1. neurodegenerative BRAIN DISORDERS
Postgraduate Interuniversity Course Human Genetics 08/12/2017
neurodegenerative BRAIN DISORDERS
Bart DERMAUT, MD, PhD
----- Notulen (1/06/16 18:06) -----
Since I'm more fluent In English when discussing science, I will give this presentation in English. First of all, I want to thank the commission for selecting me to do this audition to obtain a DR position. My name is B. D. and I currently work at the Institut Pasteur de Lille. The title of my presentation is "Understanding ..."
Centrum Medische Genetica Gent, UZ Gent, B

2. Related disorders: frontotemporal dementia –ALS spectrum
outline
Introduction
Alzheimer’s disease
Related disorders: frontotemporal dementia –ALS spectrum

3. Related disorders: frontotemporal dementia –ALS spectrum
outline
Introduction
Alzheimer’s disease
Related disorders: frontotemporal dementia –ALS spectrum

4. Neurodegenerative Brain disorders
normal
patient
societal problem is huge:
Aging population – 65+ :
16% (2015)  25% (2030)
dementia:
44 million (2014)  66 million (2030)
limited therapeutic options
genetically heterogeneous
progressive loss of neurons, neuronal function
divers:
frequent: Alzheimer (60-70%), frontotemporal dementia (<5%), Parkinson (10%)
rare: prion disorders, motor neuron disease, Huntington’s disease, …
25/04/17

5. Neurodegenerative Brain disorders
Chronic and progressive disorders
Progressive and selective loss of neurons
Motor, sensorial and cognitive system
Nosological classification following pattern of
neuronal loss and disease specific cellular markers
Neurodegenratieve aandoeningen wat zijn dat
Worden gekenmerkt door
Nosologische klassificatie: indeling in verschillende ziektetypes
op basis van patroon van verlies van neuronen
en specifieke ziektemerkers
AD: senile plaques, neurofibrillary ‘tangles’
neuronal loss
PD: Lewy bodies, depletion of dopaminergic neurons
ALS: cellular inclusions, axon swelling of
motor neurons
HD: nuclear inclusions, loss of striatal neurons
Martin J.B., NEJM 340: (1999)

6. Neurodegenerative Brain disorders
General introduction
Causes
Genetic factors
-Mendelian inheritance – monogenic:
rare familial forms of common disorders
classic monogenic e.g. repeat expansion disorder
-Multifactorial - common disorders:
several genes contribute to disease
variation in age of onset and progression point to different pathogenetic mechanisms (e.g. AD)
Environment: toxic or metabolic processes, infection, unknown

7. Patient L.D.B.  diagnosis early-onset dementia: subtype?
male, 56 years, negative neuropsychiatric history
admitted to emergency psychiatric service after car accident:
restless, incoherent thinking, stereotypical vocabulary, word finding problems
known to the police: shoplifting, aggressiveness, dangerous driving behavior
normal
patient
According to brother: last 3 yrs increasing compulsive behavior, conflicts, emotional flattening, contentless speech, memory problems
Brain imaging: atrophy of the frontal and temporal lobes
mother, maternal grantfather both demented < 65 yrs
normaal
patient L.D.B.
 diagnosis early-onset dementia: subtype?

8. Under the microscope… neuropathologist
normal
patient
neuropathologist
frontal lobe dementia or Alzheimer ?

9. CLUMPING PROTEINS Alzheimer’s disease Amyloid plaques Tau tangles
normal
patient
Alzheimer’s disease
Amyloid plaques
Tau tangles
AND
Auguste Deter
Aloïs Alzheimer
( )
Alzheimer A. Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-gerichtliche Medizin Jan ; 64:146-8.

10. CLUMPING PROTEINS
normal
patient
Aloïs Alzheimer
( )

11. CLUMPING PROTEINS Frontal lobe dementia Amyloid plaques Tau tangles
normal
patient
Frontal lobe dementia
Amyloid plaques
Tau tangles
Arnold Pick
( )

12. CLUMPING PROTEINS Frontal lobe dementia Tau tangles Arnold Pick
normal
patient
Frontal lobe dementia
Tau tangles
Arnold Pick
( )

13. CLUMPING PROTEINS Frontal lobe dementia Tau tangles Arnold Pick
normal
patient
Frontal lobe dementia
Tau tangles OR
Arnold Pick
( )
TDP-43 inclusions

14. CLUMPING PROTEINS Frontal lobe dementia Patient L.D.B. Tau tangles
normal
patient
Frontal lobe dementia
Tau tangles
Patient L.D.B. OR
Arnold Pick
( )
TDP-43 inclusions

15. CLUMPING PROTEINS Frontal lobe dementia Patient L.D.B. Tau tangles
normal
patient
Frontal lobe dementia
Tau tangles
Patient L.D.B. OR
Arnold Pick
( )
TDP-43 inclusions

16. CLUMPING PROTEINS Frontal lobe dementia Patient L.D.B.
normal
patient
Frontal lobe dementia
Tau tangles
Patient L.D.B.
Arnold Pick
( )
defect in the Tau gene
 Tau-positive familial frontal lobe dementia

17. Related disorders: frontotemporal dementia –ALS spectrum
outline
Introduction
Alzheimer’s disease
Related disorders: frontotemporal dementia –ALS spectrum

18. Alzheimer’s disease Prevalence strongly increases with age
70% are Alzheimer’s disease cases
(860,000 cases in France in 2005)
Alzheimer’s disease (AD) => characterized in the brain by :
Neurofibrillary degeneration Amyloid deposition
Intraneuronal accumulation of hyperphosphorylated Tau
Extracellular accumulation of amyloid peptides

19. Alzheimer’s disease Alzheimer disease Disease characteristics
adult-onset slowly progressive dementia (memory,
cognition, personality)
most frequent form of dementia
>60 y: 5-10%, >85 y: 45%
4 mill/y, /y in US, cost 60 miljard US dollar
25% of cases familial
- mostly late onset
- < 2% early-onset familial AD (EOFAD)
symptoms typically < 65 y
Cacace et al, 2016

20. Alzheimer’s disease Clinical features
dementia, typically begins with subtle and poorly recognized failure of memory
other common symptoms: anxiety, confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations
occasional symptoms: seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, mutism
death usually results from general inanition, malnutrition, pneumonia
typical clinical duration of the disease: 8-10 yrs, range: yrs
post mortem: macroscopic - microscopic

21. Alzheimer’s disease near and connected to hippocampus
learning processes, short term memory and conversion to long term memory in other parts (olfactory bulb, amygdala, nucleus basalis)

22. Alzheimer’s disease - Genetics
Alzheimer disease
Cacace et al, 2016
Christine Van Broeckhoven

23. Alzheimer’s disease - Genetics
Alzheimer disease
Cacace et al, 2016

24. Alzheimer’s disease - APP
Cacace et al, 2016

25. Alzheimer’s disease – PSEN1/2
Cacace et al, 2016

26. Alzheimer’s disease – APP - PSEN1/2 link
Bart De Strooper

27. Alzheimer’s disease – APP - PSEN1/2 link
Genetic counseling
first degree relatives of individuals with sporadic AD
have about a 20% lifetime risk of developing AD
presumably, when several individuals in a family have
AD, the risk is further increased
EOFAD is inherited in an autosomal dominant manner
The risk to offspring of individuals with EOFAD is
50%

28. Late-onset Alzheimer’s disease genetics: APOE
Liu et al, 2013
Credit: alzdiscovery.org/

29. Late-onset Alzheimer’s disease genetics: GWAS
Meta-analysis: individuals
Consortium>250 collaborators
Lambert et al, Nat Genet 2013

30. Alzheimer’s disease GWAS – “causal” gene/variant?
Clear!
Unclear!

31. Alzheimer’s disease GWAS – genetic landscape
APP, PS1
PS2
APOE
TREM2
ABCA7, APOE, BIN1, CASS4, CD2AP, CELF1, CLU, CR1, EPHA1, FERMT2, HLA-DRB1, INPP5D, MEF2C, MS4A6A, NME8, PICALM, PTK2B, SLC24A4, SORL, ZCWPW1
Less than 1% of the cases are monogenic forms.
The genetic attributable risk has been estimated between 60 and 80% and to date, 22 loci have been associated with AD risk.

32. Alzheimer’s disease GWAS – therapeutic strategies
Current (symptomatic) therapy
cholinergic replacement (cholinesterase inhibitors)
Therapies under development
inhibition of -secretases (PS1)
inhibition of -secretase
stimulate -secretase
Inhibit fibril formation and disaggregate amyloid
Immunization against -amyloid

33. Related disorders: frontotemporal dementia –ALS spectrum
outline
Introduction
Alzheimer’s disease
Related disorders: frontotemporal dementia –ALS spectrum

34. FTD – aLS spectrum

35. FTD – aLS spectrum
Science Feb 20;235(4791):
The genetic defect causing familial Alzheimer's disease maps on chromosome 21. St George-Hyslop PH, Tanzi RE, Polinsky RJ, Haines JL, Nee L, Watkins PC, Myers RH, Feldman RG, Pollen D, Drachman D, et al. Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease
Nature Sep 10-16;329(6135): The genetic defect in familial Alzheimer's disease is not tightly linked to the amyloid beta-protein gene. Tanzi RE, St George-Hyslop PH, Haines JL, Polinsky RJ, Nee L, Foncin JF, Neve RL, McClatchey AI, Conneally PM, Gusella JF.
Although tau neurofibrillary tangles appear to be one of the causes of the neuronal degeneration in AD, mutations in the tau gene are associated not with AD, but with another autosomal dominant dementia, FTD

36. Major neurodegenerative diseases = proteinopathies
Parkinson’s disease:
Lewy bodies (a-synuclein)
Alzheimer’s disease:
Amyloid plaques (Ab peptide)
Tau tangles (tau)
Frontotemporal dementia
Tau tangles/Pick bodies (tau)
Ubiquitin(+) inclusions (TDP-43)
Amyotrophic lateral sclerosis
2006

37. FTD – aLS spectrum
TDP-43

38. Major neurodegenerative diseases = proteinopathies
Parkinson’s disease:
Lewy bodies (a-synuclein)
Alzheimer’s disease:
Amyloid plaques (Ab peptide)
Tau tangles (tau)
Frontotemporal dementia
Tau tangles/Pick bodies (tau)
Ubiquitin(+) inclusions (TDP-43)
Amyotrophic lateral sclerosis
disease causing
mutations !
2008

39. FTD – aLS spectrum: TDP-43
ALS-causing mutations

40. ALS-FTD genetics: C9orf72 hexanucleotide expansions
Neuron 2011
Rosa Rademakers

41. ALS-FTD genetics: C9orf72 hexanucleotide expansions
Lancet Neurology 2012
Christine Van Broeckhoven

42. ALS-FTD genetics: C9orf72 hexanucleotide expansions

43. ALS-FTD genetics

44. ALS-FTD genetics