Age related cognitive decline

1
Age related cognitive decline

• Mild changes in memory and rates of information
  processing.
• New learning ability declines with normal age,
  cued recall remains stable.
• Changes are not progressive, should not affect
  ADLs.
• Thought to be secondary to frontal lobe
  dysfunction (executive function).
• All patients with memory complaint need a careful
  evaluation, we cant assume it is old age.

2
Mild Cognitive Impairment

• Phase between normal aging and dementia.
• Cognitive impairment is documented but not severe
  enough to interfere with ADLs.
• May represent a pre-demented state.
• Increased risk for progressing to AD (12 per
  year vs 1-2 for matched controls).
• Studies under way to determine if current (AD)
  treatments can slow this rate of progression.
• Guidelines from AAN recommend monitoring this
  patients closely.

3
Dementia

• Progressive decline in multiple cognitive and
  behavioral domains
• memory
• language and speech
• visuospatial ability
• abstract thinking
• judgment
• mood and personality.
• Changes are severe enough to interfere with
  social and occupational functioning (ADLs).
• Changes do not occur exclusively during delirium.

4
Dementia Differential Diagnosis

• Cortico-degenerative
• Alzheimers disease
• Frontotemporal dementia
• Vascular
• Multiple large vessel infarcts
• Single strategic infarct
• Lacunar state
• Binswangers disease
• CADASIL
• Parkinsonism-related demetias
• Parkinsons disease
• Dementia with Lewy Bodies
• Progressive supranuclear palsy
• Multiple systems atrophy
• Dementias associated with infection
• Prion diseases
• Neurosyphilis
• AIDS dementia
• Chronic meningitis(TB, fungal)

• Toxic-Metabolic conditions
• Medication-induced dementia
• Alcohol related dementia
• Heavy metal exposure
• Vitamin B12, folate deficiency
• Cushings, Addisons disease
• Hypo-hyperthyroidism
• Liver, renal failure
• Paraneoplastic (Limbic encephalitis)
• Autoimmune/Inflamatory
• Bechets disease
• Multiple sclerosis
• SLE, Sarcoid
• Temporal arteritis/other CNS vasculitis
• Trauma-related dementias
• Closed-head injury
• Chronic SDH
• Dementia pugilistica
• Miscellaneous

5
Alzheimers Disease
Dementia Differential Diagnosis

• Onset is insidious and progression slow (average
  decline 8-10 yrs).
• Features include
• Language disturbances (early) anomia/fluent
  aphasia/paraphasias/impaired comprehension
• Recent memory/learning impairment
• Apraxia/constructional ability
• Agnosia
• Alexia
• Behavioral disturbances (may precede cognitive
  impairment)
• Delusions/hallucinations in 50
• Lack of insight

6
Vascular Dementia
Dementia Differential Diagnosis

• Vascular lesions contribute to development of
  dementia.
• Second most common cause of dementia after AD
  (10-20).
• Diagnosis suggested if
• Onset of cognitive deficits associated with
  stroke
• Abrupt onset of symptoms with stepwise
  deterioration
• Neurologic exam c/w prior stroke
• Infarcts on cerebral imaging
• Presentation varies depending on location of
  infarcts.

7
Vascular Dementia and AD
Dementia Differential Diagnosis

• Vascular pathology exists in 29-40 of dementia
  patients coming to autopsy.
• Adjuvant role of vascular lesions in AD.
• CVD determines presence and severity of AD
  symptoms
• Study of 61 patients with pathologic AD criteria
• Those with brain infarcts had poorer cognitive
  function and higher incidence of dementia
• A relative small number of AD lesions resulted in
  dementia in those with lacunar infarcts.
• Diagnosis of AD plus CVD determined by imaging
  and clinical course.

8
Frontotemporal dementias
Dementia Differential Diagnosis

• Heterogeneous group of disorders 2ry to
  degeneration of frontal lobes.
• Includes Picks disease.
• Prominent behavioral changes (early)
• Disinhibition, impulsiveness, apathy, social
  inappropriateness.
• Language disturbances
• Reduction of speech, echolalia, perseveration
• Deficits in social comportment, behavior,
  language are out of proportion to memory deficit.
• Neuroimaging visualizes frontal lobe atrophy.
• SPECT fronto-temporal lobe hypoperfusion
  (earliest sign).

9
Parkinsonism related dementias
Dementia Differential Diagnosis

• Parkinsons disease dementia
• Complicates PK in 40, cognitive decline 1 year
  after movement disorder.
• Impaired recall, executive function.
• Language intact.
• Dementia with Lewy bodies
• Fluctuating cognitive performance
• Prominent visual hallucinations
• Cognitive impairment and parkinsonism emerge
  simultaneously
• Severe adverse reaction to neuroleptics used for
  behavioral problems.
• Progressive supranuclear palsy
• Multisystem atrophy
• Vascular parkinsonism
• Cortico-basal ganglionic degeneration

10
Reversible dementias
Dementia Differential Diagnosis

• Depression
• Medication induced (analgesics, anticholinergics,
  psychotropics, sedatives).
• Alcohol related (intoxication, withdrawal)
• Metabolic disorders
• Thyroid disease
• B12 deficiency
• HypoNa, hyperCa
• Liver and renal dysfunction
• Infectious
• AIDS, syphilis, chronic meningitis.
• C-J disease Rare, rapidly progressive,
  incurable, dementia.
• Cognitive impairment, motor deficits, seizures
• SDH, CNS neoplasms
• NPH triad of gait disturbance, incontinence and
  cognitive dysfunction

11
Depression
Reversible dementias

• Common cause of reversible dementia in elderly.
• Complex relationship between depression and
  cognitive impairment
• Elderly depressed patients are a higher risk of
  developing dementia.
• Demented patients can show apathy, sleep problems
  resembling depression.
• depressive pseudodementia
• Both have very poor insight on mood and
  cognition.
• No reliable tool to measure relative contribution
  of each.
• Screen for depression and treat if present.
• Follow patients and assess for improvement.

12
Delirium
Reversible dementias

• Acute confusional state associated with systemic
  illnesses, infections, toxic and metabolic
  disturbances.
• Characterized by
• Disturbance of consciousness
• Change in cognition
• Rapid onset and fluctuation of symptoms
• Patients with dementia are at increased risk for
  delirium.
• Delirium and dementia may coexist.

13
Dementia Diagnostic approach

• Not all patients with complaints of memory loss
  have dementia.
• Step 1 determine if true cognitive impairment is
  present.
• Step 2 think of other conditions that can lead
  to memory or cognitive impairment.
• Step 3 determine the nature of the dementing
  disorder.

14
Step 1 Is there cognitive impairment?

• A full dementia evaluation cant be completed in
  40 min.
• The initial visit should focus on
• History
• Physical Exam
• Medications
• Labs if indicated
• At follow-up visit arrange time for
• Mental status examination/assessment of cognitive
  function
• Full neurologic exam
• Review labs
• Imaging studies if indicated.

15
Step 1 Is there cognitive impairment?

• I. History
• History should be obtained from patient and
  family.
• Self reported memory loss doesnt appear to
  correlate well with future development of
  dementia.
• Informant-reported memory loss is a much better
  predictor of the current presence or future
  development of dementia.
• Focus history on
• Cognitive impairment
• Behavioral disturbances
• Functional impairment

16
Step 1 Is there cognitive impairment?

• Cognitive impairment
• time, character, pattern of progression.
• Life events temporally related to onset.
• Ability to learn and recall new information.
• Informant Questionnaire on Cognitive Decline in
  the Elderly.
• Behavioral disturbances
• Often the cause to seek medical attention.
• Memory impairment is not always the presenting
  feature.
• Delusions, hallucinations, changes in mood.
• Changes in personality (disinhibition,
  impulsivity, anger, agitation, anxiety).
• Functional impairment
• Assess the impact on patients social and basic
  functioning.
• Some knowledge of patients previous activities
  is necessary.
• Standarized instruments can be used (Instrumental
  ADL Scale).

17
Step 1 Is there cognitive impairment?

• II. Medications
• III. Family and Social Hx
• IV. Physical Examination
• Neurologic exam
• Focal neurologic deficits
• Signs of parkinsonism cogwheel rigidity, tremor
• Gait
• Eye movement

18
Step 1 Is there cognitive impairment?

• V. Mental Status Examination
• Level of consciousness, orientation, attention,
  speech and language, recent end remote memory,
  cognition, visuospatial skills, mood/personality.
• Standarized instruments (MMSE, ADAS, clock
  drawing, etc).
• Variable sensitivity/specificity depending on
  population.
• Affected by education and culture.
• Useful in dementia diagnosis when used along
  history and exam.
• Scores are useful to measuring change over time.

19
Mini Mental Status Examination

• Most commonly used cognitive screening instrument
  in US clinical practice.
• Maximal score is 30 points.
• Score lt24 suggests dementia (sens 87/spec 82).
• Age-specific norms that incorporate gender and
  level of education have been established.
• Not sensitive for diagnosis of mild dementia.

20
Step 1 Is there cognitive impairment?
21
Step 1 Is there cognitive impairment?

• VI. Neuropsychologic testing
• Helpful in age-related vs MCI vs dementia.
• Useful for those gray area patients
• MMSE scores 20-25.
• Functional impairment out of proportion to MMSE
  scores.
• Poor MMSE scores with little functional
  impairment.
• R/o pseudodementia
• Assists in narrowing differential diagnosis of
  dementia syndrome.

22
Step 2Problems presenting as memory loss

• Normal aging
• MCI
• Depression
• Delirium
• Stroke Syndromes
• Bradykinesia
• Abulia
• Seizures
• Excessive daytime somnolence
• Amnestic syndrome

23
Step 3 What is the nature of the dementing
disorder?

• Alzheimers disease 60-80
• Vascular multi-infarct dementia 10-20
• Parkinsons disease and related dementias 5
• Frontotemporal degeneration
• Potentially reversible causes
• Medication induced
• Alcohol related
• Metabolic disorders
• Depression
• NPH
• Remember Dementia frequently has multiple causes.

24
Step 3 What is the nature of the dementing
disorder?

• Laboratory testing
• CBC
• Electrolytes
• B12, folate
• TSH
• BUN/Cr
• LFTs
• RPR not indicated unless clinical suspicion.
• HIV, ESR, toxins, heavy metals, drugs if
  indicated.

25
Step 3 What is the nature of the dementing
disorder?

• Laboratory testing
• LP lt55yo, rapid progression, immunosuppr.,
  unusual dementia
• High CSF protein 14-3-3 96sens/99spec for C-J
  disease.
• High CSF tau and low ßAmyloid1-42 proteins.
• EEG distinguishes dementia from other diseases..
• Genetic testing for ApoE4 useful in patients
  with gt3 first-degree relatives w/demetia.

26
Step 3 What is the nature of the dementing
disorder?

• Neuroimaging
• Obtain CT or MRI in all patients.
• Important to r/o structural lesions SDH, tumor,
  NPH.
• Essential for diagnosis of VaD.
• MRI
• more sensitive for small CVD lesions as well as
  early AD changes.
• Important in documenting clinically silent
  lacunar infarcts, IWMC, cortical infarcts and
  atrophy.
• Structural MRI future use in early AD diagnosis.
• SPECT, PET scan not recommended in routine
  evaluation.

27
Dementia Treatment

• Rapidly evolving field.
• Better and new understanding of dementing
  illnesses.
• Management is changing from symptomatic to
  biologically specific.
• New disease-specific, disease-modifying
  treatments are close to being used.
• Accurate diagnosis of type of dementia is
  essential.
• Treating patient with dementia should also
  include
• Addressing safety issues
• Addressing caregiver needs and concerns
• Screening and treating for depression
• Management of other medical problems

28
Dementia Treatment

• Safety Issues
• Driving
• Cooking
• Wandering
• Aggressive Behavior
• Falls
• Falls are a problem in all dementias
• Study 1608 pts gt75yo showed twice risk of hip fx
  if MMSE score was 18-23 compared to pts with
  normal scores.
• Always evaluates pt that fall B12, myelopathy
  (C-spine spondylosis), neuropathy, visual
  impairment.

29
Dementia Pharmacologic treatment

• Symptomatic treatment of memory impairment
• Cholinesterase inhibitors
• NMDA receptor antagonists
• Symptomatic treatment of behavioral disturbances
• Delusions and halluciantions
• Depression
• Aggression and anxiety
• Disease modifying treatments
• Vitamin E and selegiline
• Estrogen replacement
• NSAIDS
• Ginkgo biloba
• Secretase inhibitors
• Immunotherapy

30
Pharmacologic treatment of dementiaCholinesteras
e inhibitors

• Patients with AD have impaired cortical
  cholinergic function.
• Cholinesterase inhibitors can improve cognitive
  function in patients with AD.
• Average benefit is small, significant in long
  term outcomes (NHP).
• Meta-analysis 29 RCT improvement of 0.1 SDs on
  ADLs, 0.09 SDs on IADLs
• Four FDA approved drugs
• Tacrine
• Donepezil
• Rivastigmine
• Galantamine

31
Cholinesterase inhibitors

• Donepezil (Aricept)
• Little peripheral activity, well tolerated.
• Once daily dosing, start 5mg qd for 4 weeks, then
  increase to 10mg qd.
• 24-week double blind study of patients with
  mild-mod AD
• 5-10mg vs placebo showed significant improvement
  (ADAS-cog)
• No consistent effect on QL measures, no effect on
  underlying disease course.
• 20 SE (nausea, diarrhea, vomiting).
• Prolonged treatment safe.
• May be useful for patients with PD and dementia.

32
Cholinesterase inhibitors

• Rivastigmine (Exelon)
• Beneficial in patients with mild-moderate AD.
• Efficacy comparable to donezepil, more GI side
  effects.
• Start 1.5mg BID and titrate every two weeks to
  6mg BID with meals.
• Galantamine (Reminyl)
• Efficacy comparable to donezepil in mild-moderate
  AD.
• 2 RCT showed 24-32mg/day slowed decline in
  cognition and ADLs.
• Similar, modest benefits in patients with VaD or
  AD plus CVD.

33
Pharmacologic treatment of dementiaNMDA
receptor antagonists

• Glutamate principal excitatory neurotransmitter
  in cortical and hipoccampal neurons.
• NMDA (N-methyl-D-aspartate) receptors are
  involved in memory and learning.
• Ischemia induces excessive NMDA stimulation
  glutamate-induce excitotoxicity.
• NMDA receptor antagonists (memantine) may protect
  from further damage in patients with VaD.
• Remaining neurons could be protected.
• Promising role for patients with VaD and silent
  brain infarcts.

34
Pharmacologic treatment of dementiaBehavioral
symptoms

• Behavioral symptoms occur in 85 of severe
  dementia.
• Agitation, hallucinations, delusion, aggression,
  depression
• Respond well to medications.
• Should be aggressively treated since often lead
  to NHP.
• Other behaviors respond better to behavioral
  therapy
• Wandering, repetitive questioning, withdrawal,
  hiding objects, etc.
• Cholinesterase inhibitors modestly improve
  neuropsychiatric symptoms.
• Reasonable to try them before moving to other
  agents.

35
Pharmacologic treatment of dementiaBehavioral
symptoms

• Delusions and halluciantions
• Delusions present in 30 pts with severe AD.
• Early visual hallucinations think about Lewy
  body dementia.
• In AD atypical neuroleptics are drugs of choice
• Olanzapine
• Quetiapine
• Clozapine
• Risperidone
• SSRI may benefit behavior, not as well studied.

36
Pharmacologic treatment of dementiaBehavioral
symptoms

• Depression
• Complex relationship between depression and
  cognitive impairment.
• No reliable tool to measure relative contribution
  of depression/dementia.
• Therapeutic antidepressant trial
• SSRIs (citalopram)
• TCAs

37
Pharmacologic treatment of dementiaBehavioral
symptoms

• Aggression and anxiety
• Provoked by confusion, delusions, sleep
  disturbances, depression.
• Improve sleep
• Behavioral modifications
• Trazodone Reduces anxiety/aggression
  particularly at night
• Can be combined with SSRI for depression
• Antiepileptic drugs
• Carbamazepine
• Valproate
• Gabapentin
• Lamotrigine
• Benzodiazepines should be limited only to brief
  stressful episodes.