pathological classification of movement disorders

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