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.

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• Neuropsychiatric & social deficits.

- depression; - delusion; - agitation;

- hallucination; - withdrawal; - insomnia;

- disinhibition.

* Dementia:- commonly progressive;

- sometimes static or fluctuates

dramatically from day to day.

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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.

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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.

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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 .

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Components of memory Fn.

- Registration: frontal lobes, hippocampal

complex.

- Retention.

- Stabilization.

- Retrieval: frontal lobes.

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* 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.

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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.

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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.

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• 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.

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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.

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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.

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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.

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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.

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-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.

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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.

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CM.

• cognitive ∆es begin with memory impairment → language & visuospatial deficits.

• 20% of pts: Nonmemory complaints such as → word-finding, organizational, or navigational difficulty.

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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.

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MIDDLE STAGES.

- Unable to work, easily lost, confused.

- Requires daily supervision.

- Social conduct, routine behaviours: OK.

- Naming → Comprhension → Fluency.

- Apraxia.

- Visuospatial deficits.

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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.

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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].

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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.

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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.

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• 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.

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• 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.

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• 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.

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* 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.

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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.

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- 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.

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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.

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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.

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• 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.

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* Cognitive presentations:

- spare memory,

- involve planning, judgement, or language.

- insight severely impaired.

* Behavioural deficits:

- apathy, disinhibition, weight gain,

- food fetishes, compulsions, euphoria.

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* 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.

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• 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.

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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.

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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.

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- 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.]

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- * 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.

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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.

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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.

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• 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.

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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.

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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.

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• 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].

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Rx of NPH.

- Ventricular shunting procedure.

→ gait may improve more than memory.

* Cxns of procedure:- subdural hematoma.

- infection.

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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.

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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.

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* 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.

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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 .

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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.

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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.

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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.

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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.

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SYSTEMIC DISEASES.

*can produce chronic confusion & dementia. hypothyroidism, vasculitis, hepatic failure, renal failure, pulmonary disease.

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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.

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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.

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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.

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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].

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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.

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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.

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• 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.

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* 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.

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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.

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Caregiver frustraton & burn out

→ Education & counseling about dementia.

→ Utilize daycare facilities.

→ Approach local & national support

groups.

THANK YOU.

☺