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DEMENTIA amnesia

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					     DEMENTIA.

NEUROLOGY SUBSPECIALITY
       SEMINAR.
      Sept 20, 2006.
              DEMENTIA.
Defn:- an acquired deterioration in cognitive
       abilities;
     - impairs the successful performance
       of activities of daily living.
     - affects > 4million Americans.
* Cognitive abilities lost in dementia:
  Memory (most common), language, visuo-
  spatial ability, calculation, judgement.
…ctnd
• Neuropsychiatric & social deficits.
   - depression; - delusion; - agitation;
   - hallucination; - withdrawal; - insomnia;
   - disinhibition.
 * Dementia:- commonly progressive;
               - sometimes static or fluctuates
                 dramatically from day to day.
…ctnd
MEMORY.
 Three major storage buffers -
 1) WORKING ~ :- lasts <30sec; limited
    storage capacity; 7+2 bits of info in ~ .
     - ↑ ly vulnerable to distraction. TEST?
 → RAS, prefrontal & parietal lobe
     networks.
…ctnd
2) EPISODIC ~ :- min – mths; or even yrs.
            - ‘what’, ‘where’, & ‘when’.
            - multiple ~/ day → informn
              consolidated. TEST?
        → Hippocampal Cpx: vulnerable
                       to metabolic insults.
  New ~ → physiologic changes in synapses
  → Neocortex.
…ctnd
3) REMOTE/LONG-TERM/ ~: wks – lifetime.
   - most of personal experiences and
     knowledge.
→ Lt anterior temporal cortex; ? Neocortex.
   - new protein synthesis required for ~.
   - stabilization process: physical changes
      at neuronal synapses .
…ctnd
Components of memory Fn.

- Registration: frontal lobes, hippocampal
                 complex.
- Retention.
- Stabilization.
- Retrieval: frontal lobes.
…ctnd
* Semantic memory: anterior temporal
                     neocortex.
* Declarative memory: episodic memory
                     prototypical example.
* Procedural memory: Amygdala, basal
  ganglia, cerebellum, sensory cortex.
* Executive Fn: planning, initiating, &
   regulating behaviour; frontal lobes.
…ctnd
FUNCTIONAL ANATOMY.
Dementia:- the result of quantity & location
             of neuronal loss.
Episodic memory: dorsomedial nucleus of
  the thalamus + medial temporal lobes.
 - Unilateral lesion: mild-moderate amnesia.
 - Bilateral lesion: severe anterograde
                     learning disorder.
…ctnd
The medial temporal lobe memory system.
- components: the hippocampus & adjacent
                 cortex; fast, limited capacity.
- Crucial fn: learning & establishing
  declarative memory & semantic assocn.
- Learning →reorganization & consolidation
 → memory stored in neocortex.
…ctnd
• Cholinergic system: important role in
  memory → choline acetyltransferase,
  cholinergic receptors, Nucleus basalis of
  Meynert = deficient in AD.
• Behavior & mood: NA, serotonergic, and
  dopaminergic pathways.
• LTP: involved in memory acquisition &
  storage; occurs in the hippocampus.
…ctnd
CAUSES OF DEMENTIA.
- Age group, country, access to medical
  care, racial/ethnic background.
- Reversible / Irreversible.
- The single strongest risk factor: AGE.
 Benign forgetfulness of the elderly.
 Mild cognitive impairment (MCI).
    MCI → AD (12% / yr).
APPROACH TO THE PATIENT.
• 3 MAJOR ISSUES:
  - most accurate Dx.
  - treatable or reversible component?
  - alleviation of burden on caregivers.

Hx:- Onset, duration, tempo of progression.
   - Specific clinical patterns of disease.
   - Systemic diseases; drugs/toxins;
   - Occupation; deficiencies;psychiatric dis.
…ctnd
 P/E.
- Document dementia.
- Systemic diseases.
- Specific clinical findings of the dementias.
- Detailed neurologic exam.
COGNITIVE & NEUROPSYCHIATRIC exam
- MMSE: confirm Dx, follow-up, Px.
- Functional assessment.
…ctnd
LAB TESTS.
- AAN: Routine- TFT, vit B12 level, CT/MRI.
ALZHEIMER’S DISEASE (AD).
 EPIDEMIOLOGY.
• Most common cause of dementia in
  western countries.
• Most important risk factors: old age &
   + family Hx; other: female gender.
• >70yrs : 10% significant memory loss
  (>50% due to AD);>85yrs: 20-40% of popl.
• Env’tal factors: No significant role.
…ctnd
PATHOLOGY.
- Hippocampus, temporal cortex, nucleus
  basalis of Meynert: severe pathology.
- Microscopy: Neuritic plaques, NFTs.
- Neuritic plaqes:Aβ amyloid, proteoglycans,
  Apo є4, α1antichymotripsin.
 Aβ amyloid in cerebral arterioles: amyloid
  angiopathy→ cerebral lobar hemorrhages.
..ctnd
-NFTs:silver staining, twisted neurofilaments
   in neuronal cytoplasm.
- ↓ Ach, choline acetyltransferase, &
   nicotinic cholinergic receptors in cortex.
- ↓ NE levels in locus coeruleus (brain
   stem).
GENETICS.
1) APP gene, chrom 21.
2) Presenilin-1 (PS-1) on chrom 14; S182.
…ctnd
3) Presenilin-2 (PS-2): chrom 1; STM2.
 * Both 2) & 3)→ ↑ plasma Aβ42 amyloid.
4) Apo є gene: chrom 19 – late onset familial
  & sporadic AD.
   * three alleles: 2, 3, 4; Apo є 4 allele has
  strong association with AD.
• Apo є testing: in demented patients who
  meet clinical criteria of AD.
…ctnd
CM.
• cognitive ∆es begin with memory
  impairment → language & visuospatial
  deficits.

• 20% of pts: Nonmemory complaints such
  as → word-finding, organizational, or
  navigational difficulty.
…ctnd
EARLY STAGES.
- Subtle memory loss; benign forgetfulness.
- MCI: memory loss < 1.5 SD from normal.
- Progressive interference with daily
  activities.
- Patients : Anosognosia OR considerable
  insight.
- ∆ of env’t may be bewildering.
…ctnd
MIDDLE STAGES.
- Unable to work, easily lost, confused.
- Requires daily supervision.
- Social conduct, routine behaviours: OK.
- Naming → Comprhension → Fluency.
- Apraxia.
- Visuospatial deficits.
…ctnd
LATE STAGES.
- Some pts: ambulation W/o purpose.
- Judgement, reason, cognition are lost.
- Delusions: common; Capgras synd(10%).
- Disinhibition, aggression ↔ passivity.
- Disturbed sleep-wake patterns.
- Some pts: parkinsonian features; but
  rarely have tremor.
…ctnd
END-STAGE.
- Rigid, mute, incontinent, & bedridden.
- The simplest tasks need aid.
- ↑ DTR; myoclonic jerks ( spont.,induced)
- Generalized Szs may occur.
- DEATH: 20 to malnutrition, secondary
  infections, pulmonary emboli,or Ht disease
*Typical duration of AD: 8 – 10yrs[ 1-25yrs].
…ctnd
DIAGNOSIS.
- EARLY:- R/O other etiologies of dementia.
           - CT/MRI may be normal.
- As AD PROGRESSES.
     * CT/MR: diffuse cortical & hippocampal
  atrophy; 20 enlargement of ventricles.
     * Fnal imaging studies.
     * EEG, routine CSF exam: Normal.
     * Blood Apo є genotyping.
…ctnd
Rx.
- No cure; No highly effective drug.
• Mx focuses on:
  - judicious cholinesterase inhibitor use,
  - Smc Mx of behavioural disorders,
  - building rapport with the pt, family
    members, & other caregivers.
…ctnd
• FDA approved cholinesterase inhibitors:
  - Tacrine ( expensive, hepatotoxicity.)
  - Donepezil (Not hepatotoxc, 5-10mg qd.)
  - Rivastigmine.
  - Galantamine.
  ═> * improve caregiver ratings,
     * ↓ rate of cognitve test score decline
        over a period of upto 3 yrs.
…ctnd
• ERT : controversial results on protection.
• Antioxidants:- in moderately advanced AD.
      * selegline.
      * Vit E 1000U BID (inexpensive, ↓SE).
 ═> both slowed institutionalization &
    progression to death.
• (one study): Memantine [ an NMDA
  receptor antagonist]- slowing of disease
  progression over a 28 wk course.
…ctnd
• Vaccination Vs Aβ protein: not safe in
  human trials.
• SSRIs: for mild-moderate depression.
• Mx of behavioural disturbances.
     VASCULAR DEMENTIA.
• Two general categories:
  1)Multi-infarct dementia.
    - multiple strokes → chronic cognitive
                           deficits.
    - Strokes: large or small; several d/t
                regions of the brain.
    - Occurrence of dementia → total
             volume of damaged cortex.
…ctnd
 * Hx:- discrete episodes of sudden,
       stepwise neurologic deterioration.
       - HTN, DM, CAD.
* P/E:- focal neurologic deficits.
* Neuroimaging: multiple areas of infarction.
• Normal aging:cerebral amyloid angiopathy
   of aging→ Hemorrhagic lobar stroke.
• AD + amyloid angiopathy:↑ cerebral
   infarction.
…ctnd
2) Diffuse white matter disease.
   / Binswanger’s Disease/.
   - insidious onset dementia, progresses
      slowly.
   - early Sms: mild confusion, apathy,
  depression, psychosis, personality ∆es,
  memory or executive fns.
   - Later: Judgement difficulties,
            dependence on others.
…ctnd
 - euphoria, elation, depression, or
   aggressive behaviour.
  - Both pyramidal & cerebellar Sns may be
 present in the same pt; gait disorder:50%.
   - Advanced disease:urinary incontinence,
     with or w/o pseudobulbar palsy.
      Minority of pts: Szs & myoclonic jerks.
   * Pts usually have a Hx of HTN.
…ctnd
 CADASIL.
- AD; diffuse white matter disease.
- Progressive dementia; 5th-7th decade,
- Multiple family members; Hx of migraine
  with or w/o HTN.
- Skin Bx: Xc dense bodies( media of aa.)
- Mutations in the notch 3 gene.
- No known Rx.
…ctnd
Rx of Vascular Dementia.

- Rx of HTN, DM, atherosclerosis.
• Recovery of lost cognitive Fn not likely.
- Anticholinesterase Cpds appear to be
  useful.
FRONTOTEMPORAL DEMENTIAS
   & RELATED DISORDERS.
 FRONTOTEMPORAL DEMENTIA.
- Often b/n 50 & 70 yrs; prevalence ~ AD.
- M=F; Sporadic or familial.
- Behavioral Sms often predominate in the
  early stages, unlike AD.
- Clinically heterogenous: disinhibition,
  dementa, apraxia, parkinsonism, motor
  neuron disease.
…ctnd
•   Many families: AD pattern;
•   Mutations: tau gene, chrom 17.
•   Other families: chrom 3 & 9 linked to FTD.
•   Early Sms: cognitive, behavioral, & sties
    motor abnormalities→ degeneration of
    anterior frontal & temporal regions, basal
    ganglia & motor neurons.
…ctnd
* Cognitive presentations:
  - spare memory,
  - involve planning, judgement, or language.
  - insight severely impaired.
* Behavioural deficits:
   - apathy, disinhibition, weight gain,
   - food fetishes, compulsions, euphoria.
…ctnd
* Asymmetric Lt frontal cases: Nonfluent
  aphasias → → Mutism.
* Lt anterior temporal degeneration:
   Semantic dementia → visual agnosia.
   ═> primary progressive aphasia.
* Rt frontal or temporal cases: loss of
  empathy, disinhibition, antisocial behavior.
…ctnd
• Memory & visuospatial skills are relatively
  spared in most FTD pts.
- Anatomic hallmark of FTD: marked
  atrophy of temporal &/or frontal lobes.
- Microscopy: gliosis & neuronal loss;
  swollen neurons with tau staining
  cytoplasmic inclusions.
- Depletion of seratonergic & glutamatergic
  neurons; cholinergic system relatively OK.
…ctnd
Pick’s disease:-same anatomic involvement
  as FTD, but Pick’s bodies stain for both
  silver & tau.
Rx of FTD.
- Smc; No Rx to slow progression or
  improve cognitive Fn.
- Serotonin-modifying antidepressants
   → behavioral changes in FTD.
…ctnd
PROGRESSIVE SUPRANUCLEAR PALSY.
- A sporadic neurodegenerative disease.
- 6th-7th decades; unknown etiology.
- Progresses faster than PD:Death in 5-10yr
- Falls & a vertical supranuclear gaze palsy
  → symmetric rigidity & dementia.
- Xc: a stiff, unstable posture with hyper-
  extension of the neck & slow gait; freq’t
  falls.
…ctnd
- Freq’t falls due to axial rigidity, inability to
  look down, & bad judgement.
- Tremor is distinctly uncommon.
- Dementia often precede the motor synd. &
  usually present at the time of presentation.
- PSP often confused with PD[ 20% of pts:
  dementia, often 20 to DLB.]
…ctnd
- * Dementia in PD:
   - ↑ ing age; - a long disease duration;
   - ↑ ing severity of extrapyramidal Sns;
   - presence of depression.
- MRI: midbrain atrophy.
- PET: symmetric frontal & striatal
       hypometabolism.
Rx: response generally not highly
 effective for antiparkinsonian
 medications.
…ctnd
CORTICAL BASAL DEGENERATON.
- A slowly progressive sporadic dementing
  illness; 6th-7th decades.
- Unilateral onset: rigidity, dystonia, apraxia,
  bradykinesia of one arm =>’’Alien hand.’’
- Eventually:- condition becomes bilateral;
               - includes dysarthria, slow gait,
                 action tremor, & dementia.
…ctnd
MRI: focal cortical loss in the contralateral
       superior frontal & parietal lobes.

 Rx: largely ineffective.
DEMENTIA WITH LEWY BODIES.
• Xed by: visual hallucinations, falls,
  parkinsonism,& fluctuating alertness.
• Dementia can precede or follow the
  appearance of parkinsonism.
• Pts are ↑ly susceptible for metabolic
  perturbations: delirium ppted by an infect-
  ion/systemic condition OR by L-dopa.
• Spontaneous fluctuations: episodic
  confusion ↔ lucid intervals.
…ctnd
• DLB pts: relatively better memory, but
  more severe visuospatial deficits, than AD
  patients; Capgras syndrome.
• Key neuropathologic feature → Lewy
  bodies throughout the cortex, amygdala,
  cingulate cortex, & substantia nigra.
• Profound cholinergic defect → fluctuations
  & visual hallucinations.
…ctnd
Rx of DLB.
- Anticholinergic Cpds.
- Exercise programs.
- Antidepressants.
- Atypical antipsychotics in low doses.
- Dopaminergic medications: pts extremely
  sensitive → titrate carefully.
OTHER CAUSES OF DEMENTIA.
HUNTINGTON’S DISEASE.
- An AD, degenerative brain disorder.
- CAG repeat; huntingtin; chrom 4.
- Hallmarks: chorea, behavioural disorders,
  frontal/executive disorder.
- Memory OK; attention, awareness, judge-
  ment: seriously deficient at early stages.
- Disinhibition, depression, OCD: common.
- No specific Rx; partial response to
  haloperidol, phenothiazines, &
  benzodiazepines.
…ctnd
NORMAL-PRESSURE HYDROCEPHALUS.
- Relatively uncommon syndrome.
- Abnormal gait, dementia, urinary
  incontinence.
- Neuroimaging: communicating hydroceph-
  alus; patent acquiduct of Sylvius.
- LP: opening pressure in the ↑ normal
  range & normal CSF analysis.
…ctnd
• NPH: obstruction to normal flow of CSF
  over the cerebral convexity & delayed
  absorption into the venous system.
• Enlarged lateral ventricles with little ↑ in
  CSF pressure.
• Some pts: previous meningitis, SAH, head
  trauma.
• Early & prominent gait disturbance & no
  cortical/hippocampal atrophy [unlike AD].
…ctnd
 Rx of NPH.
- Ventricular shunting procedure.
  → gait may improve more than memory.

 * Cxns of procedure:- subdural hematoma.
                     - infection.
…ctnd
PRION DISEASES ( CJD).
- Rapidly progressive disorders.
- Dementia, focal cortical Sns, rigidity,
  an akinetic state, and myoclonus.
- EEG: repetitive bursts of diffuse sharp
         waves.
- Diffusion/flare MRI: cortical ribboning and
  basal ganglia hyperintensities.
…ctnd
THIAMINE ( VIT B1) DEFICIENCY.
* Wernicke’s encephalopathy.
 → malnurished (frequently) alcoholic pt with
  confusion, ataxia,& opthalmoplegia.
- Damage to dorsomedial thalamic regions
  correlates closely to memory loss.
Rx:- medical emergency.
    - Thiamine 100mg IV/IM/d for 7d; then
       10mg po/d until complete recovery.
…ctnd
* Korsakoff’s syndrome.
  - due to prolonged unRxed B1 deficiency.
  - irreversible dementia/amnestic synd.
  - impairment in recent memory & learning.
  - pt easily confused, disoriented.
  - confabulation is common.
  - MRI: mammilary body atrophy.
  - No specific Rx; irreversible damage.
…ctnd
VITAMIN B12 DEFICIENCY.
- Macrocytic anemia.
- Myelopathy (most common), peripheral
  neuropathy, damage to cerebral
  myelinated fibers → Dementia.
- Rx: cobalamin 1000μg / wk for 8 wks ,
      ff by 1000 μg / mth .
…ctnd
       NICOTINIC ACID DEFICIENCY
                  (PELLAGRA).
- sun-exposed skin rash, glossitis, and
  angular stomatitis.
- Spastic paraparesis,peripheral neuropathy
- Fatigue, irritability, and dementia.
 Rx:- Nicotinamide or nicotinic acid
       100-200 mg PO TID for 5 days.
…ctnd
CHRONIC INFECTIONS OF THE CNS.
- Dementia particularly associated with
  chronic meningitis.
- Headache, meningismus, cranial
  neuropathy, &/or radiculopathy.
- 20-30% of advanced stages of RVI pts
  become demented( 20 OI or HIV itself):
  psychomotor retardation, apathy, impaired
  memory.
…ctnd
PRIMARY & METASTATIC CNS TUMORS.
- If tumor growth begins in the frontal or
  temporal lobes → memory loss or
  behavioural changes.
- Focal neurologic Sns; seizures.
• LIMBIC ENCEPHALITIS: a paraneoplastic
  syndrome; associated with occult Ca.
 → confusion, agitation, Szs, poor memory,
  mov’t disorder, dementia, sensory neurop.
…ctnd
NONCONVULSIVE SEIZURE DISORDER.
- confusion, clouding of consciousness,
  garbled speech.
- If persistent → complex partial status
                     epilepticus.
- Etiology: small stroke, trauma, idiopathic.
- EEG: Sz discharges.
- Rx: anticonvulsants.
…ctnd
SYSTEMIC DISEASES.
*can produce chronic confusion & dementia.
 hypothyroidism,
 vasculitis,
 hepatic failure,
 renal failure,
 pulmonary disease.
…ctnd
CHRONIC METAL EXPOSURE.
- Dementing syndromes may follow chronic
  exposures to lead, mercury, arsenic, or
  aluminium (dialysis dementia syndrome).
- Key to Dx: Hx of exposure at home, work,
  or as a consequence of dialysis.
Rx:- avoid re-exposure.
    - chelation: EDTA(lead); BAL(arsenic).
    - deionized water for dialysis.
…ctnd
RECURRENT HEAD TRAUMA.
* Professional boxers: ‘’punch drunk’’ synd
   or dementia pugilistica.
   - personality ∆(early) → memory loss,
   dementia, parkinsonian Sns, ataxia (late).
* Chronic subdural hematoma.
  - occasionally associated with dementia.
   Mx: evacuation of hematoma.
…ctnd
TRANSIENT GLOBAL AMNESIA.
- Xed by the sudden onset of a severe episodic
  memory deficit; usually >50yrs.
- Confused pt; repeatedly ask about present
  events; No other neurologic Sms/Sns.
- Recovery after a period of Hrs.
- Recurrent in 25% of pts.
- ?etiology: CVD, migraine, epilepsy, cardiac
             arrhythmias.
…ctnd
PSYCHOGENIC AMNESIA.
- Event-specific amnesia for personally
  important memories: occurs after violent
  crimes, sexual abuse, alcohol intoxication.
- Fugue states:more prolonged psychogenic
  amnesia; Amnesia for personal identity &
  events closely related to the personal past.
     * Recent memory & learning ability: OK.
    → lasts hrs-days [sties wks-mths].
…ctnd
PSYCHIATRIC DISEASES.
* Depression (pseudodementia): memory &
   language intact; psychosocial milieu.
* Schizophrenia: earlier age of onset, intact
   memory; delusions more cpx & bizarre.
* Conversion reaction.
  - cognitive test not yielding despite bitter
   complaints by pts of memory loss.
…ctnd
CHRONIC DRUG OR MEDICATION USE.
- Drugs prescribed by physicians →
   important causes of dementia.
  * sedatives, tranquilizers, analgesics.
  → confusion, lethargy, & memory loss.
  Mx: discontinuation of the offending
      medication often improves mentation.
GENERAL SYMPTOMATIC Rx OF
  THE DEMENTED PATIENT.
GOALS:- Rx of correctable causes,
      - provide comfort & support.

• Remove sedating/cognition-impairing
  drugs or medications.
• Rx of depression- SSRIs preferred.
• Rx of Szs.
…ctnd
• Behavioral problems: difficult to Rx.
  1st :search for potentially modifiable env’tal
  or metabolic factors before drug Rx.
     - hunger; - UTI; - toothache;
     - constipation; - lack of exercise;
     - lack of exercise.
   If difficult to Mx: Nursing home placement
  & institutionalization.
…ctnd
* Agitation & insomnia:Haloperidol 0.5-2mg,
   trazodone, buspirone, or propranolol.
* Difficult behaviors: New atypical antipsych-
   otics including risperidone, olanzapine,
   and quetiapine.
* Nondrug behavioral intervention.
  10 GOAL: make the demented pt’s life
   comfortable, unCxed, & safe.
…ctnd
 Memory aids: note books, lists, posted
 daily reminders.
 stress familiar routines, short-term tasks,
 walks, & simple physical exercises.
 Avoid hostile responses;
  Instead →explanation, reassurance, calm
 statements, distraction.
 Ensure safety of the environment.
…ctnd
 Caregiver frustraton & burn out
 → Education & counseling about dementia.
 → Utilize daycare facilities.
 → Approach local & national support
   groups.
THANK YOU.

   ☺