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Dementia Michael A Hill, MD Professor Of Psychiatry * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * NGF -- see previous discussion. – PowerPoint PPT presentation

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Title: Dementia

  • Michael A Hill, MD
  • Professor Of Psychiatry

Dementia An acquired syndrome characterized by
  • Short-term memory impairment (i.e. learning) AND
  • At least one of the following
  • Aphasia - language memory impairments
  • Apraxia - motor memory impairments
  • Agnosia - sensory memory impairments
  • Abstract thinking / Exec. function impairments
  • Impairment in social and/or occupational fn
  • Sxs not explainable by another disorder

Etiology Pathogenesis
  • Dementia results from impaired functioning of
    multiple brain systems in both cortical and
    sub-cortical areas that are associated with
    short-term memory (i.e. learning) and other
    higher cognitive functions. Generally this is
    due to structural brain damage that is often
    progressive and relatively irreversible

Clinical Presentation of Dementia
  • Always associated with cognitive disturbances and
    functional impairments
  • Visuospatial impairments and behavioral
    disturbances are usually seen as well
  • Specific symptoms will vary by type of dementia
    (Frontal lobe dementias present with personality
    change and executive dysfunction to a much
    greater degree than memory impairment)

Memory Impairments
  • Difficulty learning or retaining new information
    (repeated conversations)
  • Information retrieval deficits (cant recall
    names, list generation deficits)
  • Personal episodic memory impairment (misplacing
  • Declarative (semantic) memory (WHAT) gt procedural
    memory (HOW)

Language Deficits
  • List-generation deficits verbal fluency (esp.
    in AD)
  • Word-finding difficulties (naming problems)
  • Less complex sentence structure
  • Relatively preserved auditory comprehension (can
    understand directions)

Visuospatial impairments
  • Visual recognition impairments (trouble
    recognizing familiar faces - CAPGRAS syndrome
  • Spatial deficits (getting lost in familiar
    surroundings, 3-D drawing deficits,
    constructional apraxia)

Functional Impairments
  • Deficits appear first in IADLs (managing
    finances, driving, shopping, working, taking
    medications, keeping appointments)
  • Eventually problems with ADLs (feeding, grooming,
    dressing, eating, toileting)
  • Rate and specific pattern of loss will vary by
    individual and somewhat by diagnosis
  • NB Functional impairment and performance on
    cognitive testing may not correlate strongly
    early in the course of dementia

Behavioral Symptoms
  • Nearly universal and often the main focus of
    treatment. Inability to manage these symptoms is
    highly correlated with institutional placement.
  • passivity (apathy, social withdrawal)
  • disinhibition (inappropriate sexual behavior or
    language, loss of social graces, aggression)
  • self-centered behaviors (childishness, loss of

Epidemiology Prevalence increases with age
Lower numbers represent moderate to severe
Incidence Of Alzheimers Disease by Age
Diagnostic ApproachEarly Detection Screening
  • Careful history from patient and reliable
  • PE with focus on neurological exam and cognitive
  • Cognitive testing tools such as MMSE are helpful.
    Score below 24-27 often concerning depending on
    premorbid abilities
  • Functional Assessment tools such as the
    Functional Activities Questionnaire

Primary Care Screening Tools
  • MMSE (normal varies somewhat by age and
    educational level an 80 y/o with only 4 years
    of education would be expected to only get a
  • Clock Test easy to do, quick. Draw a clock,
    put numbers in correct locations, set hands to
    10 til 2.
  • List generation number of animals that can be
    named in 60 seconds. lt12 is definitely abnormal,
    12-18 is marginal. Can also do words beginning
    with letter F. 10 in one minute is normal.
    Often very impaired in Alzheimers and some types
    of FTDs.
  • Trails B testing is useful if frontal lobe
    deficits suspected (e.g. fronto-temporal
    dementias, AIDS dementia)
  • Go No-Go Testing (inability to inhibit

Cognitive Testing
  • Serial 7s (5 answers) - If you can do it, thats
    good, but as many as 50 of normal elderly cant
    (WORLD backwards is not much better as only 62
    of elderly can do it with no errors)
  • Orientation If you are disoriented thats bad,
    especially to month or year, however many early
    dementia patients are fully oriented (40)
  • 3-item recall Not being able to recall 2/3 is
    bad as only 19 of dementia patients can do this,
    but 74 or normal elderly can
  • MMSE Sensitivity 87, Specificity 82

MMSE norms by Age and Educational Level
  • Educational level

Diagnostic Work-Up
  • This is done to
  • (1) rule out disorders besides dementia (e.g.
  • (2) to identify reversible/treatable dementias
  • (3) to clarify the specific dementia syndrome
  • Routine Assessment CBC with diff, serum
    electrolytes, Ca, glucose, BUN/CR, LFTs, TFTs,
    B12 folate, U/A, RPR, head imaging
  • When indicated Sed. rate, HIV, CXR, heavy
    metals, LP, EEG, functional imaging, Lyme titers,
    endocrine studies, rheumatologic studies,
    Neuropsychological Testing

Guidelines For Use of Specialized Testing
  • LP Suspicion of metastatic CA, CNS infections,
    neuropsyphilis, hydrocephalus, vasculitis. Also
    for dementia lt55 and rapidly progressive
  • Neuroimaging - consider in all new cases.
    However without focal symptoms or signs, seizures
    or gait disturbances in an individual over age 70
    - consider this optional
  • Functional Imaging (SPECT, PET, MRS, fMRI) to
    clarify type of dementia when necessary (and in
    the future to track course of illness and
    response to tx)
  • EEG - can help distinguish delirium from
    dementia, can help with seizure disorder and JCD
  • Neuropsychological testing language barriers,
    MR, legal proceedings

Mild Cognitive Impairment
  • Some cognitive deficits apparent on testing but
    not to dementia level (MMSE 24-29) range
  • Minimal, if any, functional impairments
  • 13-15 per year progress to dementia (A.D.) but
    not all progress and some improve (especially
    amnestic type aMCI)
  • Predictors of progression ApoE4 alleles, poor
    performance on cued recall (amnestic type) and
    hippocampal atrophy by MRI

  • More appropriately called reversible dementia
  • The classic case is depressive pseudodementia
    with overstated cognitive impairments due to
    decreased concentration and poor effort
  • However, depression may be a risk factor for
  • 50 of elderly patients with depressive
    pseduodementia have Alzheimers at 5 year

Late-Life Depression
  • Defn First Major Depressive Episode occurs
    after age 65
  • High correlation with dementia (50 go on to
    develop dementia within 3 years!)
  • Many of these depression may be vascular or
    post-stroke depressions

Most Common Dementias
  • Alzheimers Disease (AD) (50-75)
  • Lewy Body Dementias (DLB) (10-30)
  • Vascular Dementias (VaD) (15-20)
  • Alcohol-related dementias (including Korsakoffs
    (infrequent) and etoh-induced))
  • HIV dementia - most common dementia in those
    under age 55

Classification of Dementias
  • Primary versus secondary based on the
    pathophysiology leading to damaged brain tissue
  • Cortical versus sub-cortical depending on the
    cerebral location of the primary deficits
  • Reversible versus irreversible depending on
    optimal treatment expectations
  • Early (before age 65) versus late onset

ALZHEIMERS Pathophysiology
  • Neuritic plaques -extracellular - abnormal
    insoluble amyloid (beta) protein fragments
  • Neurofibrillary tangles - intracellular -
    disturbed tau-microtubule complexes
    (hyperphosphorylated tau)
  • Cholinergic system degeneration with significant
    loss of neurons in certain areas (such as Nucleus
    Basalis of Meynert)
  • Degeneration often begins in enterorhinal cortex
    and progresses to other limbic structures

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Lewy Body Pathology
  • Concentric spheres found within vacuoles
    (eosinophilic cytoplasmic inclusions)
  • Seen in cortex, midbrain and brainstem neurons in
    patients with idiopathic parkinsonism,
    Alzheimer's disease and especially Lewy Body
  • The main structural component is
    alpha-synuclein. Ubiquitin is sometimes seen also.

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Risk Factors for AD
  • Age
  • Family history / genetics
  • Downs syndrome (trisomy 21)
  • Head Trauma (esp. late in life) TBI may double
  • Female gender (mixed results age bias and
    possible higher clinical expression in women)
  • Ethnicity (Caucasians have the lowest risk)
  • Late-onset depression (after age 65)
  • Mild Cognitive Impairment (MCI)

Additional Risk Factors for Dementia
  • Cerebrovascular disease (and the risk factors for
    CV disease including smoking, diabetes,
    hyperlipidemia, hypertension) is associated with
    vascular dementia risk
  • Recurrent MDD may be associated with risk of
    dementia in general. (Kessing and Anderson found
    risk of dementia to be 6 times higher in patients
    with 5 or more prior episodes.)1
  • Subclinical Hyperthyroidism (especially when
    antithyroid antibodies are present.2

1Kessing LF, Anderson PK. J Neurol Neurosurg
Psychiatry. 2004751662-1666 2Kalmijn S, Mehta
KM, Pols HA, et al. Clin Endocrinology (Oxf)
Genetic risk factors
  • Chromosome 19 - autosomal recessive -
    Apolipoprotein E-4 allele - associated with
    late-onset disease (not relevant for
  • TOMM40 newly identified affects age of onset
  • Chromosome 1, 14, 21 - autosomal dominant
    mutations - associated with early-onset/familial
    cases (5). Amyloid processing genes.
  • CLU clusterin and PICALM (phosphatidylinositol-b
    inding clathin assembly protein)
  • Chromosome 9 ubiquilin 1 polymorphisms
    needs replication
  • BDNF val/val variant might be protective

Protective Factors in AD
  • Education
  • Anti-inflammatory agents (those that decrease
    amyloid production)
  • Estrogen replacement therapy (/-)
  • Smoking ()?nicotine/past use(-) CVD/current
  • APO E-3, CETP VV (longevity gene)
  • Vitamin E other antioxidants?
  • Homocysteine reduction
  • Statin use (protects against PD, AD?)

Vascular dementia
  • Includes Binswangers disease, MID, anoxic
    damage, post-CABG, inflammatory diseases
  • RISK FACTORS age, hypertension, diabetes and
  • 2nd most common dementia but incidence drops
    after the age of 75 (unlike Alzheimers disease)
  • In one study, 87 of vascular dementias at
    autopsy had AD pathology1

1Nolan KA, Lino MM, et al. J Am Geriatr Soc,
Other less common dementias
  • Primary degenerative dementias
  • Diffuse Lewy Body dementias (7-26 of dementias)
  • Frontotemporal dementias (Picks, ALS,
  • Neurological disorders associated with dementia
  • PSP, Parkinsons dementia, NPH, neoplasms, head
    trauma, subdurals, demyelinating diseases

Less common dementias (cont.)
  • Infectious causes
  • neurosyphilis, Lyme disease
  • post-encephalitic dementias (esp. herpes)
  • viral, parasitic, bacterial and fungal
  • opportunistic infections or brain abscess
  • Human prion disease (transmissible spongiform
    encephalopathies) - sCJD, Mad-cow
    disease(vCJD), Kuru, fatal familial insomnia

General medical causes of dementia
  • Thyroid and adrenal diseases
  • Vitamin deficiency states (thiamin, niacin, B12)
  • Metabolic derangements (hepatic encephalopathy,
    dialysis dementia, etc.)
  • Medications (sedatives, antihypertensives,
    narcotics, anticholinergics)
  • Whipples Disease, sarcoidosis, Wilsons disease
  • Toxins (heavy metals, organic poisons)

Rapidly Progressive Dementias
  • Hashimotos Encephalitis (treatable with
  • Cerebellar degeneration syndromes
  • Transmissible spongiform encephalopathies (prion
  • Paraneoplastic syndromes
  • Postviral encephalitis
  • Rare cases of AD, DLB, FTD

Economic Burden
  • 80 to 100 billion per year in total treatment
  • Alzheimers disease is the third most expensive
    disease to treat in the United States, following
    cancer and heart disease
  • Currently 4 million people have Alzheimers
    disease in the U.S.
  • More than 213,000 per family for the remainder
    of the patients life, including direct and
    indirect treatments costs (47,000 per patient
    per year)

General Treatment Principles
  • Treatment Of Underlying Disease Process (Primary
  • Management Of Behaviors and Symptoms (Secondary
  • Caregiver Support and Education

Reversible Dementias
  • May become irreversible if not treated soon
  • Many dementias may be arrestible if not fully
  • Rule out depressive pseduodementia and delirium
    which can mimic dementia
  • Some reversible dementias include hypoT4, B12
    def., some infections and tumors, drug-induced
    syndromes, etc.

Primary Treatment Strategies
  • 1. Prevention
  • Identify risks and mitigate
  • Develop neuroprotective strategies for those at
  • 2. Slow or halt progression of illness
  • Understanding pathophysiology leads to treatment
  • 5 year delay in onset ---gt 1/3 decrease in
  • Delaying institutionalization by 1 month saves
    1.2 billion/yr
  • 3. Reverse symptoms
  • Compensate through augmentation of remaining
    neurons or other systems
  • Reversal of destructive processes regeneration
    of tissue

Delayed Onset Incidence
ALZHEIMERS Pathophysiology
  • Neuritic plaques -extracellular - abnormal
    insoluble amyloid protein fragments
  • Neurofibrillary tangles - intracellular -
    disturbed tau-microtubule complexes
    (hyperphosphorylated tau)
  • Cholinergic system degeneration with significant
    loss of neurons in certain areas (such as Nucleus
    Basalis of Meynert)
  • Degeneration often begins in enterorhinal cortex
    and progresses to other limbic structures

  • Reduce Serum anticholinergic load
  • Precursor strategies (e.g. lecithin and choline)
  • Receptor/synaptic strategies
  • Metabolic strategies (anticholinesterases)

Serum Anticholinergic Load Cognitive Impairment
  • 90 of community elderly sample had detectable SA
  • An SA level gt2.8 pmol/Ml was 13X more likely to
    be associated with an MMSE of 24 or less in the
    general elderly population than in those with
    undetectable SA levels
  • Univ Of Pittsburgh, AAGP 5th Annual Meeting, 2002

Commonly Prescribed Non-Psychiatric Drugs with
Significant Anticholinergic Activity
  • cimetidine ranitidine
  • prednisolone
  • theophylline
  • digoxin/Lanoxin
  • furosemide
  • nifedipine
  • diphenhydramine (OTC)
  • To a lesser extent codeine, warfarin,
    dipyradimole, isosorbide dinitrate

Current AChE Inhibitors
promotes binding of acetylcholine and stimulates
pre-synaptic release of ACh
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Anticholinesterase Side Effects(i.e.
  • GI nausea, vomiting, diarrhea, increased
    gastric acid secretion
  • Muscle cramps
  • Fatigue
  • Insomnia
  • Syncope (2 vs 1 for placebo) (?bradycardia)

most common with rivastigmine
  • Calcium channel modulation and excitatotoxic
    systems attenuation (such as memantine)
  • Anti-inflammatory/immunosuppressive
    strategies(e.g. NSAIDs)
  • Gene therapy for defective protein regulation
  • Toxin removal (Desferroxamine, clioquinol) /
    Ventriculoperitoneal shunting (COGNIShunt)
  • Amyloid Protein strategies
  • Other Neuroprotective strategies

Neuroprotective Strategies
  • Nerve Growth Factor
  • Acetyl-l(levo) carnitine (ALCAR)
  • Estrogen
  • Homocysteine reduction( folate, B6, B12)
  • Antioxidants (Vit E, Gingko, deprenyl)
  • Statins (Lipitor, Pravachol) (may lower
    abnormal amyloid levels)
  • B-blockers in AD
  • Rosiglitazone (Avandia) -anti-inflammatory,
    amyloid processing modulation activities
  • Levetiracetam(Keppra) for aMCI reduces
    hippocampal hyperactivity

Nutraceutical Strategies
  • Vitamin E (antioxidant)
  • Homocysteine Reduction (folate, B6, B12)
  • Beta-carotene
  • Physicians Health Study II found a cognitive
    protective effect of 50 mg every other day over
    two decades of use
  • Gingko (antioxidant)
  • Resveratrol (a type of polyphenol found in red
    grape skins and thus red wine)
    ?anti-inflammatory, anti-aging, anti-cancer

Vitamin E
  • Potent antioxidant properties
  • Has been shown to slow progression at least as
    much as Deprenyl in one head-to-head study
  • Recent study showed no difference from placebo in
    preventing progression from MCI to AD over 3 yrs
    but higher dietary intake over 10 years in
    non-demented patients resulted in 26 lower
    incidence of AD (Rotterdam Study)
  • Few side effects even in high doses, though
    recent studies in Europe suggest a higher death
    rate in those on hi-dose Vitamin E
  • Doses used in recent studies up to 1000 IU bid
  • Consider 400-800 IU per day for prevention
  • May work better if combined with Vitamin C

  • At this point the summary of many studies
    suggests that Hormone replacement therapy (HRT)
    is questionably effective in slowing the onset of
    AD in some women
  • The earlier started, the better. Limited
    exposure may be best.
  • Progesterone may be detrimental
  • Tacrine response can be enhanced by Estrogen
  • WHY? neurotrophic effects, incr. ChAT, high
    serum E2 suppresses Apo E

  • Lovastatin(Mevacor), pravastatin(Pravachol),
    simvastatin(Zocor), atorvastatin(Lipitor)
  • May prevent aggregation of B-amyloid in the
    brain by preventing cholesterol build up. May
    activate alpha-secretase.
  • Conflicting evidence recent U of Wash study did
    not find a benefit, but looked at older
    individuals on statins only a short while.
  • Earlier studies were more positive
  • Not sure if all these drugs are equal Ability to
    enhance tissue plaminogen activator (tPA) and
    thus production of plasmin may be important.
    Plasmin may activate alpha-secretase and can also
    increase production of BDNF.
  • AKA amyloid-beta peptide or ABeta

  • Glutamate
  • is the principal excitatory neurotransmitter in
    brain regions associated with cognition and
    memory (i.e. it stimulates cholinergic neurons)
  • Glutamate hypothesis of dementia
  • suggests that overactivation of these neurons
    leads to excitatoxic damage to these brain areas
    (by allowing calcium to continuously leak in to
    cells). It is post-synaptic receptor sensitivity
    rather than excess release of glutamate that is
    the problem.
  • Memantine
  • is a weak antagonist of glutamate-gated NMDA
    receptor channels which prevents overactivation
    during memory formation but allows normal

  • Trade name Namenda
  • Dose range 5 to 20 mg (bid dosing)
  • Side effects Constipation, somnolence,
  • Agitation was significantly less likely in
    memantine groups than placebo

NSAID Use AD in Elderly Patients
  • 2708 patients enrolled
  • Examined NSAID use and prevalence of Alzheimers
  • NSAID users had 50 lower risk of being affected
    by AD
  • Aspirin trended this way but was not significant
  • Treatment studies have not shown any consistent
    benefits yet however.
  • Landi, et al, Am J Geriatric Psychiatry,
    March-April, 2003

Abnormal Amyloid Protein Strategies
  • Most genetic mutations associated with AD affect
    amyloid processing
  • Senile plaques contain abnormal amyloid B
    fragments (that precipitate out of solution
  • Attack enzymatic pathways that lead to production
    of abnormal type and amount of amyloid ( beta or
    gamma-secretase inhibitors)
  • Enhance alpha-secretase system to promote normal
  • Prevent aggregation (NSAIDS may do this!)
  • Alter the abnormal gene expression
  • GAG mimetics (glycosaminoglycans) Alzhemed
    interferes with formation of insoluble amyloid
    protein fragments

Anti-amyloid Treatments
  • Gamma and beta secreatase inhibitors
  • Poor response to gamma inhibitors in Phase III
    trials so far
  • Aggregation inhibitors (e.g. tamiprosate)
    negative in Phase III trials
  • Immunotherapy
  • AN-1792 worked in mice but high rate of
    encephalitis in humans less powerful antigen
    form being developed
  • Passive immunization bapineuzumab monocloncal
    AB against amyloid-B protein
  • Autophagy enhancers

Reversal Strategies
  • Destroy the current plaques/amyloid
  • Vaccination Strategy AN-1792 vaccine is in
    testing. This is an amyloid B protein fragment
    which can induce antibodies that bind to plaques
    and activate microglial destruction processes.
    Trial halted b/o menigoencephalopathies
  • Plaque busters
  • Alzhemed prevents Amyloid B fragments from
    forming fibrils
  • Clioquinol - A metal-protein-attenuating compound
    (MPAC) that inhibits zinc and copper ions from
    binding to beta-amyloid, thereby helping to
    dissolve it and prevent it from accumulating.
  • Transthyretin shows promise at interfering with
    toxic effects
  • Generate new tissue -
  • Neuroregeneration strategies (STEM cells)
  • Neurotransplantation strategies

Other Drugs in the Pipeline
  • Tau protein modulators (to prevent abnormal
    phosphorylated tau protein
  • Beta and gamma-secretase inhibitors
  • Alpha secretase stimulators
  • Bryostatin CA drug that stimulates brain
    protein production. Reduces B-amyloid levels in
    mice, enhances memory and learning.
  • New generation NSAIDS (flubiprofen) testing in
    humans looks promising
  • Immune enhancers (immunoglobulin)
  • New vaccines and new anticholinesterases

Caregiver Burden
  • Alzheimers caregivers spend an average of 69 to
    100 hours per week providing care
  • Caregivers of patients suffering from
    dementia(compared to control subjects) reported
  • 46 more physician visits
  • Over 70 more prescribed drugs
  • More likely to be hospitalized
  • More than 50 of caregivers are at risk for
    clinical depression

Staging of Dementias
  • MILD difficulties with checkbook maintenance,
    complex meal preparations, complicated medication
  • MODERATE difficulties with simple food
    preparation, household or yard work. May need
    some assistance with self-care
  • SEVERE Need considerable assistance with
    feeding, grooming and toileting
  • PROFOUND Largely oblivious to surroundings,
    totally dependent
  • TERMINAL Bed bound require constant care

Common Associated Problems
  • depression (occurs in 20-40 - esp. AD and VaD)
  • psychosis (occurs in 30- 50) - usually see
    paranoid delusions (theft, infidelity)
  • wandering/purposeless activity
  • agitation/threatening behavior
  • sleep disturbances
  • delirium - minor insults can lead to major

  • Definition - transient, usually reversible,
    dysfunction of global cerebral metabolism or
    physiology that has an acute or subacute onset
    manifested by a wide array of neuropsychiatric
    abnormalities, and often associated with
    life-threatening medical disorders
  • AKA acute organic brain syndrome, acute

Delirium (signs and sx)
  • Symptoms Impairments of alertness (arousal) and
    attention are the core deficits. Symptoms will
    wax and wane as alertness and attention decreases
    and increases. Functions that depend on
    attention and alertness including orientation,
    perception, working memory and awareness will be
    impaired leading to a host of potential secondary
    sx such as psychosis, sleep-wake cycle
    disturbances, agitation, anxiety, and
    neurological abnormalities (dysgraphia,
    constructional apraxia, tremor, etc.)
  • Signs EEG slowing, asterixis, sleep/wake cycle
    changes, S100B elevations in CSF?
  • (S100B is a 21-kDa calcium-binding protein
    produced and released primarily by astrocytes in
    the CNS, where it exerts neurotropic and
    gliotropic actions. Several studies have
    investigated the potential role of S100B as a
    peripheral biochemical marker of neural injury.

Delirium vs Dementia(summary)
  • General rules of thumb
  • Delirium Dementia
  • acute chronic
  • reversible
  • physiological structural
  • primary attention primary memory
  • deficits
  • Delirium and dementia can coexist in fact
    delirium is very common in demented patients

  • Criteria
  • A. Disturbance of consciousness with decreased
  • B. Change in cognition or development of
    perceptual disturbances
  • C. Develops rapidly and fluctuates over time
  • Code as Delirium due to...
  • 1. General Medical Condition (specify)
  • 2. Substance Intoxication/Withdrawal
  • 3. Multiple Etiologies
  • 4. NOS

Epidemiology of Delirium
  • Very Common - 10-15 med/surg inpatients (30 if
    elderly) 2/3 of patients admitted from NH have
  • 30 of Adult Burn Patients
  • 80 of delirious patients have pre-existing
  • Mortality rates for elderly hospitalized patients
    with delirium is as high as 65 in some studies
    (double the non-delirious rate)
  • As many as two thirds of deliria go undetected
  • Annual costs exceed 8 billion
  • All sudden mental status changes in dementia
    patients should be considered a delirium until
    proven otherwise

Etiology of delirium
  • many potential causes
  • often multifactorial (only 56 have a single
    probable etiology)
  • infections, metabolic derangements, anoxia, drug
    intoxications, withdrawals, CNS disease, toxins,
    fevers, etc.
  • susceptibility increased by aging, brain injury
    (esp. dementia and CV disease), polypharmacy
    (esp. anticholinergic load), malnutrition and
  • suspect UTI, dehydration and/or pneumonia in
    dementia patients with delirium

DELIRIUM - General Treatment
  • Treatment
  • Must look for medical cause(s) and treat as the
    primary intervention
  • Secondary symptoms can be helped by drugs such as
    haloperidol or risperidone (unless the cause of
    the delirium is NMS) and by reorientation
    strategies. Quetiapine has also become popular
    due to minimal dopamine blocking properties
  • Avoid anticholinergic, antihistaminic, and
    sedating drugs

Specific Treatments
  • Anticholinesterases may be useful if cholinergic
    systems are impaired (which may be the case in
    most deliria)
  • Thiamine for W-K, benzodiazepines for
    etoh/sedative withdrawal delirium
  • Benzodiazepine antagonists have been useful in
    some cases of hepatic encephalopathy
  • What about stimulants?

Behavioral Problems in AD
  • Almost universally a problem at some point
  • 60 of AD at any one time exhibiting significant
    symptoms (usually delusions and/or agitation)
  • Common problems by order of prevalence
  • agitation
  • depression
  • delusions/psychosis
  • Additional behavioral problems
  • disinhibition, apathy, personality change,
    anxiety, wandering, insomnia

Causes of Behavioral Problems
  • Biological (due to the disease process itself
  • Psychological (loss of function and autonomy,
    attempts to maintain some control, denial of
    deficits, etc.)
  • Social (family distress, economic issues, family
    conflicts over care)
  • Environmental (increased sensitivity to changes,
    issues of safety, etc.)

General Treatment Strategies
  • Define symptoms clearly
  • Rule out other psychiatric illness (e.g. MDD)
  • Rule out medical causes for the symptoms (e.g.
    intercurrent illness, medication reactions, etc.)
  • Identify non-pharmacologic strategies
  • Pharmacotherapy

Environmental Strategies
  • Identify provocations and rectify if possible
  • Appropriate re-orientation strategies task
  • Optimize sensory input i.e. correct visual and
    hearing impairments
  • Behavior management strategies that respect the
    patients need for control and autonomy
    (announcing intentions, single-step instructions
  • Optimize physical activity, social stimulation,

Management Issues
  • Alleviate patients distress
  • Reduce care-giver burden
  • Delay institutionalization
  • Assure safety
  • Patients often become more like themselves

Caregiver information and support
  • Caregivers should
  • Encourage independence for the Alzheimers
    patient without sacrificing security
  • Assist the patient, but only if necessary (i.e.
    allow the patient as much control as possible)
  • Learn to compromise
  • Develop ways to share activities
  • Establish a support network get other family
  • Educate themselves (

Depression and Alzheimers
  • Common early in the course of the illness
  • Incidence 40-50
  • Use SSRIs first avoid anticholinergic
  • ECT can be helpful but may temporarily worsen
    cognitive symptoms

Treatment of Depression
  • Recognize that irritability and/or apathy
    /withdrawal may be indicative of depression
  • Allow patient choices and control
  • Identify pleasurable activities (such as singing
    old songs, pet therapy, etc.)
  • Cognitive enhancers (e.g. Aricept) may help
  • Consider Ritalin for apathy, poor appetite

  • Non-aggressive
  • verbal complaining, constant requests for
    attention, repetition of words, constant talk,
  • physical pacing, disrobing, stereotypies, trying
    to get to a different place
  • Aggressive
  • Verbal threats, name calling, obscenities
  • Non-verbal biting, scratching, spitting,
    kicking, pushing, swinging fists

Treatment of Agitation/Violence
  • Identify and reduce provocative stimuli if
  • Optimize communication with patient
  • Environmental modifications
  • Pharmacotherapy - target underlying cause
    (neuroleptics, antidepressants, mood stabilizers,
    beta blockers, buspirone, trazodone)

Medications for Agitation
  • Buspirone Takes a while to work
  • Antidepressants (SSRIs, Trazodone)
  • Anticonvulsants (esp. valproate)
  • Atypical Antipsychotics (stroke/mortality risk
  • Low dose narcotics? Marinol?
  • Anticholinesterases and/or memantine
  • Estrogen?
  • Benzos ataxia, worsening memory and
    disinhibition are problematic.

Treatment of Psychosis
  • Recognize common delusions as relating to
    impaired STM (improving memory may help - e.g.
  • Delusions often fade with time even without tx
  • Traditional antipsychotics
  • Low potency (chlorpromazine) orthostasis,
    sedation, anticholinergic
  • High potency (haloperidol) EPS/TD but otherwise
    well tolerated
  • New generations drugs (e.g. olanzapine,
    quetiapine, risperidone)- less EPS/TD but still
    see anticholinergic, BP and sedative effects

Atypical Antipsychotics Risk of Serious Adverse
  • Retrospective review revealed a small (2-3) but
    2 fold increase in risk of stroke in demented
    patients receiving these agents compared to
  • FDA required Black Box warning due to 1.6 to
    1.7-fold increase in mortality in pooled sample
    of gt5000 persons with dementia exposed to these
    agents (in particular this was found in studies
    of olanzapine, risperidone and aripiprazole)

12Hermann N, et al. CNS Drugs 200519(2)91-103
Atypical Antipsychotics Risk of Serious Adverse
  • The risk with traditional antipsychotics may be
    even higher.13
  • Recent meta-analysis of 15 trials (some
    unpublished) by Schneider in JAMA14 confirmed a
    small increase in death with these agents
    compared with placebo. This was significant for
    the pooled data but not the individual drug data.
    The OR was 1.54

13Gill S, et al. BMJ 2005330(7489)445
14Schneider LS, et al. JAMA 2005294(15)1934-1943
Recommendations on Use of Antipsychotic Agents in
  • Have a justifiable use -gt severe, distressing
    psychotic symptoms e.g. Do not use first-line
    for non-psychotic behavioral disturbances.
  • Use lowest amounts for shortest possible times
  • Caution patients and family about risk but
    remember that older agents may be worse, and
    there is little data on other psychotropics to
    suggest that they are safe.

Treatment of Wandering
  • Lock doors (but in a way that is confusing for AD
    patient but not others)
  • Wander guards
  • Decrease agitation (see above)
  • Environmental changes (such as using visual
    patterns to redirect wandering, wander gardens)

  • Common symptom of frontal lobe damage which can
    occur in most dementias
  • Can be part of depression but usually a
    stand-alone symptom
  • Bothers family more than patient, so hard to
  • Donepezil has been shown in one study to delay
    onset of this sx
  • Stimulants may or may not help

Int J Psychiatry. 2011 26(2)
Treatment of Insomnia
  • Sleep hygiene (avoid caffeine, etc.)
  • Treat causative psychiatric or medical disorders
  • Phsysiological remedies - melatonin, warm milk,
    lavendar oil
  • Medications - Benadryl, benzos, sedating
    antidepressants or antipsychotics (all these
    drugs can make memory and confusion worse)
  • Light Therapy - to reset natural circadian
    rhythms for sleep

Sexually Disinhibited Behavior
  • Includes sexual talk, sexual acts, implied sex
    acts, false reporting
  • Treatment or sexual aggression and/or
  • Psychosocial reminders, move to private room,
    clothing modification, staff education
  • Pharmacological SSRIs, antiandrogens
    (medroxyprogesterone acetate, cyproterone
    acetate), estrogen patches

Wandering Behavior
  • 4-26 of dementia patients in Nursing Homes
  • If not located within 24 hours, 46 will die
    (usually of hypothermia or dehydration)
  • TX Vigilance, wander guards, complicated exits,
    reduce agitation
  • Safe Return nationwide identification program
    alert system for law enforcement officials, TV
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