Transcript ppt

Cortical Dementias
•
•
•
•
Definitions
Differentiating Dementia from normal
aging
Prevalence
Common causes of dementia
Broad, Practical Definition of Dementia
A primary and progressive decline of
intellect due to structural brain disease to
the point that customary social,
professional, and recreational activities of
daily living become compromised.
Major neurocognitive disorder
DSM- V
•
A. Evidence of significant cognitive decline in ≥1 cognitive domain
• Concern of the individual, informant or clinician
• Impairment in cognitive performance, preferably documented by
standardized neuropsychological testing
•
B. The cognitive deficits interfere with independence in everyday
activities.
•
C. The cognitive deficits do not occur exclusively in the context of a
delirium.
•
D. The cognitive deficits are not better explained by another mental
disorder.
Major neurocognitive disorder
DSM- V Domains
•
Complex attention
•
Executive function
•
Learning and memory
•
Language
•
•
Perceptual – Motor
•
Social cognition
Intellectual Dysfunction
Acquired
Reversible
Heavy Metal/Organic
poisoning
Hyperthyroidism
Hypothyroidism
Hypernatremia
Hyponatremia
Hydrocephalus
Tumor
Respiratory diseases
Kidney diseases
Vitamin Deficiencies
(B12, folate) etc.
Developmental
Irreversible
Idiopathic
Autism
Pervasive Devel. D/O
Mental Retardation
Symptomatic
Vascular Dementia
Parkinson’s (PD)
Multiple Sclerosis
Huntington’s (HD)
Dementia w/ Lewy Bodies (DLB) Epilepsy
Multiple System Atrophy (MSA)
CNS Lupus
Traumatic Brain Injury
Alzheimer’s (AD)
Prog.Supranuclear Palsy (PSP)
Infectious (HIV, Herpes,
Corticobasal Degeneration (CBD)
CJD, BSE)
Fronto-Temporal Dementias (FTD)
Posterior Cortical Atrophy (PCA)
Amyotrophic Lateral Sclerosis (ALS)
Scope of Problem
We are an aging society
Age 65+ = 40 million
Age 65+ = 87 million
Risk of Dementia Increases with
Age
AD accounts for
between 60%
and 80% of all
cases of
dementia
Risk of dementia increases with
age, differs by ethnicity
Projected prevalence of AD
Alzheimer’s Association, (2013) Alz &
Dementia
Projected prevalence and cost of AD
Alzheimer’s Study Group (2010) Alzheimer’s Association
Defusing the Bomb
•
•
•
•
Early, accurate diagnosis
Modify disease course
Ameliorate symptoms
Address patient safety and vulnerability
• Make important decisions when competent
•
Adjustment and planning for the family
Cognition and aging
•
Cognitive abilities generally develop through young
adulthood and reach a peak in 3rd or 4th decade of life
•
Relative stability through 5th and 6th decade, with some
decline common in the 7th decade
•
Declines commonly found in
•
•
•
•
•
Processing speed
Focusing of attention
Reduced mental flexibility and working memory
Reduced learning efficiency and free recall
Individual trajectories
Age-related cognitive
trajectories
Normal
Cognitive
Performance
MCI
AD
Age
Mild Cognitive Impairment
(MCI)
•
•
•
•
‘Petersen’ criteria
• Memory complaint, preferably corroborated by an
informant
• Objective memory impairment (1.5 SD below
mean)
• Normal general cognitive function
• No impairment in functioning/not demented
Amnestic & Non-amnestic subtypes
5 -16 % of amnestic MCI convert to AD per year
44 % of MCI in population revert to ‘normal’ per year
Which Population Does the Patient Belong to?
Memory Score
SD units
0.5
0
0.5
Normal,
Age-Associated
Memory
Decline
??
Range of
Scores d/t
Imperfect
Reliability
Observed
Score 2
1.0
1.5
Observed
Score 1
Mild
Cognitive
Impairment (MCI)
2.0
2.5
Dementia
??
Time 1
Test
Time 2
Test
Behavioral heterogeneity of
MCI
Profile
M
C
I
Etiology
Amnestic
Alzheimer’s Disease
Multiple Domain
Mild Impairment
Alzheimer’s Disease
Vascular Dementia
Normal Aging
Non-mnemonic
Frontal Temporal Dementia
Primary Progressive Aphasia
Dementia with Lewy Bodies
Alzheimer’s Disease
Adapted from Neurodegenerative Diseases Beal, Lang, Rudolph eds, Cambridge Univ Press, 2005
Cortical Dementias
Useful Classification of
Dementias
•
Reversible vs Irreversible
• Reversible: B12 deficiency
• Irreversible: Alzheimer's disease
•
Cortical vs subcortical vs mixed
• Cortical: Alzheimer's Disease
• Subcortical: Multiple sclerosis, Vascular dementia
• Mixed: Dementia with Lewy bodies
Cortical Dementias In The Elderly
•
Alzheimer's Disease (~70%)
•
Dementia with Lewy bodies (~10%)
•
Pick's Disease/Fronto-temporal dementia (~10%)
•
Focal atrophy w/out distinctive histology (~10%)
Alzheimer’s Disease
NINDS/ADRDA Criteria
•
Definite Alzheimer's disease:
•
•
•
Probable Alzheimer's disease:
•
•
•
•
•
Dementia established by clinical and neuropsychological examination.
Cognitive impairments progressive and in two or more areas of cognition
Onset of the deficits 40 -90 years
Absence of other diseases capable of producing a dementia syndrome.
Possible Alzheimer's disease:
•
•
•
1984
Meets the criteria for probable Alzheimer's disease
Has histopathologic evidence of AD via autopsy or biopsy
Dementia syndrome with an atypical onset, presentation or progression
No known etiology
No co-morbid diseases capable of producing dementia
Proposed Revision to ARDA Criteria
Dubois, 2007
Memory Decline in Dementia
Heaton, 2004
Age (yrs)
Gross Cortical Changes
Normal Brain
Alzheimer's
Brain
Plaques and Tangles
Alzheimer’s Brain
Early AD pathology is not global
• Plaques most prevalent
in temporal and posterior
association cortex
• Primary sensory cortex
largely spared
• Eventually, plaques
distributed in frontal
cortex
Adapted from Cummings, JAMA, 2002
Early cognitive impairments are not
global
•
Memory deficits tend to be prominent early.
•
But many present with progressive cognitive
symptoms other than memory including language,
mood, visuospatial, and executive abilities
•
Eventually, most AD patients follow a common
pathway which includes memory and other cognitive
deficits.
AD Tx: Cholinesterase inhibitors
Mechanism:
slows the
breakdown of
acetylcholine by
blocking the activity
of
acetylcholinesterase
Efficacy: modest benefit on measures of cognitive function and ADLs
Slower declines compared to placebo
Alleviates noncognitive manifestations (agitation, wandering, inappropriate behavior)
Doesn’t address the underlying cause of the degeneration of cholinergic neurons
Adverse effects - nausea, vomiting, diarrhea, and dizziness.
AD Tx: NMDA (N-methyl-Daspartate) receptor antagonist
•
•
Memantine (Axura, Akatinol, Namenda, Ebixa, Abixa, Memox) –
approved 2003
Mechanism:
•
•
•
•
•
slows the breakdown of acetylcholine by blocking the activity of
acetylcholinesterase
At normal levels, glutamate aids in memory and learning,
too high = excitotoxicity
Efficacy: moderate decrease in clinical deterioration, small positive
effect on cognition, mood, behavior, and the ability to perform ADLS in
moderate to severe AD. No sig benefit in mild disease
SE: confusion, dizziness, drowsiness, headache, insomnia, agitation,
and/or hallucinations
Where are we now?
• We have no cure for Alzheimer’s disease
• We have no disease modifying therapies
for Alzheimer’s disease
• We have only minimally effective
symptomatic treatments for Alzheimer’s
disease
Timing is everything
Cognitive trajectories
Asymptomatic
Symptomatic
Responsive substrate?
Unresponsive substrate
Sperling et al. (2011) Alzheimer’s & Dementia
Dementia with Lewy
Bodies
Diagnostic Criteria for DLB
•
Dementia may have less prominent memory
impairment at onset. Cognitive deficits in attention,
frontal-subcortical skills, and visuospatial abilities may
be prominent.
•
Core features
• Fluctuation of cognition; pronounced variation in
attention and alertness.
• Hallucinations: recurring, visual, well-formed and detailed
• Spontaneous parkinsonism
Other Features of DLB
•
Repeated falls
•
Syncope
•
Delusions
•
Sensitivity to neuroleptics
Pathological Hallmarks of DLB
•
Cortical Lewy bodies
•
Beta amyloid plaques
•
Neurofibrillary tangles
•
Neuronal and synaptic loss
Frontal Lobe Dementias
Fronto-temporal Dementia
Primary progressive aphasia (PPA)
Semantic dementia: intact speech, but words convey less meaning.
Use of broad general terms ("animal" for "cat." ). Comprehension
declines.
Progressive nonfluent aphasia, halting, "tongue-tied" and
ungrammatical speech. Impaired ability to read and write
FTD movement disorders
Corticobasal degeneration causes shakiness, lack of
coordination, and muscle rigidity and spasms.
Progressive supranuclear palsy causes walking and balance
problems, frequent falls and muscle stiffness, and affects eye
movements.
Behavioral variant frontotemporal dementia (bvFTD) Behavioral dyscontrol,
apathy, neglect of personal hygiene, compulsions or rituals, poor planning and
judgment. Subtle changes may be mistaken for psychiatric disturbance
FTD
“Frontal syndrome“
• Onset mid 40s – early 60s
• Lasts 3-17 years
• Average duration: 8 years
• 40% of patients have a family history of a similar
dementia
•
Cortical Atrophy of FTD
Neuropathology of Pick's
Disease
•
Pick bodies