dementia

A brief overview of diagnosis and treatment

Amy Sanders MDAssistant Professor of Neurology

Einstein Aging StudyEinstein-Montefiore Brain Aging Center

Albert Einstein College of Medicine

Coming Up

• Dementia: definitions

• Dementia: evaluation

• Dementia: subtypes

• Alzheimer’s Disease: diagnosis and Rx

• Other Dementia Subtypes: diagnosis and Rx

4.5million

7.7million

2000 2030

Hebert LE, Arch Neurol 2003

13.2million

2050

•What is dementia?

A species of insanity characterized by failureor loss of the mental powers…….

• A syndrome defined by a non-acute decline in cognition that interferes with functioning in everyday living

Multiple cognitive deficits, including MEMORYIMPAIRMENT and at least one of

- aphasia (language impairment)- apraxia (impaired motor activity)- agnosia (impaired recognition)- executive function disturbance (planning)

Disturbance interferes significantly with work or usual social activities/relationships [“ADLs”]

WHAT IS DEMENTIA?

Memoryloss

Problem solvingJudgmentSocial skills

Language

MORE THAN 6 MONTHS

NO NO

Diagnostic Procedures? LABS

?IMAGING

?LP

?EEG

?GENETIC TESTING

Laboratory Tests

• AAN Guideline: B12, thyroid function

• AAN Guideline: maybe syphilis serology

• AAN Guideline:depression screening

• Other labs: CBC, basic chemistry,

LFTs, parathyroid

Imaging

• Structural Neuroimaging: CT, MRI

• Volumetrics: labor-intensive, research

• PET: adjunctive, AD vs FTD

• Amyoid imaging: PIB, research

Klunk, et al. Ann Neurol 2004

Pittsburgh compound B

Active research: biomarkers

EEG: non specific

GENETICS

• Not currently recommended for routine clinical diagnosis

• Complex genetics for late-onset AD

• APOE ε4 allele: susceptibility gene for AD

• Progranulin mutations: FTD

Medication Review

• MANY medications may worsen cognition– Some anti-hypertensives (ß-blockers, CCBs)– Anti-cholinergics– Prednisone– Digitalis– Opiates/narcotic analgesics– Benzodiazepines– Even NSAIDS

DEMENTIA SUBTYPES

ALZEIMER’S DISEASE• Age-related neurodegenerative disease associated

with cognitive decline• Memory, judgment, language• Behavior and mood• Pathology: deposition of amyloid (plaques) and

hyperphosphorylation of tau (NF tangles)• Neuronal cell death and impaired neuronal

function• ? Complex Genetics, vascular risk factors,

Oxidative Stress, inflammation, hormones?

Struldbrugg – race of immortals who “turn to dotage and entirely lose their memories…”

Impaired memory, aphasia, erratic behaviour, paranoia and auditory hallucinations

Alzheimer A. Uber eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift fuer Psychiatrie 1907; 64:146–8.

K. Maurer, S. Volk, H. Gerbaldo. Auguste D and Alzheimer's disease.  Lancet 1997; 349: 1546-1549

Why is AD Important?

• Incidence rising—longer lifespans

• Most common neurodegenerative disease

• Most common illness leading to nursing home placement

• $156 billion worldwide cost in 2003

• Treatment available

• Long-term planning (HCP, long-term care)

a new . . . GREAT SUCKING SOUND

Alzheimer’s Disease• NINCDS-ADRDA criteria (probable AD)

• Dementia - established by clinical exam,documented by screening testsconfirmed by neuropsych tests

• Deficits in 2 or more areas of cognition

• Progressive worsening of memory/cognition

• No disturbance of consciousness

• onset 40-90 years, usually > 65y

• Absence of other systemic/brain disorders

• Memory loss that affects job skills. • Difficulty performing familiar tasks. • Misplacing things.

• Problems with language. • Disorientation to time and place.• Poor or decreased judgment. • Problems with abstract thinking. • Changes in mood or behavior. • Changes in personality. • Loss of initiative.

Ten Warning Signs – Alzheimer Association

Memory

Non-memory

Abnormal behaviors & AD

Symptom Months after memory

Calculation defect 25Language 31Irritability 39Gait disorder 47Wandering 50Sleep disorder 51Violence 64Incontinence 67  

Folstein & Bylsma,1999

AD: presentation

• Helpful to have informant

• Insidious onset of short-term memory complaint

• Trouble with names, word-finding difficulty

• Getting lost, forgetting parking location

• Trouble calculating – e.g. tips, checkbook

• Planning – recipes, trip planning

AD: behavioral components

• Apathy – loss of initiative

• Depressive symptoms – up to 30%

• Anxiety

• Paranoia, delusions – later stage disease

• Agitation – late disease

AD: Treatment

• Treat the disease: pharm and nonpharm

• Treat the collateral sx – behavior, mood

• Take care of the caregiver-respite

-health lit

AD Pharmacotherapy• Cholinesterase inhibitors

-donepezil (Aricept)

-galantamine (Razadyne [reminyl])

-rivastigmine (Exelon)

• NMDA receptor antagonist– Memantine (Namenda)– Moderate to severe AD, may be additive

Pointers

• Discussion with patient/family: expectations

• Start low and titrate: for all AChI

• Most common side effects: GI (N/V/D)

• Can switch agents

• Withdraw when no longer benefitting or no longer able to interact with family members

Donepezil

• 5 mg qd starting dose (minimum therapeutic dose)

• With or without food, take in a.m.

• Increase to 10 mg after 4-6 weeks

• Half life 70 hours, hepatic metabolism

Galantamine

– Start at 8 mg qd (minimum therapeutic = 16 mg)– Take with food (full meal)– Increase to 16 mg after 4 weeks – 24 mg is maximum dose– Most common side effect: GI– If treatment interrupted for more than 1 week, re-

start at 8 mg and repeat titration– Half-life 7 hours, hepatic metabolism

Rivastigmine

– Start at 1.5 mg BID (minimum therapeutic = 6 mg)– Take with food (full meal) for both doses– Stepwise increase monthly (1.5, 3, 4.5, 6 mg)– 12 mg (6 mg BID) is maximum dose– Most common side effect: GI– If treatment interrupted for more than 1 week, re-start at

1.5 mg BIDand repeat titration– Half-life 90 minutes, renal clearance

Memantine

– Start at 5 mg qd – Take with or without food – Stepwise increase weekly by 5 mg– 20 mg (10 mg BID) is maximum dose– Side effects fewer than with AChI (dizzy, HA)– Half-life 70 hours, partial hepatic clearance

Pharmacologic Treatment of Behavioral Symptoms

• NOT FIRST LINE• Complicated; generally off-label• Rule out other causes• Start low, go slow. Briefest use possible.• Agitation: atypical neuroleptics, anticonvulsants,

benzodiazepines• Depression: SSRIs, S-NE RI, other• Insomnia: trazodone, alprazolam, zolpidem,

ramelteon (may cause carryover sedation)

Vascular Dementia

• 2nd-most common subtype• May be present even in cases

without prominent memory loss• Executive function often

predominates• Vascular risk factors • Gait dysfunction

Diffuse

Lacunes

Multi-infarct

Chui, Arch Neurol, 2000

Variations on the Theme

• “stroke” dementia

• Subcortical pattern: lacunes, severe WMD

• CADISIL

• Often “mixed” with AD

VaD Treatment

• No targeted pharmacologic therapy

• Modification of vascular risk factors

• Aspirin used anecdotally

• Symptomatic treatment of affective symptoms

Dementia with Lewy Bodies

Central Feature: dementia is ESSENTIAL

Core Features:Parkinsonism (spontaneous)Visual hallucinations-recurrent, vivid/detailedFluctuations-attention and alertness especially

Suggestive Features:Severe neuroleptic sensitivity -- worseningREM sleep disorder -- acting out dreamsLow dopamine transporter uptake in BG (SPECT/PET)

McKeith, Neurology, 2005

DLB Treatment

• COMPLICATED– Parkinsonism– Cognition and fluctuations– Hallucinations, psychosis, agitation– REM sleep behavior disorder

“The cold within him froze his old features ... and stiffened his gait.”

“…vivid and detailed hallucinations featuring friends and relatives are common. And like Scrooge’s visions, these phantasms are distressing, often terrifying. Finally, in Lewy body dementia, hallucinations occur early in the disease, frequently before the cognitive deficits are apparent.” Sanders, “Diagnosing with Dickens,”

Sunday NYT Magazine 12/17/06

Frontotemporal dementias

Core• insidious onset, gradual progression• Early decline in social skills• Early decline in regulation of personal conduct• Early emotional blunting• Early loss of insight

SupportiveBehavioral disorderSpeech and language disturbancesPhysical signs – frontal signs, parkinsonism, labile BPInvestigations: neuropsychology, EEG, MRI

Neary, Neurology, 1998

Initial-Carving Doctor Banned

'Dr. Zorro' Blamed Brain Disorder for Scarring Patient

FTD Treatment

• Few options

• AChI not effective, may cause agitation

• Perhaps some role for SSRIs

• Safety assessment

• Depression common in caregivers and can be a reason for earlier nursing home placement