pathological classification of movement disorders
TRANSCRIPT
Pathological Classification of Movement Disorders
Lisboa, 8 de Fevereiro 2017
Ricardo Taipa, MD, PhD
Neuropatology Unit / Portuguese Brain Bank
Departament of Neurosciences
Centro Hospitalar Universitário do Porto
Movement Disorders
✓ Hypokinetic rigid syndromes
✓Parkinsonian syndromes
✓ Hyperkinetic
✓Chorea, dystonia, ballism, myoclonus, tremor, tics
✓ Mixed forms
Dysfunction of basal ganglia, thalamus, brainstem nuclei, cerebellar cortex and
nuclei, mortor cortical areas and lower motor neurons of the spinal cord
Jellinger K, J Neural Transm, 2019Kovacs GG, J Clin Pathol, 2019
Kovacs G, Int J Mol Sci, 2016
Neuropathological diagnosis
Love S, 2004
Anatomical functional systems
(Dysfunction of the cortico-basal ganglia-thalamocortical circuits)
1st level
Kovacs G, Int J Mol Sci, 2016
Neuropathological diagnosis
Cellular vulnerability
2nd level
Neurons or glial cells / groups of neurons
PBB archive
NFT (neurons)
Gallyas
Astrocytic plaque
Gallyas
Kovacs G, Int J Mol Sci, 2016
Neuropathological diagnosis
Proteinopathy
3rd level
PBB archive
Aβ TAU
TDP43α-syn
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
Progressive Supranuclear Palsy
Kovacs GG et al,Acta Neuropathol, 2020
Neuropathology hierarchical progression
✓ disease specific
✓ relation with clinical phenotype and disease progression
Parkinson´s disease
Braak et al, Neurobiol Aging, 2003
Neuropathological diagnosis
Clinical symptoms are determined by the anatomical region showing neuronal
dysfunction and not necessarily by the distribution of the altered protein
Importantly, some forms of NDD (hereditary spastic paraplegia, some spinocerebellar
ataxias, etc.) no specific protein inclusions are detected by currently available methods
Kovacs GG, J Clin Pathol, 2019
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
α-Synucleinopathies α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
PBB archive
Brás et al, Acta Neuropathol, 2020
‘Synucleinopathies’ is an umbrella term grouping together different
diseases in which the pathological aggregates of ɑ-synuclein are a
defining characteristic
Parkinson´s disease, PD dementia, Dementia with Lewy bodies, MSA
α-Synucleinopathies
Taipa et al, Frontiers in Dementia, 2012 PBB archive
Lewy body pathology (neuron)
Parkinson´s D. / PDD / D. Lewy Bodies
Glial cytoplasmatic inclusions
Multiple System Atrophy
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
α-Synucleinopathies
Taipa et al, Frontiers in Dementia, 2012
Lewy body pathology
Adler et al, J Neuropathol Exp Neurol, 2019
Classification based in clinical data- Parkinson´s disease - PD with dementia- Dementia with Lewy Bodies
PBB archive
Timeline of development of synpathology across different brain regions
α-Synucleinopathies
Genetic Parkinson´s disease
Taipa et al, Brain, 2016
There are forms of PD that do not have LBs(Jiang and Dickson 2018)
Taipa et al, Frontiers in Dementia, 2012
Lewy body pathology
PBB archive
α-Synucleinopathies
PBB archive
Glial cytoplasmatic inclusionsMultiple System Atrophy clinical subtypes
MSA-P (parkinsonism dominant) MSA-C (cerebellar dominant)
Striatronigral Olivopontocerebellar
Distribution of glial inclusions
Jellinger et al, Mov Disorders, 2005
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
Tauopathies
Group of adult onset neurodegenerative diseases including Alzheimer´s
disease and frontotemporal lobar degeneration spectrum diseases
Defined by intracellular aggregation and transcellular propagation of the
microtubule-asssociated protein tau (MAPT)
Rösler et al, Progr Neurobiol, 2019
TAU - AD TAU - PSP
PBB archive
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
Tauopathies
Rösler et al, Progr Neurobiol, 2019
Secondary tauopathiesPrimary tauopathies
3R
4R
Mixed 3R/4R
• Anatomical areas, cell types, tau isoforms• Morphology of tau immunoreactivities
Classification of primary taupathies
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
Tauopathies
Rösler et al, Progr Neurobiol, 2019
Primary tauopathies4R
Gallyas Tau
Gallyas Tau
PSP
CBD
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
PBB archive
Tauopathies
Rösler et al, Progr Neurobiol, 2019
Primary tauopathies3R
Pick´s disease
Taipa et al, Frontiers Neurol, 2012
Mixed 3R/4R
Alzheimer´s disease
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
Tauopathies
Rösler et al, Progr Neurobiol, 2019
Most tauopathies are sporadic
Rare MAPT mutations cause autosomal dominant FTLD
Forrest et al, Brain, 2018
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
TDP43 proteinopathies
ALS and FTLD-TDP are sporadic andfamilial neurodegenerative diseasescharacterized neuropathologically bycellular aggregates of TDP-43.
Kawakami et al., ActaNeuropathol, 2019
Taipa et al; J Alzheimers Dis. 2012
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
TDP43 proteinopathies
James Rowe, Int Rev Neurobiol, 2009
Sousa AL, Taipa R, et al., Neuropathol Appl Neurobiol, 2017
Frontotemporal lobar degeneration-TDP with
“multiple system atrophy phenocopy syndrome”
Hensman Moss DJ et al., Neurology, 2014
2009
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
Den Dunnen, Handb Clin Neurol, 2017
Trinucleotide repeat diseases
CAG-repeat coding for glutamine – common mechanism Many of the trinucleotide repeat disorders cause ataxia
1C2
SCA3AD
α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other
degenerative
Immune disorders
PBB archive
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
Prion diseases α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other
degenerative
Immune disorders
Kovacs and Budka, Int J Mol Sci, 2009Hermann et al, Neurology, 2018
Other degenerative and metabolic disorders α-Syn
Tauopathies
TDP43
CAG repeat disord
Prion
Other degenerative
Immune disorders
Hayflick et al., Handb Clin Neurol, 2018 Li et al., Neuropathol Appl Neurobiol, 2013
Jellinger K, J Neural Transm, 2019
Immune disorders
α-Syn
Tauopathies
TDP43
Prion
CAG repeat disord
Other degenerative
Immune disorders
Secondary parkinsonism
Genetic and molecular-biological classification
α-Synucleinopathies Tauopathies
Polyglutamine repeat (CAG) disorders
(Huntington D, SCA3, DRLPA, ...)
Other hereditary degenerative disorders
(NIBA, Ferritin, Wilson´s disease)
Immune (paraneoplastic or non-paraneoplastic)
Inherited metabolic disorders(Gaucher, Nieman-Pick, …)
Neuropathological diagnosis
Secondary parkinsonism(vascular, drug and toxins)
TDP43 proteinopathies
Prion protein
Unidade de NeuropatologiaPorto and Douro Valley
Portugal