Definition dementia, Reversible dementia, Taupathy, Synucleinopathy, LBD, Lewy body dementia, PD dementia, Parkinson's, MSA, FTD, Frontotemporal dementia, CBD, CBS, corticobasal dengeneration, Pick's disease, TDP-43, Alzheimer's disease, RBD, frontal lobe, temporal, parietal, occipital, Pimple sign MSA, Cuneus, Cingulate gyrus, Braak staging, 3R, 4R taupathy, Pick bodies, Steele Richardson syndrome, Humming bird, Penguin sign, Mickey mouse sign, morning glory sign PSP, FTD-MND, scarecrow, Tinman, The yellow brick road, PPA, semantic, phonemic, aphasia, memory, speech, Dyslexia, Surface dyslexia, Agrammatism, Genetics, MAPT, PGRN, progranulin mutation, tau, FUS, C9ORF72

1. APPROACH TO DEMENTIA
Dhananjay Gupta

2. DEMENTIA
 Syndromic term describing
 Decline in cognitive abilities of sufficient severity to
interfere with function during daily activities (shopping,
paying bills, cooking, driving etc)
 DSM-V: “Major neurocognitive disorder” for dementia

3. REVERSIBLE
DEMENTIA
 D drug (anticholinergics), BZD, Opioids, anti-psychotics
 E Emotional (depression), Endocrine (hypo-thyroid)
 M metabolic (uremia)
 E eye or ear dysfunction
 N NPH
 T tumours or space occupying lesion
 I infections (syphilis, HIV, meningitis, encephalitis)
inflammatory (SLE, MS)
 A anemia (B12 deficiency/ folate), arachnoid SAH

4. YOUNG ONSET
DEMENTIA
17-45 years: Frontal CLAMPS
 Frontal FTD
 C Chorea/ Huntington's
 L Lupus
 A Autoimmune encephalitis/ vascuilitis
 M MS/ sclerosis
Mitochondrial diseases
 P Prion diseases
 S Storage diseases

5. YOUNG ONSET
DEMENTIA
30-65 years:
 AD
 HD
 FTD
 DLB
 MS
 CBD/ prions
 PD dementia
 Vascular Dementia
 Alcohol related dementia

6. Rapidly
Progressive
Dementia
 Prions
 Neoplastic
 Autoimmune
 Paraneoplastic
 Infections (viral encephalitis/ whipples/ lymes disease)
 TB/ HIV dementia/ Syphilis/ fungal meningitis
 CNS vasculopathy (Sussac syndrome/ Aβ related angitis)
 Toxic/ metabolic (Vitamin B1, B12, Alcohol, CLD, CKD)
 Drug toxicity (Lithium, Methotrexate)

7. Rapidly
Progressive
Dementia
 Wilson’s disease
 Non convulsive status epilepticus
 Neurodegenerative diseases with rapid time course
 Neuro-sarcoidosis
 Surgical condition:
 Subdural
 Primary or secondary hydrocephalus

8. SYNUCLEINOPATHIES
P: PDD: Parkinson disease dementia
M: MSA: multi-system dementia
L: Lewy body dementia
Features of SYNUCLEINOPATHIES
Anosmia
Parkinsonism
REM sleep disorder
Autonomic disturbances
TAU- PATHIES
A: Apraxia of speech
C: CBD/ CBS
T: Traumatic encephalopathy (CTE)
P: PSP
A: Agrammatic aphasia
P: Picks disease – FTD
A: Agyrophilic grain disease (AGD)
ACT PAPA TAU

9. FTLD: Fronto-temporo-Lobar degeneration diseases
FTLD tauopathies FTLD Non-taupathies
Pick’s disease FTLD-U (ubiquitin)
CBD/ CBS FTLD-MND
PSP
Neuro-fibrillary tangle-only dementia
TDP-43 Proteinopathy
AD
FTLD- MND
Guam Parkinson's dementia complex
LATE: Limbic predominant age related TDP-43 encephalopathy

10. SYNUCLEINOPATHIES
A. DLBD
B. PDD
C. MSA

11. 1. DLB
 20% dementia
 2nd most common cause of dementia
 1961: Okazaki: described dementia with hallucinations
 Lewy bodies demonstrated later
 Lewy bodies immuno-reactive for α-synuclein
 F/s/o synucleinopathy: anosmia/ RBD/ autonomic
disturbances may precede dementia
 Onset of RBD: 61.5 years
 Onset of dementia: 68.1 years
 Sometimes RBD may precede dementia even by 50 years

12. Epidemiology
 20% dementia (Norway)
 2nd most common cause of dementia
 70% are males
 70 years: mean age of onset 72.5 years
 Compared to AD:
oH/o depression +
oFamily history of PD +
oEarlier admission to nursing home
oShorter survival than AD

13. PRODROMAL
DLB
MCI due to
DLB DLB
• RBD
Anosmia
• Autonomic
D/b MCI due to AD
o Delirium
o Hallucinations
o Parkinsonism
o Preserved memory
D/b dementia due to AD
o Staring into space
o Disorganized speech
o Drowsiness
o Daytime sleepiness
Fluctuations resemble delirium

14. Clinical feature
1. Typically RBD
2. Followed by MCI/ cognitive decline
3. Followed by Parkinson’s and hallucinations
4. Susceptible to delirium
5. But do not have provoking factors for delirium
6. Can rarely present with rapidly progressive dementia

15. Hallucinations
1. Detailed
2. Vivid images of animals and people
3. Children and insects are also common theme
4. Occur in clusters in evening
5. Insight is variable
6. Hallucinations within 5 years of dementia likely d/t DLBD
(Ferman, 2013)

16. RBD
1. RBD refers to loss of normal REM sleep with atonia
2. Patient acts out of dreams
3. Gold standard: Polysomnogram
4. DLBD with RBD:
 Males
 Earlier PD
 Hallucinations
 Lower braak tangles score
5. RBD increases Sn of diagnosis of DLBD

17. Others
1. Autonomic dysfunction:
 Orthostatic hypotension
 Incontinence
 ED
2. Greater neuroleptic sensitivity than AD
3. Worsening of motor symptoms, confusion, agitation with
 Haloperidol
 Risperidone
4. Falls (PD+ autonomic)
5. Delusions
6. Depression, anxiety, apathy

18. D/b Parkinson’s disease
PD present in 50% DLBD at presentation
Symmetrical
Action tremor >> Rest tremor
More severe PD features like:
a. Impaired facial expression
b. Rigidity, gait difficulty
c. Difficulty in getting up from chair
Higher proportion of patient not responding
to L-dopa
Lewy bodies and Lewy neurites are found in
cortical and limbic regions also.
(D/b PD- found only in brainstem)
D/b AD (Ferman 2004)
Cognitive fluctuations
Presence of following fluctuation features
a. Staring into space
b. Disorganized speech
c. Drowsiness
d. Day time sleepiness
63% DLBD, 12% AD, 0.5% normal adults
D/b PD-D/ AD/ VaD (Lee et.al. 2014)
Presence of following features
a. Differences in daytime functioning
b. Somnolence
c. Drowsiness
d. Daytime altered levels of consciousness
Sn 78-80%, Sp 73-79%

19. AD DLBD
1. Cognitive fluctuations Uncommon Common
2. Incidence More common Less common
3. Hallucinations Uncommon Common
4. Neuro-psychology Early episodic memory,
executive
Perform better on tests of naming and verbal
memory
Late visuo-spatial Worse tests of visuo-spatial ability, attention
5. MRI brain Hippocampal atrophy Preserved hippocampal volume
Less global atrophy
More involvement of posterior meso-pontine
region
6. FDG-PET Characteristic parieto-occipital
hypometabolism,
“Cingulate island”
7. Dopamine transport scan
(DAT)
Decreased nigro-striatal uptake compared to
AD, particularly in putamen
8. Treatment More cholinergic loss of function
Respond better to AChEIs

20. Topographical distribution of brain hypometabolism in the whole DLB group. [18F]FDG-PET. From: Silvia Paola Caminiti. Brain
glucose metabolism in Lewy body dementia: implications for diagnostic criteria. Alzheimer's Research &Therapy2019

21. Comparison of brain perfusion
SPECT images for moderate AD
and moderate DLB.
DLB showed lower perfusion in
occipital cortex than AD (arrows).
In contrast,AD showed lower
perfusion in medial temporal areas
(arrowheads).
From: Role of Neuroimaging in
Alzheimer's Disease, with
Emphasis on Brain Perfusion
SPECT.
J Nucl Med. August 2007 vol. 48 no.
8 1289-1300
J Nucl MedAugust 2007 vol. 48no. 8 1289-1300

23. 18F-FDG PET (top row) and β-CIT
SPECT images (middle row) overlaid
on MRI.
White arrow points to posterior
cingulate cortex on 18F-FDG PET
study, demonstrating
cingulate island sign of DLB.
From:
Seok Ming Lim.The 18F-FDG PET
Cingulate Island Sign and Comparison
to 123I-b-CIT SPECT for Diagnosis of
Dementia with Lewy Bodies. J Nucl
Med. 2009; 50:1638–1645

24. Sagittal FDG PET images of the brain
A.The normal brain shows no areas of
hypometabolism. B. Patient with AD
demonstrates decreased FDG uptake
in the precuneus (green arrowhead)
and the posterior cingulate cortex (blue
arrowhead). C. DLB and D. PCA patient
images both show occipital lobe
hypometabolism with relative sparing
of the primary visual cortex generating
the “occipital tunnel” sign (white
arrowheads).
The DLB patient displays sparing of
the posterior cingulate cortex (blue
arrowheads), whereas the PCA patient
does not.
The patients with AD, DLB, and PCA all
have decreased frontal lobe activity
compared with normal (orange
arrowheads).
Sawyer, D.M., & Kuo, P.H. (2017). "Occipital
Tunnel" Sign on FDG PET for Differentiating
Dementias. Clinical nuclear medicine, 43 2,
e59-e61

25. MRI of a dementia with Lewy bodies patient - prodromal stage with clear atrophy of the insula (red and green arrows). Insula is a
key region for cognition, emotions and neurovegetative aspects which has been implicated in the genesis of
both hallucinations and cognitive fluctuations. https://blogs.biomedcentral.com/on-medicine/2016/08/02/insula-biomarker-dementia-lewy-bodies/

26. Pathology
1. α-Synuclein is the primary protein
2. Many patients also have amyloid plaques
3. These plaques are diffusely present, but, without tau
4. α-Synuclein found in both brain and SC
5. In SC – affects the IML cell column and Onuf’s nucleus
6. In Brain – Braak (2003) proposed staging scheme
 Earliest involved- DMNX (vagus) in medulla
 F/b pons, midbrain, basal forebrain
 Then cortex – particularly frontal/ temporal
7. Lewy bodies and Lewy neurites:
 In PD – mainly in brainstem,
 In DLBD – also in limbic and cortical regions

29. DLB attacks many parts of the
central and peripheral nervous
system. [Courtesy of Bradley
Boeve.]
From:
https://www.alzforum.org/news
/conference-coverage/
dementia-lewy-bodies-
research-ready-clinical-trials

30. http://labiotech.eu/major-cns-disease-milestones-in-biotech-2015/

31. Propagation of alpha-synuclein
pathology from the olfactory bulb:
possible role in the pathogenesis of
DLBD.
Olfactory system is
• a part of the limbic system and,
• it has direct and reciprocal projections
with neocortical regions
• as well as several brainstem nuclei.
Braak (2003): α –Synuclein pathology
affects the olfactory bulb, ant. Olfactory
nucleus and DMNX first and then spreads
caudo-rostrally to involve other nuclei.
OB olfactory bulb; Am amygdala; Ent anterior
entorhinal cortex; SN substantia nigra; LC locus
coeruleus; DMV dorsal motor nucleus of the
vagus; ENS enteric nervous system.
Light red arrows weak incursions of alpha-
synuclein pathology; dark red arrows aggressive
incursions of alpha-synuclein pathology.
https://www.researchgate.net/publication/321426949_
Propagation_of_alphasynuclein_pathology_from_the_
olfactory_bulb_possible_role_in_the_pathogenesis_of_

32. Propagation of alpha-synuclein
pathology from the olfactory bulb:
possible role in the pathogenesis of
DLBD.
Involvement of the amygdala by α-SYN
pathology in Lewy body disorders.
a)First nuclei affected from the
caudorostral route in PD.
b)First nuclei affected from the
hypothetical olfactory route in DLB.
OB olfactory bulb; A-Co superficial cortical
nuclei of the amygdala;
A-BL basolateral nuclei of the amygdala;
A-Cen central subnucleus of the
centromedial amygdalar nuclei;
Syn alpha-synuclein pathology
https://www.researchgate.net/publication/32142
6949_Propagation_of_alpha-
synuclein_pathology_from_the_olfactory_bulb_
possible_role_in_the_pathogenesis_of_dementi
a_with_Lewy_bodies

33. TREATMENT DLBD
1. Cognition AChEIs Greater loss of cholinergic function, with comparatively intact
structural integrity – so more useful than AD
DLBD patients without markers of AD (hippocampal atrophy/ PiB-
PET positivity) more likely to respond
2. Parkinsonism L-dopa Levodopa responsive, but less than PD
L-/carbidopa: introduce at a low dose, titrate slowly
Dopa agonist Avoid
Exacerbate hallucinations/ behavioural issues
Anti-cholinergic Cause confusion
Selegiline Exacerbate psychosis
3. Depression/
psychosis
Typical Anti-psychotic contraindicated
Increased mortality
Atypical Also increase mortality
Low dose, minimum duration
Quetiapine/ clozapine may be used
4. Autonomic Hypotension
ED
Fludrocortisone, Midodrine
PDE-5 inhibitors

34. RBD
1. Most common sleep disorder
2. Screen for sleep apnoea
3. Treatment is individualized
4. Non pharmacological measures:
 Remove sharp objects around bed
 Barriers between bed partners
 Bed alarms
5. Pharmacotherapy:
 Melatonin can improve RBD
 Clonazepam is 2nd line treatment
 Though ideally BZDs should be avoided

35. B. PD-D
1. Parkinson's disease dementia
2. 80% PD patients do develop dementia
3. D/b DLBD by: presence of PD
4. Preceding cognitive decline for atleast 1 year
5. Have greater Substantia nigra neuronal loss
6. Rivastigmine may be used
D/b Parkinson’s disease and DLBD
PD present in 50% DLBD at presentation
Symmetrical in DLBD, Action tremor >> Rest tremor
More severe PD features like:
a. Impaired facial expression
b. Rigidity, gait difficulty
c. Difficulty in getting up from chair

36. C. MSA
1. OPCA: Olivo-ponto-cerebellar atrophy
2. Striato-nigral degeneration
3. 58% Europeans have MSA-P (dopa non-responsive PD)
4. MSA-C is more common in Japan
5. Mean age of onset: 54
6. Mean survival: 5.7 years
7. Presence of cognitive sx at diagnosis is against MSA
D/b Parkinson’s disease and MSA-P
Parkinsonism in MSA lacks the classical rest tremor, dopa response
Progresses more rapidly
Associated other symptoms like
• Pyramidal
• Stridor/ dysarthria/ dysphagia/ oro-facial dystonia/ myoclonus

37. C. MSA
1. Pathology is degeneration of the
2. Putamen and lateral Substantia Nigra
3. Hallmark lesion is glial cytoplasmic inclusions, that consist
4. of filamentous inclusions of synuclein in oligodendroglia

38. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(09)70288-1/fulltext?version=printerFriendly

39. TAUPATHIES/ PICKCOMPLEX
A. CBD
B. PSP
C. FTD

40. TAU:
o Normal proteins that stabilize
microtubules
o Abundant in neurons in CNS
o These are products of alternative
splicing from single gene: MAPT
(chromosome 17)
o Heat stable proteins essential for
microtubule assembly
o Accumulation of hyper-
phosphorylated tau in neurons
leads to neurodegeneration
o Hyperphosphorylation of tau
leads to self assembly of tangles
of paired helical filaments and
straight filaments
https://www.humpath.com/spip.php?article1264

41. Exp Gerontol. 2017 Aug;94:103-107
Normal microtubule
Taupathy microtubule

42. Tau protein undergoes differential splicing.
Inclusion of EXON10 in splicing of tau, forms
four microtubule binding domains (4R).
Exclusion of EXON10 results in 3 binding
domains. (3R)
Normally in body 4R:3R = 1:1
MAPT (FTD) mutations interfere with
splicing and lead to excessive EXON10
inclusion, increasing the 4R:3R tau ratio.
In AD, decreased levels of PKA (protein
kinaseA) due to calpain I activation suppress
its role in tau exon 10 inclusion.As a result,
levels of 3R-tau increase.
This leads to aggregation of tau and the
formation of neurofibrillary tangles in the
affected neurons.
Jianhua shi. TheJournal of biological chemistry.
vol. 286, no. 16, pp. 14639 –14648, April 22, 2011

43. Monica Javidnia. An update on clinical trials targeting human tauopathies. ClinTrials Degener Dis. 2017;2:66-76
SecondaryTaupathy
PrimaryTaupathies

44. A. CBS/CBD
1. Rebeiz et. al. 1960s: described 3 cases with
2. Akinetic rigid state + Apraxia + unique pathological features
3. Called it “Cortico-dentato-nigral degeneration
with neuronal achromasia”
4. Later name changes to “Corticobasal ganglionic degeneration”
5. Progressive Asymmetric Rigidity + Apraxia = CBD
6. Asymmetric Rigidity + Apraxia + Alien limb phenomenon ±
7. Cortical sensory loss,
8. Myoclonus, dystonia, parkinsonism

45. A. CBS/CBD
Four clinical phenotypes of CBD pathology
1. CBS
2. Frontal-behavioural- spatial syndrome
3. Non-fluent/ agrammatic variant of PPA
4. PSP-syndrome
CBD is the most common pathological substrate of CBS (50%)
 Mean age of onset: 64 years
 Average duration: 6.6 years

46. Term Definition
 CBD • Pathologic diagnosis with abnormal aggregation of hyperphosphorylated tau.
• Pathologic findings also include cortical atrophy, ballooned neurons, and nigral degeneration.
Historical studies use the term “corticobasal degeneration” for both clinical and pathologic
diagnoses, but currently this term is reserved for pathologic diagnosis alone.
 CBS • Clinical syndrome characterized by the presence of a gradually progressive movement
disorder and higher cortical dysfunction.
• 2013 cr-CBD criteria: probable or possible
 FBS Executive dysfunction, behavioral or personality changes, and visuospatial deficits.
 naPPA o Effortful, agrammatic speech accompanied by
o Apraxia of speech, groping, distorted speech, and/or
o Relatively preserved single-word comprehension but
o Impaired grammar or sentence comprehension.
 ALP A variety of behaviors, including
o purposeless wandering of the limb,
o dissociation from one’s own limb,
o impulsive hand groping or grasping, intermanual conflict, enabling synkinesis, and magnetic
apraxia

47. CBD = Rigidity + Apraxia
Cortical Basal ganglionic Others
 Alien limb phenomenon  Rigidity  Depression
 Cortical sensory loss  Bradykinesia  Dis-inhibition
 Mirror movements  Dystonia  OCD
 Cognitive impairment  Tremors
 Behaviour impairment  Poor levodopa response
 Myoclonus
Capgrass delusions (identical imposter) and
Hallucinations are quite rare as compared to
other neuro-degenerative diseases.

48. Neuropsychology
Prominent deficits in:
1. Executive function
2. Language
3. Visuo-spatial
4. Cognitive and behavioural disturbances
5. Can present as bvFTD
*Pathology/ MRI shows asymmetric frontal atrophy (contralateral to
the affected limb).
**FDG-PET: hypometabolism in the posterior frontal and anterior
parietal regions.

49. Gross Pathology:
Involves:
• atrophy of the Superior
frontal gyrus
• Thinning of corpus callosum
• Loss of pigment in
substantia nigra
4R-Tau accumulates in the
• Cortex
• Basal ganglia
• Basal nucleus of Meynert
• Thalamus
• Brainstem
Paulo Roberto de Brito-Marques.
Clinicopathologic analysis of
progressive non-fluent aphasia and
corticobasal degeneration: Case
report and review. Dementia and
Neuropsychologia. 2011;5(2)

50. Ballooned neuron in a patient with CBD. B: Astrocytic plaque as revealed by tau immunostaining. (Courtesy of
Rudolph J. Castellani, MD). Astrocytic plaques are hallmark of CBD and consist of tau-positive without amyloid.
Source: https://neupsykey.com/corticobasal-degeneration/

51. CBD:
A. T1- midsagittal image:
atrophy of the midbrain
tegmentum (arrow).The
area of the midbrain
tegmentum is 73 mm2.
B. macroscopic specimen of
the midbrain shows marked
atrophy (arrow).
C. macroscopic view of the
midbrain shows
discoloration of the
substantia nigra
D. microscopic view of the
substantia nigra shows
argyrophilic threads and
granular or fibrous inclusion
bodies (arrows).
A.M. Tokumaru. Imaging-
Pathologic Correlation in
Corticobasal Degeneration. AJNR.
November 2009, 30 (10) 1884-1892

52. CBD:
84-year-old woman.
A. CoronalT1-weighted image
shows symmetric high
signal intensity bilaterally in
the subthalamic nuclei
(arrows).
B. A macroscopic specimen
shows a brownish change
in the subthalamic nuclei
(arrows).
C. On microscopic examination
(AT8 stain),
antiphosphorylated tau
antibody–positive neurons
and gliosis are observed
A.M. Tokumaru. Imaging-
Pathologic Correlation in
Corticobasal Degeneration. AJNR.
November 2009, 30 (10) 1884-1892

54.  Swedish BioFinder study
 Detect accumulation of Tau in the brain with novel specific PET
radio ligands.
 Used tau-tracer 18F-AV1451 (previously named T807)
 AD: pathology involves hippocampus, temporo-parietal junction,
cingulate cortex
 Tau accumulation in:
 Motor/ sensory cortex: CBD
 Limbic region/ hindbrain: PSP pathology
http://biofinder.se/data-biomarkers/tau-pet-imaging/

55.  Progressive Supranuclear palsy
 Classically characterized by:
√ Symmetric
√ Akinetic-rigid syndrome +
√ Recurrent, Unexplained falls
√ Gaze restriction (DOWNgaze), Poor levodopa response
B. PSP
J. Clifford Richardson Pathologist Jerry Olszewski Neurologist John C. Steele

56.  Taupathies
 4R (4-repeat) taupathies
 Similar areas of brain (cortex, brainstem)
 CBD: more tau in motor and sensory cortex
 PSP: more in limbic, hindbrain, pontine, inferior olivary, dentate
 Both have distended/ ballooned nuclei
 Subthalamic nuclei involvement
 HMF: Executive function, language and visuo-spatial
 Behavioural and cognitive dysfunction
 Can mimic bvFTD
CBD and PSP

57. Dickson, D.W., Ahmed, Z., Algom, A.A., Tsuboi, Y., & Josephs, K.A. (2010). Neuropathology of variants of
progressive supranuclear palsy. Current opinion in neurology, 23 4, 394-400 .

58. Adam Boxer.Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. The Lancet Neurology. 2017; 16(7)

59.  4R- taupathy
 Globose NFT tangles in subcortical centres:
 Globus pallidus, STN and substantia nigra
 Also affects cortex, pontine nuclei, olivary and dentate nuclei
 Neuronal loss correlates with NFT, rather than astrocytic pathology
 Tufted astrocytes also seen.
Pathology
H&E stain
distended neurons
with globose NFT
Bodian stain Tau positivity
https://path.upmc.edu/cases/case238/micro.html

60. PSP
Humming bird/
Penguin bird
sign on mid-
sagittal view.
Beak formed by MB
tegmentum, head
by rostral MB, body
by pons, wings by
cerebellum.
Mickey mouse
and morning
glory flower sign
on axial cuts of
midbrain due to
selective atrophy of
tegmentum,
preserved tectum
and peduncles.
Menoufia Medical Journal. 2017; 30(1): 325-26, https://teddybrain.wordpress.com/2013/01/02/hummingbird-sign-and-mickey-mouse-sign/

61. PSP – PIMPLE SIGN:
Figure shows pimple sign absent,
possible or definite in PSP-
syndromes.
Pimple sign refers to focal area of
midbrain hypometabolism on PET.
Botha, Hugo et al.The pimple sign of
progressive supranuclear palsy syndrome.
Parkinsonism & Related Disorders.Volume
20 , Issue 2 , 180 - 185

62.  Taupathy
 “Dementia of frontal type”
 “Non- Alzheimers dementia”
 Arnold Pick: Czeck Psychiatrist (1892)
 Described a patient of progressive aphasia
 A.w. frontal and temporal lobe atrophy.
 1911: Alois Alzheimer: described pathological
 Hallmark – Pick bodies: rounded inclusions.
 1982: Mesulam: coined the term ‘PPA’
C. FTD

63.  FTD: clinical syndromes, characterized by degeneration of the
frontal and temporal lobes.
 FTLD: Pathological syndromes a.w. FTD
 Early-onset dementia
 45-65 years: prevalence of AD and FTD almost same
 Median survival: 6 years
 But FTD-MND patients: 3 years
 3 clinical variants of FTLD: bvFTD, PNFA, semantic dementia
FTD

65. International Conference on Frontotemporal Dementias 2014. https://www.alzforum.org/print-series/338771

66. International Conference on Frontotemporal Dementias 2014. https://www.alzforum.org/print-series/338771

67.  Characterised by change in behaviour and personality
Disinhibition
Executive dysfunction: poor planning, loss of judgement
Difficulty with organization
Loss of insight
Social inhibition/ isolation
Anti-social behaviour
Peculiar affiliations
OCD/ alcohol abuse, drug use
 So these patients may be diagnosed as a primary psychiatric
disorder like bipolar/ schizophrenia.
bvFTD

68. bvFTD clinical features
Executive dysfunction Change in personality Psychiatric Others
 Poor planning Social isolation Apathy MND
 Loss of judgement Peculiar affiliations Inertia ↓Pain response
 Difficulty organization  Anti-social behaviour Obsessive, compulsive
 Loss of insight  Socially inappropriate behaviour Loss of concern for family
 Lack empathy  Loss of manners/ decorum Utilization behaviour
Inappropriate, rash, impulsive decisions Perseverative behaviours
Altered eating patterns
Change in dietary preference
ꝉ Interest in sweets, overeating
 Language deficits occur but are not presenting complaints
 Neuropsychological testing in early disease may be normal
 Less episodic memory impairment than AD or semantic variety PPA.

69. International Consensus Criteria for bvFTD
 Neurogenerative disease Progressive deterioration of the behaviour and/or cognition
 Possible bvFTD 3 of the following 6 behavioural/ cognitive
A. Early behavioural disinhibition: (one of the following)
A.1. Socially inappropriate behaviour
A.2. Loss of manners or decorum
A.3. Impulsive, rash, careless actions
B. Early apathy or inertia: (one of the following)
B.1. Apathy
B.2. Inertia
C. Early loss of sympathy or empathy: (one of the following)
C.1. diminished response to other peoples needs and feelings
C.2. diminished social interest, inter-relatedness or personal warmth
D. Early perseverative, stereotyped or compulsive/ ritualistic behaviour:
D.1. Simple repetitive movements
D.2. Complex, compulsive, ritualistic behaviour
D.3. Stereotypy of speech
E. Hyperorality and dietary changes: (one of the following)
E.1. Altered food preference
E.2. Binge eating, increased comsumption of alcohol, cigarettes
E.3.Oral exploration or consumption of inedible objects

70. International Consensus Criteria for bvFTD
 Possible bvFTD 3 of the following 6 behavioural/ cognitive
F. Neuropsychological profile: executive/ generation deficits with relative
sparing of memory and visuo-spatial function (all of the following)
F.1. Deficits in executive tasks
F.2. Relative sparing of episodic memory
F.3. Relative sparing of visuo-spatial skills
 Probable bvFTD All of the following should be present
A. Criteria for possible bvFTD
B. Exhibits significant functional deficits
(by caregiver report/ or evidenced by Clinical dementia rating scale/ or Functional
ActivitiesQuestionnaire scores)
C. Imaging results consistent with bvFTD (one of the following):
C.1. Frontal and/or anterior temporal atrophy (CT or MRI)
C.2. Frontal and/or anterior temporal hypoperfusion or hypometabolism
 bvFTD with definite FTLD
pathology
A. Meets criteria for possible or probable FTD + one of
B. Histopathological evidence of FTLD on biopsy/ post-mortem
C. Presence of known pathogenic mutation

71. International Consensus Criteria for bvFTD
 Exclusion criteria for bvFTD A and B should be negative for any bvFTD
C should be negative for probable bvFTD, maybe positive for possible FTD
A. Pattern of deficits is better accounted for by other non-degenerative nervous
system or medical disorders
B. Behavioural disturbance is better accounted for by a psychiatric disorder
C. Biomarkers strongly indicative od AD or other neurodegenerative process

72. fvAD bvFTD
1. Memory Early loss of memory Late
2. Language Phonemic and semantic paraphasia Loss of socio-emotional aspect of speech
3. Fluency Semantic > phonemic impaired Phonemic > semantic fluency impaired
4. Behaviour Compulsive or perseverative
behaviours uncommon
Collection/ hoarding, ritualistic and dis-
inhibited behaviours (involves food)
5. Personality Agitation and irritability Apathy, dis-inhibition, loss of empathy
6. Thought content Delusions (theft/ infidelity/ paranoid) Mental rigidity
7. Body habitus Depression + wt loss Hyperphagia + wt gain
8. Movement disorder Myoclonus
9. Parkinsonism Late Early
10. MRI Symmetrical atrophy
Temporal > frontal
Post. Callosum, perisylvian
Symmetrical (MAPT)
Asymmetrical (PGRN)
11. CSF P-tau/Aβ 42 ratio: >0.21 ng/ml CSF progranulin levels <60 ng/ml
12. Biomarkers Apoє 4 positive Negative
Russell Sawye. Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road. Journal of Clinical Movement Disorders (2017) 4:2

73. A. fvAD Scarecrow
was searching for a brain because he had
none, and without a brain he cant
consolidate memory or object knowledge.
While his phonemic fluency was
preserved, fvAD Scarecrow had difficulty
with semantics and was irritable and
paranoid, believing the crows were gearing
to bothering and stealing from him. He
was very tremulous.The wind could
suddenly jolt him (stimulus-sensitive
myoclonus)
B. bvFTDTin Man had no heart,
so his behavior and emotions were
affected from the outset.The “heartless”
bvFTDTin Man lacked empathy and was
very ritualistic, only going out to chop
wood.
His rituals included hyperphagia, making
him heavier than the straw-filled fvAD
Scarecrow. Furthermore, bvFTDTin Man
was insufficiently lubricated, making him
appear parkinsonian. He was missing
PGRN and his frontotemporal region
asymmetric, as judged by a crooked hat.Russell Sawye. Journal of Clinical Movement Disorders (2017) 4:2

74. Russell Sawye. Diagnosing the frontal variant of Alzheimer’s disease: a clinician’s yellow brick road. Journal of Clinical Movement Disorders (2017) 4:2

75. bvFTD svPPA Agrammatic/ nPPA
1. % of FTD 50% 25% 25%
2. Pathology Tau- orTDP-43 TDP type C Tau-
3. Anatomy Insula, amygdala, orbito-frontal,
anterior cingulate cortex
L.Anterior temporal L. Inferior frontal
4. Behaviour Aberrant Normal, early Normal, early
5. Fluency Fluent Fluent Non-fluent
6. Naming Normal Some anomia Some anomia
7. Repetition Normal Fluent Non-fluent
8. Comprehension Normal Impaired Intact for simple items
9. Reading Normal Surface alexia Intact for short items
10. Diet ↑Sweets, overeat Develop food fads
Cristian E Leyton. Frontotemporal dementias: Recent advances and current controversies. Ann Ind Acad Neurol. 2010 (13).
Howard S Kirshner. Frontotemporal dementia and primary progressive aphasia, a review. Neuropsychiatric Disease and Treatment. 2014; 10

76.  Primary Progressive Aphasia.
 Refers to a group of disorders where neuro-degeneration targets
the language network.
 Two variants: PNFA/ agrammatic nPPA and Sematic variant come
under the umbrella of FTD
 The Logopenic variant is mostly caused by the Alzheimer’s
pathology and is a variant of AD
PPA

77. Agrammatic non-fluent PPA
 Insula
 Inferior frontal involvement
 Left sided
Semantic variant PPA
 Anterior temporal involvement
 Left sided > right
Logopenic variant PPA
 Alzheimer's pathology
 Inferior parietal
 Posterior temporal
Miguel Angel Santos Santos. Clinocopathological correlations and neuroimaging biomarkers in PPA. University of Barcelona. 2017
https://ddd.uab.cat/pub/tesis/2017/hdl_10803_457508/mass1de1.pdf

78.  Progressive agrammatic/ nonfluent aphasia.
 Nonfluent hesitant speech
 Agrammatism: telegraphic speech, misuse of pronouns
 Errors in sentence construction
 Word and object knowledge is relatively preserved
 Apraxia of speech may co-occur
 Comprehension for complex sentence may be impaired
 Overtime, patients develop Parkinson’s syndrome
nPPA

79.  Semantic variant PPA.
 Fluent aphasia.
 Prominent Anomia, with loss of single word meaning
 Nouns are particularly difficult to comprehend
 Patient will replace a specific word with more general words
 Like replace the word “mobile” with “it” or “this”
 Grammar intact,
 Repetition is relatively spared
svPPA

80.  Surface dyslexia
 Characterised by regularization errors.
 Selective impairment in reading words with exceptional spelling-to-
sound correspondences (irregular words),
 where they are ‘over-generalized’ and pronounced as they are spelled
(e.g., ‘sew’ pronounced ‘sue’)
 “Colonel”, “yacht”, “pint”
 Anterior temporal atrophy (L>R)
 R. temporal involvement: prosopagnosia, loss of visual object meaning
svPPA

81.  CT/ MRI brain
 Functional Imaging: PET/ SPECT
a. bvFTD: b/l fronto-temporal hypometabolism
b. PPAOS: focal hypometabolism in supplementary motor
cortex and superior premotor cortex
c. svPPA: anterior temporal hypometabolism
d. nfPPA: inferior frontal hypometabolism
 PiB-PET
 Lab: serum and CSF studies normal
 Serum Progranulin levels
 Plasma and CSF TDP-43 levels
Investigations

82. bvFTD
Significant atrophy of the mesial frontal cortex, the
anterior cingulate gyrus (yellow)
https://www.neurologyadvisor.com/slideshow/neurodegenerative-diseases/when-
its-not-alzheimers-differential-dx-of-frontotemporal-lobar-degeneration/
Significant atrophy of the right temporal cortex (yellow)
with enlarged temporal horn of lateral ventricle
B. Dewer et al. / Clinical Radiology 71 (2016) 40-47

83. Coronal T1-weighted brain MRI sections. Nonfluent–agrammatic variant primary
progressive aphasia (nfvPPA), showing asymmetric (predominantly left sided)
inferior frontal, insular and anterior–superior temporal gyrus atrophy;
Semantic variant primary progressive aphasia (svPPA), showing asymmetric
(predominantly left sided) anterior inferior and mesial temporal lobe atrophy;
Logopenic variant primary progressive aphasia (lvPPA), showing atrophy
predominantly involving left temporo-parietal junction (posterior–superior temporal
and inferior parietal cortices).
a, amygdala; ATL, anterior temporal lobe;
BG, basal ganglia; h, hippocampus; IFG,
inferior frontal gyrus/frontal operculum;
ins, insula;OFC, orbitofrontal cortex;
PMC, posterior medial cortex (posterior
cingulate, precuneus); STG, superior
temporal gyrus;TPJ, temporo-parietal
junction
Charles R. Marshall. Primary progressive aphasia: a clinical approach. Journal of Neurology. June 2018,Volume 265

84.  40% FTD: positive family history
 Autosomal Dominant
 3 major genes a.w. FTD
a) MAPT: 5-10%
b) Progranulin: 10%
c) Chromosome 9 open reading frame 72 (c9orf72): 15%
 Other genes implicated:
a) Charged multivesicular body protein 2B (CHMP2B) – chr 3
b) Valosin containing protein (VCP) – chr 9
c) TAR binding protein (TDP43) mutations
 Inclusion body myopathy
 FTD VCP mutations
 Pagets disease of bone
Genetics

85.  FTP and parkinsonism linked to chromosome 17
 Refers to MAPT and progranulin
MAPT mutations
 First diagnosed genes
 Behavioural and personality changes, a.w. parkinsonism
 Anterior temporal atrophy is characteristic
 Chromosome 17
 Median onset: 45 years
 Median survival: 7 years
 MAPT a.w. FTD, CBS, PSP-S
FTD-P-17

86.  FTP and parkinsonism linked to chromosome 17
 Refers to MAPT and progranulin
Progranulin (PGRN) mutations
 Clinical variability +
 Low plasma progranulin levels detected in patients
 Asymmetric fronto-parietal and posterior temporal atrophy
 Chromosome 17
 Median onset: 59 years
 Median survival: 6 years
 PGRN a.w. bv-FTD, PPA, AD-dementia
FTD-P-17

87.  FTP and parkinsonism linked to chromosome 17
 Refers to MAPT and progranulin
Progranulin (PGRN) mutations
 Progranulin acts as growth factor with anti-inflammatory properties
 It is expressed in neurons and glia
 Neuronal PGRN regulates synaptic function
 It has neuroprotective and neurrotrophic properties
 Haploinsufficiency (mutations) cause reduced PGRN levels
 Cause loss of trophic support ---> neuronal loss
 A.w. other autoimmune diseases and ꝉ TNF-α levels
FTD-P-17

88. Model of intracellular processing of
PGRN into stable, lysosomal
GRNs. Sortilin and other receptors
target endocytosed and newly
synthesized PGRN to lysosomes.
Within lysosomes, PGRN is
proteolytically cleaved, in part, by
cysteine proteases into mature,
stable GRN proteins.
Ablation of sortilin results in the
reduced production of GRNs.
Further, lysosome dysfunction
caused by alkalizing agents or
TMEM106B overexpression
inhibits the processing of PGRN
into GRNs.
FTD-GRN patients are
haploinsufficient for GRNs, which
may drive lysosome dysfunction
leading to neurodegeneration.
Christopher J. Holler. eNeuro. 9August 2017, 4 (4)

89.  Most common cause of FTD-MND/ FTD-ALS
 Non-coding repeat expansion in chromosome 9
 Normal ppl: 2-23 copies of GGGGCC repeats
 FTD/MND: have hundreds- thousands repeats
 MC phenotype associated is bvFTD
 FTD or parkinsonism or psychosis
 c90rf72 a.w. bv-FTD, PD, CBS, AD-dementia
 C90rf72 also the most common cause of Huntington's chorea
 Repeat length does not determine the phenotype
 Onset: 52 years, Survival 5 years
C9ORF72

90. Genetic FTD:
1. MAPT mutations demonstrate
symmetrical atrophy in ventral
frontotemporal regions,
particularly in the anterior
temporal poles.
2. GRN mutation carrier
demonstrates marked
Asymmetrical atrophy, most
notable in dorsal, frontotemporal
regions, with additional
involvement in posterior areas.
3. C9ORF72 expansion shows
diffuse, symmetrical atrophy in
frontal, temporal, and parietal cortical
regions as well as cerebellum.
Yokoyama JS. Neuroimaging features of C9ORF72
expansion. Alzheimers Res Ther. 2012;4(6):45.

91.  Like 3 mutations, 3 major proteins are a.w. FTLD
a) Tau (FTLD-tau) – 40%
b) TAR DNA binding protein of 4.3 kd (FTLD-TDP) – 50%
c) Fused in sarcoma protein (FTLD-FUS) – 9%
FTLD-tau:
 Picks disease is the prototype 3R-taupathy
 Picks disease accounts for <5% of all FTLD
 Picks disease gross atrophy: knife edge like
 Histology: pick bodies – circumscribed tau positive inclusions
 Also seen are ballooned neurons
Pathology

92. Gross pathology, Picks disease (FTD):
Knife-edge like atrophy of frontal lobe
Pick cells: ballooned
neurons
with dissolution of
chromatin
Pick bodies: tau-positive, spherical
cytoplasmic neuronal inclusions,
composed of straight filaments
http://neuropathology-web.org/chapter9/chapter9cFTD.html, http://frontalcortex.com/?page=oll&topic=24&qid=1278

93.  Like 3 mutations, 3 major proteins are a.w. FTLD
a) Tau (FTLD-tau) – 40%
b) TAR DNA binding protein of 4.3 kd (FTLD-TDP) – 50%
c) Fused in sarcoma protein (FTLD-FUS) – 9%
FTLD-TDP:
Pathology
Type A Type B Type C
• Neuronal inclusions
• Intranuclear inclusions
• Dystrophic neurites
Neuronal cytoplasmic
inclusions
Neurites and
Pick bodies
Progranulin mutations C9ORF72 VCP mutations
Less likelyC9ORF72 C9ORF72 have classical
cerebellar inclusions
a.w. FTD-MND Semantic PPA

94. NormallyTDP 43 resides inside nucleus of cell. In neuro-
degeneration, it relocalizes to cytoplasm, forms inclusions,
gets cleaved, hyper-phosphorylated and aggregates.
Tau-protein is dissociated from microtubules and accumulates
into pathogenic tangles in the cytoplasm.
Hock EM. J Neurochem. 2016 Aug;138 Suppl 1:163-83

95.  Like 3 mutations, 3 major proteins are a.w. FTLD
a) Tau (FTLD-tau) – 40%
b) TAR DNA binding protein of 4.3 kd (FTLD-TDP) – 50%
c) Fused in sarcoma protein (FTLD-FUS) – 9%
FTLD-FUS:
Pathology
Neuronal filament Basophilic inclusion A-FTLD-U
Neuronal filament inclusion
disease
Basophilic inclusion
disease
Atypical FTLD with
May also be a.w.
• MND
• Parkinsonism
ubiquitin only
immuno-reactive
changes
Inclusions reactive to neuro-
filament + alpha- internexin
Inclusions +, not reactive
to neurofilament
Does not have
inclusions

96.  Loss of C9orf72 protein function
 10-15% FTDs
 Decreased survival (<3 years)
 MND with bvFTD has a longer survival than MND with the
language FTDs
 Subtle cognition and executive dysfunction is now increasingly
identified in MND
FTD-MND

97. Clinical, Genetic, and Pathological
Overlap of ALS and FTD
ALS and FTD represent a
continuum of a broad
neurodegenerative disorder with
each presenting as extremes of a
spectrum of overlapping clinical
symptoms.
Major known genetic causes for
ALS and FTD are plotted according
to the ratio of known mutations.
(B) Pathological protein inclusions
in ALS and FTD, according to the
major protein misaccumulated.
Inclusions of TDP-43 and FUS/TLS
in ALS and FTD reflect the
pathological overlap of ALS and
FTD.
From: Ling SC, Polymenidou M, Cleveland
DW. Converging mechanisms in ALS and FTD:
disrupted RNA and protein

98.  NO FDA approved drugs for FTD
 SSRI improve behavioural function (Huey et.al. 2006)
 Antipsychotics increase risk of death
 So FDA has issued warning against them
 Non-pharmacological interventions:
 Home safety evaluation
 Removal of weapons from home
 Family education, caregiver support
 Physiotherapy, speech therapy etc.
Treatment

101. THANKYOU!