2. NORMAL AGEING
• BEFORE 60:
general knowledge and vocabulary are stable
Problem solving & reasoning decline
• Age related decline affects cognitive speed &
working memory with delayed memory
rel.preserved.
4. MCI
• A SYNDROME between normal ageing and
dementia
• Independence in community & ADL preserved
• DSM V- MILD NEUROCOGNITIVE DISORDER
Q.what’s the importance of creating MCI group?
• To identify people at greater risk of having dementia
• Annual conversion rate: general popn.-1-2%
MCI-10-15%
8. • Biomarkers predict the probability of
conversion to dementia
• Risk factors for conversion:
1. APO E4 allele
2. Temero-parietal hypometabolism on FDG-PET
3. Amyloid deposition on Ab-PET
Q.What about people who revert back?
Even These people have got a higher conversion rate
12. HISTORY
• The most important component
• From the pt or the informant(majority)
1. Premorbid functional status
2. Are the ADL imapired
3. Presenting symptom(domain affected 1st )
4. Mode of onset
5. Rate of progression
13. • The questions we seek an answer to:
• True or pseudodementia
• Cortical or subcortical dementia
• Reversible or irreversible
• Associated findings other than dementia
14. PSEUDO-DEMENTIA
1. Acute ,non-progressive
2. Better at night
3. Self referred
4. Impaired attention
early
5. Orientation intact
6. Affective before
cognitive
7. Gives up on testing
8. Language intact
TRUE DEMENTIA
1. Insidious ,progressive
2. Sundowning
3. Referred by others
4. Memory impairment
5. Orientation impaired
6. Cognitive before
affective
7. Obvious effort on
testing
8. Aphasic errors
15. SUBCORTICAL CORTICAL
LANGUAGE NORMAL APHASIA
SPEECH DYSARTHRIC NORMAL ARTICULATION
ATTENTION IMPAIRED LATE
ALERTNESS SLOW NORMAL
CALCULATION LATE EARLY
PERSONALITY APATHETIC DISINHIBITED IF FRONTAL
INVOLVEMENT
MOVEMENT DISORDERS ABSENT COMMON
PRAXIS NORMAL AFFECTED
MEMORY RETRIEVAL DEFICIT ENCODING DEFECT
24. Medical history
• Head injury(single or repeated)
• h/o stroke,DM,HTN,AF, smoking or other vascular
risk factors-vascular cause
• h/o cancer or autoimmune disorder-
paraneoplastic or autoimmune cause
• h/o seizures, meningoencephalitis, sleep apnea ,
brain irradiation
25. FAMILY HISTORY
1. Genetic cause or RF
2. Not on only first degree
rel.
3. Not only h/o
dementia(parkinsonism,AL
S or psychiatric condn.)
MEDICATIONS
1. Exacerbate dementia
2. Eg.anticholinergics(TC
A,antihistaminics),BZD,
antipsychotics(typical/
atypical)
26. Neuropsychiatric history
• Purpose: potenetially treatable symptoms &
narrowing down the DD.
• All pts. Should be screened for depression
• They can be the presenting features of a
neurodeg process
27. Cognitive assessment
• MMSE and MOCA etc.
• Role:
• Domains affected
• Brain structures involved
• Severity of impairment
• Following a pts progression
28.
29. ALZHEIMER’S DISEASE
EPIDEMIOLOGY
PREVALENCE
70% of dementia
MCI-men & dementia –women
Prevalence increases with increasing age
INCIDENCE
Double every 4.4 years after 60
MEDIAN SURVIVAL AFTER DIAGNOSIS:
4 yrs for men & 6 yrs for women
30. Risk factors
• Hypertension
• Diabetes and elevated glucose
• Head injury
• Others: smoking, cerebrovascular disease,
anemia & obesity
• Dietary fat intake (saturated and trans-
unsaturated fats)
31. Protective factors
• Leisure activities
• Early life cognitive abilities
• COGNITIVE RESERVE HYPOTHESIS
Education
• Improvement in aerobic fitness correlate with
increased hippocampal volumeExercise
• Moderate alcohol(1-6 /day) better than
abstinence
• Weekly fish consumption
Diet
32. Clinical features
EARLY PRESENTATION
• Episodic memory
impairment
• s/o vulnerability of the
medial temporal lobe
PATTERN OF PROGRESSION
• Heterogenous
• Recent memory, impaired IADLMild AD
• Aphasia,executive basic ADLModerate AD
• Agitation & Complete loss of
independenceSevere AD
Feldman and woodward ,2005
33. • Early(but after episodic m imp.)
• Temporal neocortex
• Category fluency test
SEMANTIC
MEMORY
• Mild until late as compared to bvFTD
EXECUTIVE
FUNCTION
• Mild to moderate stage
• Word finding to frank aphasia
LANGUAGE
DISTURBANCE
• Early common
• Getting lost easliy
VISOSPATIAL
SKILLS
• Late
• Early in atypical formsAPRAXIA
34. • Knowing how but knowing what.
• Episodic memory loss ,anomia,executive dysfunction
and visuospatial difficulty with preserved ability to
walk,see,hear and feel.
• Spread of AD pathology
• Semantic memory
Anterior
temporal lobe
• executive dysfunctionFrontal lobe
• Visuospatial dysfunctionOccipito-
temporal lobe
37. Biomarkers
CSF BIOMARKERS
• Reduction in CSF Ab 42 and
elevation in CSF tau protein
(sens 85%,spec 86%)
NEUROIMAGING BIOMARKERS
• Structural imaging(MRI,CT)
• Cerebral amyloid
angiopathy(Gradient echo)
• Functional
imaging(PET,SPECT)
• Amyloid imaging
• Task free functional MRI
• Tau imaging
38. Neuroimaging(structural)
• MRI>>CT scan
• Medial temporal lobe atrophy of the hippocampus and the
entorhinal cortex with dilatation of the temporal horns-early
characteristic
• aMCI-atrophy limited to medial temporal lobe
• AD onset-atrophy of lateral temporal , parietal and frontal cortices
• Dementia stage-global atrophy in a tempero-parietal distribution
• T2 FLAIR hypertintensities contribute to cognitive impairmnet
39. Functional imaging
• Decreased blood flow on
SPECT and hypometabolism
on FDG-PET in tempero-
parietal distribution.
• Hypometabolism in
hippocampus and posterior
cingulate-aMCI
Amyloid imaging
• Pittsburgh compound B
• Amyloid burden in living
subjects
• For Preclinical AD and MCI
d/t AD
• Differentiation AD vs FTD
40. Longitudinal tracking of biomarkers
• Appearence of biomarkers years before
clinical manifestation.
20 yrs
• CSF Ab 42
decline
15 yrs
• PET Ab 42
abnormalities
15 yrs
• Brain volume
loss
• Increased CSF
tau
10 yrs
• FDG-PET
abnormalities
41. Genetics
Early onset
• APP- chr 21-first
• Presenilin 1(PSEN1)-most
common
• Presenilin 2(PSEN2)
Late onset
• APO E(20% of all late onset)
• E4-high risk(91% lifetime
risk)
• E3-neutral
• E2-protective
42. • Myoclonus, seizures
• Early dyscalculia, corticospinal tract signs
• Cerebral white matter changes
APP(amyloid
precursor
protein)
• Myoclonus ,seizures with significant
aphasiaPRESENILIN 1
• Russian family
• Increased seizure frequencyPRESENILIN 2
43. Atypical AD
• Focal cortical syndromes without initial
memory impairment
POSTERIOR CORTICAL STROPHY
LOGOPENIC APHASIA
FRONTAL VARIANT AD
44. POSTERIOR
CORTICAL ATROPHY
• Parieto-
occipital
atrophy
• NFT -occipital
lobe
• Balint syn.
• Gerstmann syn
• Visual field loss
• APO E4 allele
LOGOPENIC
APHASIA
• Left tempero-
parietal atrophy
• NFT left
hemisphere
language areas
• Naming,repetition
& word retrieval
impaired
• Motor speech and
grammar spared
FONTAL VARIANT AD
• NFT burden in
frontal lobe
• Early impairment
of frontal lobe
functions
• behavioural and
personality
changes found
OTHERS
• CBS
• PP agrammatic
aphasia
• Sv PPA
45. FRONTOTEMPORAL DEMENTIA
FTD
• Clinical syndrome characterized by
degeneration of frontal and temporal lobe
FTLD
• Spectrum of pathologies associated with FTD
46. • 3 clinical variants
1. Behavioural variant FTD(bvFTD)
2. Semantic variant primary progressive aphasia(svPPA)
3. Progressive agrammatic or non fluent aphasia(PNFA)
• 45-64 y age group
• An early onset dementia(30% > 65 yrs)
• Median survival
6yrs-FTD
3yrs-FTD-ALS
47. bvFTD
The characteristic clinical features
Change in personality and behavior such as
disinhibition
Executive dysfunction such as poor planning, loss of
judgement, difficulty with organization
change in dietary preference, particularly an
increased interest in sweets
Apathy
Utilization behaviors
Obsessive compulsive and perseverative behaviors.
Lack of empathy and insight
48. • Motor neuron disease(10-15%) more common
with bvFTD than PPA.
NEUROPSYCHOLOGICAL TESTING
• Early in the disease testing is normal.
• episodic memory impairment less than AD
• Executive function deficits are characteristic
• Semantic memory is spared
50. PROGRESSIVE AGRAMMATIC
NONFLUENT APHASIA
• Word knowledge relatively
spared
• Non-fluent, hesitant speech
• Agrammatism: telegraphic
speech
• Apraxia of speech
• Parkinsonism later on
SEMANTIC VAR. APHASIA
• Prominent anomia(word
meaning lost)
• Fluent speech ,exchange
Words with “it”
• Grammar intact
• Surface dyslexia
• Behvioural issues similar to
bvFTD
• Parkinsonism or MND rare
51. Neuroimaging(MRI and FDG PET)
• Orbitofrontal ,insula ,anterior cingulate, medial &
dorsolateral prefrontal lobesbvFTD
• Left anterior temporal lobesvPPA
• Left inferior frontal lobe
Agrammatic
PPA
• Superior premotor or supplementary motor
Speech apraxia
52. Genetics
• 40% of FTD have a positive family history
• Autosomal dominant inheritance(3 MAJOR genes)
• 20% OF FAMILIAL CASES
MAPT
• 20% OF FAMILIALPROGRANULIN
• 25% OF FAMILIAL CASESC9ORF72
55. DLB
• 2nd m.c.c. of dementia
• Prodromal DLB:
loss of smell
RBD
Autonomic dysfunction
Mean Age of onset of RBD(61.5y) and cognitive decline(68y)
• naMCI precedes
57. NEUROIMAGING(vs AD)
• MRI: Inf. Frontal
,Parietotemporal Atrophy
• FOCAL ATROPHY : midbrain
• Preserved hippocampal
volumes, less global atrophy
• FDG-PET:
(characteristic)parieto-
occipital hypomatabolism(sens
90%,spec 87%)
• DAT scan: decreases
nigrostriatal uptake
PATHOLOGY
• Lewy bodies in limbic and
cortical regions(vs
Brainstem in AD)
• Earliest: DMN vagus,
olfactory bulb
58. VASCULAR DEMENTIA
• VASCULAR COGNITIVE IMPAIRMENT: all forms
of cognitive impairment related to vascular
disease.
• 60-64 yrs
• Men
• Component of 25% of dementia cases
• RF: vascular Risk factors
Apart from the Loss of synaptic density irrespective of alzheimers pathology.reduction in volume of hippocampus by 1% every year.
location of dentate ??????????
Analogous term MND
Language,executive,visuospatia and memory -other domains
For having dementia as compared to the controls with AD biomarkers
Informant who knows the patient well
Potentially or partially treatable: 9%
Treatable co-existing disorder: 23%
Vitamins ,SUSAC SYNDROME(SICRET)
As in CTE(chronic traumatic encephalopathy)
Eg.AD & FTD due to the same disease
11% at 65
32% at 85
Ab42 and insulin are dealt with by insulin degrading enzyme
Reduced ab42 in csf of patients after head injury just like preclinical AD
Preservation of procedural memory(basal ganglia and cerebellum) in the absence of declarative memory.
Early involvemeent of the medial temporal cortex with sparing of motor and sensory cortices
Biomarkers of Ab plaques-CSF amyloid Ab, Ab PET
Neurodegeneration –CSF tau,FDG-PET,atrophy on structural MRI
Ab is the product of APP.
Ab 42: Ab40 ratio change
PCA-CBD,prion diseases
OPTIC ATAXIA,PARALYSIS OF GAZE,SIMULTAGNOSIA
Neurodegeneration targets the language networks.
Mint vs tough
Tough as tug
Words prononced phonetically
svPPA-seek social attention & hv food fads but bvFTD are socially wiothdrawn and overeat
Apraxia of speech: distorted sound substitutions,trial error articulatory movements
MRI -Atrophy of the following
FDG PET-hypometabolism seen in respective areas
Microtubule associated protein Tau
Dec uptake in BG on SPECT DAT scan
Myocardial scintigraphy
Fluctuation: 3D S
Well formed animate objects(vis hall).systematized delusions supportive
Symmetrical,action tremor >>rest tremor
Pt acting out his dreams
80 % have a adverse reaction to antipsychotics (even the atypical ones)increased mportality
MIBG imaging
Lewy bodies without tauopathy
Quetiapine and clozapine can be used if needeed
Large vessel:Focal signs: hemiparesis,hemianesthesia,visual field defects
Small vessel:pseudo bulbar findings& parkinsonism
VaD vs AD: executive dysfunction>>> memory impairment
To a prior h/o SAH, meningitis l/t dysfunction of the arachnoid granulations
Gait is the core problem and the most responsive to drugs
Mask facies ,tremor ,rigidity absent
DESH(disproportionately enlarged subarachnoid space hydrocphalus)
Temp.shunt 10 cc/hr
