzheimer in 1901.

DSM-5: http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.dsm17

Alzheimer’s Disease

• Insidious onset

• Gradual progression of impairment– Memory-predominant deficits on standard testing– Lacks clinical features to suggest other degenerative etiologies

• Pathology: β-amyloid

• Biomarkers: – CSF β-amyloid/tau ratio– MRI– FDG-PET; Amyloid-PET; Tau-PET

Lewy Body Disease: McKeith Criteria

Supportive Clinical Features:Neuroleptic sensitivityAutonomic dysfunction

Core Features:Fluctuations

Visual hallucinationsREM sleep behavior disorder

Parkinsonism (bradykinesia/rigidity > tremor)

DementiaMcKeith et al. Neurology 2017.

Pathology: α-Synuclein

DLB: Parkinsonism• Seen in 70-90% of

patients

• Cognitive changes usually precede parkinsonism or are seen within one year from onset of parkinsonism

Farlow et al. UpToDate 2015.

REM sleep Behavior Disorder (RBD)

• 50-80% of DLB patients

• Can precede dementia onset by decades

Howell and Schenck. JAMA Neurol 2015.

Frontotemporal Disorder(s)• Younger age of onset compared to AD and LBD

• Behavior-variant– Behavioral disinhibition: socially inappropriate, loss of manners, impulsive,

lack of empathy, hyperorality, etc.– Prominent executive dysfunction. Other cognitive domains could be

preserved in the beginning.

• Language-variant– Primary progressive aphasia

• Difficulty with language is the primary feature and cause of functional impairment.

– May involve non-language domains as disease progresses.

• Other: Corticobasal degeneration; Progressive supranuclear palsy

• Pathology: Tau

Rascovsky et al. Brain 2011; Gorno-Tempini et al. Neurology 2011.

Cognitive disorder due to vascular disease

• Multi-infarct– Presenting symptoms depend on location of infarct(s)– Step-wise progression– CT/MRI – encephalomalacia/lacunar infarcts

• Subcortical– May or may not have focal findings on exam– Gait instability– Urinary symptoms not explained by urologic disease– Executive dysfunction > memory deficits– Could present as gradual progression instead of step-wise– CT/MRI – extensive white matter small vessel ischemic changes

Wright et al. UpToDate 2017.

Primary Care Providers: Critical Role

• Identify patients with cognitive symptoms

• Rule out medical/mental conditions that may cause cognitive disturbance (e.g. hypothyroidism, B12 deficiency, depression, etc.)

• Optimization of risk factors management (e.g. hypertension, hyperlipidemia, diabetes)

• Manage majority of dementia cases longitudinally

PCP: Case Identification

• Affordable Care Act: Medicare Annual Wellness Visit should include “detection of any cognitive impairment”.

• What to ask? – WHEN did it start: Make sure to ask specifically when the

VERY FIRST sign of memory loss emerge, no matter how minor it seemed.

– HOW did it start: Gradual versus Sudden. – HOW did it change: Progressive, Static, or Fluctuating. – WHO noticed it: Important to obtain collateral history from

family/friends whenever possible. – WHAT happened at onset: Stroke, head trauma,

neurological/systemic illnesses, hospitalization, surgery/general anesthesia, etc.

PCP: Case Identification

• Neurological exam• Cognitive Screen: many options

– http://www.alz.org/documents_custom/awv_algorithm_webA.pdf

• Lab workup: – Basic: TSH, B12, MMA, Vitamin D. – Syphilis serology if has history of high-risk sexual behavior

or from areas with high prevalence– CBC/CMP if no recent baseline– Other labs as deemed necessary based on history

• Imaging: – Either done prior to neurology visit or after. – MRI most ideal if no contraindication.

PCP: When to refer

• Patients with atypical presentations:– Young/early-onset (age < 65)– Rapidly progressive– Other neurological signs and symptoms (e.g. seizures, focal

deficits)– Suspicion of uncommon diagnoses (e.g. normal pressure

hydrocephalus, autoimmune encephalopathy)

• Diagnosis uncertain (e.g. normal-aging versus neurodegenerative disease versus depression)

Treatments: Overview

• Non-pharmacological– Exercise– Diet– Nutritional Supplements– Cerebrovascular risk factors management

• Pharmacological– Cholinesterase inhibitors (donepezil, galantamine,

rivastigmine)– NMDA-receptor antagonist (memantine)– Combination therapy

Non-Pharmacological Interventions

Exercise• Evidence for slowing down progression of functional decline, but no definitive benefit on cognition.

– Rolland et al 2007: • 134 nursing home residents • Randomized to exercise program (1-hr session x 2/week x 12 months) or routine medical

care• Exercise group showed significantly slower decline in ADL score

– Pitkala et al 2013: • 210 home-dwelling patients• Randomized to group-based exercise, home-based tailored exercise programs, and controls• Exercise groups showed significantly slower functional deterioration at 6 months and

fewer falls

– Hoffmann et al 2015: • 200 mild-AD patients• Randomized to supervised moderate-to-high intensity aerobic exercise or control group• Exercise group showed reduced neuropsychiatric symptoms; in the subgroup exercising

with high attendance and intensity there was also significantly slower cognitive decline.

Hoffmann et al 2015; Pitkala et al 2013; Rothman et al 2012; Rolland et al 2007.

Exercise

Koo et al 2013.

Diet• Mediterranean diet (31% lower relative risk)

– Rich in n-3 polyunsaturated fatty acid (PUFA) – Vegetables, fruit, legumes– Moderate amount of fish– Low-moderate amount of red wine during meals– Olive oil

• Higher adherence is associated with lower mortality in AD.

Cao et al 2015; Scarmeas et al 2007. Image source: Wikipedia.

Nutritional Supplements

• Vitamin B group: Controversial – 28% relative risk reduction (Meta-analysis, Cao et al 2015).– May slow down the atrophy of specific brain regions key to AD process and

associated with cognitive decline in MCI patients (RCT, Douaud et al 2013).– High-dose folate/B6/B12 in 409 mild-moderate AD patients showed no benefit in

cognition (RCT, Aisen et al 2008).

• Vitamin D– Deficiency: Meta-analysis showed ~2.4x relative risk of cognitive impairment. – Vitamin D Receptor (VDR): expressed in prefrontal cortex, cingulate gyrus, basal

forebrain, caudate/putamen, thalamus, substantia nigra, LGN, hypothalamus, cerebellum.

– VDR gene polymorphism: associated with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis.

Cao et al 2015; Schlogl and Holick 2014; La Fata et al 2014; Douaud et al 2013; Etgen et al 2012; Farina et al 2012; Aisen et al 2008; Miller et al 2005; Sano et al 1997.

Nutritional Supplements

• Anti-oxidants – Vitamin E: Controversial

• 20% relative risk reduction (Meta-analysis, Cao et al 2015).• 2000 IU/day showed benefit in slowing down functional decline, but no benefit for

cognition, in moderately-severe and mild-to-moderate AD patients, respectively. No additional benefit on top of memantine therapy (Sano et al 1997, Dysken et al 2014).

• No convincing evidence that vitamin E is of benefit in the treatment of AD or MCI (Cochrane Systemic Review, Farina et al 2012).

• CAUTION: High dose (≥ 400 IU/day) Vit E may have increased risk for all-cause mortality (also controversial).

– Vitamin C and Flavonoids: No significant benefits in meta-analysis.

Cao et al 2015; Schlogl and Holick 2014; La Fata et al 2014; Etgen et al 2012; Farina et al 2012; Aisen et al 2008; Miller et al 2005; Sano et al 1997.

Reduce cerebrovascular risk factors• Management of:

– Smoking– High cholesterol– Diabetes mellitus– High blood pressure– Obesity– Sleep apnea

Cao et al 2015.

Pharmacological Interventions

Cholinesterase inhibitors: Overview• Mechanism: Augment cholinergic activities in Central Nervous System

• Donepezil, Galantamine, Rivastigmine

• FDA-approved for mild-moderate AD– Donepezil: Also approved for severe AD (2006)

• Similar efficacy between the three.– Symptomatic therapy: improvement in cognition, function, and behavioral disturbance. – No survival benefits.

• Similar adverse effect profiles– GI (nausea, vomiting, diarrhea, loss of appetite), dizziness, headache, AV block, bradycardia

• Choosing an agent:– Cost: Formulary vs Non-formulary

– Individual patient’s tolerability (may be different despite similar AE profiles)

Deardorff et al 2015; Suh et al 2011; Seltzer 2010; Herrmann et al 2009; Birks and Harvey 2006; Micromedex.

Cholinesterase inhibitors• Donepezil (Aricept ®) (1996)

– 5 mg daily 4-6 weeks Target 10 mg daily.– Moderate-Severe AD: can increase up to 23 mg daily (Some cognitive benefits but

higher risk of adverse effects)

• Galantamine (Razadyne ®) (IR – 2001, ER - 2004) – IR: 4 mg BID increase every 4-6 weeks Target 12 mg BID.– ER: 8 mg daily increase every 4-6 weeks Target 24 mg daily.– IR versus ER: Pharmacologically equivalent. ER has better 1-year persistence (54%) than

IR (44%).

• Rivastigmine (Exelon ®) (Oral – 2000, Transdermal – 2007)– Oral: 1.5 mg BID increase every 2-4 weeks Target 6 mg BID.– Transdermal: 4.6 mg/day 4-6 weeks Target 9.5 mg/day

• 13.3 mg/day patch: approved for severe AD (ACTION study)– PO vs TD: TD is better tolerated with less GI adverse effects. – Also approved for dementia due to Parkinson’s disease

Adler et al 2014; Sadowsky et al 2010; Seltzer 2010; Herrmann et al 2009; Micromedex.

Cholinesterase inhibitors: Donepezil 23 mg

Farlow et al 2010.

NMDA-Receptor Antagonist• Mechanism: Neuroprotection by reducing excitotoxicity due to

CNS glutamate.

• Modest benefits in moderate-severe AD patients. – Delays functional and cognitive decline.– Improves behavioral disturbance.– Possibly disease-modifying.

• Adverse effects: Headache, confusion, dizziness, diarrhea

• Memantine (Namenda ® - 2003, Namenda XR ® - 2010)– Memantine: 5 mg daily increase every 1 week Target

10 mg BID. • Generic formulation available.

– Memantine ER: 7 mg daily increase every 1 week Target 28 mg daily.

• No generic version of yet

• IR versus ER: No direct comparison of efficacy. ER can be sprinkled in applesauce (dysphagia patients).

Matsunaga et al 2015; Plosker 2015; Reisberg et al 2003; Micromedex.

Combination Therapy• Donepezil + Memantine

– Improvement/delayed progression of cognition and function.

– Some controversy about whether the modest benefits are clinically meaningful or not.

• NICE (UK) meta-analysis: insufficient evidence to support combination therapy when compared with memantine therapy alone.

• Namzaric ® (donepezil-memantine 10-14 mg or 10-28 mg, once daily) – Approved 12/2014

– Brand-name only– No Phase III trial for Namzaric per se. Approval

based on prior trials for memantine ER and donepezil.

Greig 2015; Deardorff et al 2015; Tariot et al 2004.

Treatment: Variations

• LBD: – May show greater response to cholinesterase inhibitors than AD– Same pharmacological therapy strategy as AD.

• Vascular cognitive disorder:– Same pharmacological therapy strategy as AD

• FTD: – No definitive evidence to support the use of cholinesterase

inhibitors or memantine. – Some report of potential worsening of cognitive/behavioral

symptoms on cholinesterase inhibitors or memantine– Trial of cholinesterase inhibitors may still be pursued if AD remains

a possible differential

Lee SE and Miller BL. UpToDate 2016.

SUMMARY• Distinguish common etiologies of cognitive disorder in geriatric population:

– Alzheimer’s disease: Insidious onset, memory-predominant deficit– Lewy body disease: McKeith Criteria– FTD: Behavior versus language variants– Vascular: History of stroke/TIA and supporting CT/MRI findings

• Primary care providers play a critical role in the management of cognitive disorders: Identification; Rule out other conditions; Longitudinal follow-ups; Referral of unusual cases

• Exercise, Mediterranean diet, control of cerebrovascular risk factors, and possibly vitamin B/D/E supplementation are beneficial in patients with cognitive disorders.

• Cholinesterase inhibitors (donepezil, galantamine, rivastigmine), NMDA-Receptor antagonist (memantine), and combination therapy are indicated for Alzheimer’s disease, Lewy body disease, and vascular cognitive disorder (choice depends on the stage/severity).

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Thank you!

Questions?