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Neuropathology of Parkinson disease and related disorders

Charles Duyckaerts,

Neuropathology department,

Piti‐Salpetriere Hospital, Paris

59 years

33 years 42 years

Parkinson syndrome

• Akinesia• Rigidity• Tremor

Motor Syndrome

Non-motor Syndrome • Dysautonomia

• Sleep disorders

• Gastrointestinal dysfunction

• Behavioral changes…

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α‐Synuclein immunohistochemistry

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S Nigra

L Coeruleus

DN of the X

S Nigra

L Coeruleus

S Nigra

L Coeruleus

N. basalis of Meynert

Basal magnocellular complex : acetylcholine

α‐synuclein IHC

Amygdala

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CA2‐3

H. Braak et al. Neurobiol Aging 2003; 24 :197-211

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Lewy type inclusions

Lesions Symptoms

Brainstem pigmented nuclei

Substantia nigra Parkinsonism

Locus coeruleus RBD

Dorsal nucleus X,IRZ

Dysphagia / Vegetativesymptoms

NBM Attention deficit, memory trouble

CA2-3 Hallucinations ?

Amygdala Emotion, face perception?

Cortex Dementia

Bulbe Olfactif Anosmia

Clinical data Neuropathology(Kosaka classification)

• Motor symptoms• RBD• Vegetative symptoms

Parkinson diseasedementia

Lewy body dementia

Brainstem type

Transitional type

Diffuse type

• Lewy bodies are found in numerous structures of the central nervous system

• They are associated with neuronal loss (at least in the brainstem and nucleus basalis)

• And with clinical symptoms

Striato-nigral degeneration. R.D. Adams, L. van Bogaert, H. van der EeckenJ Neuropathol Exp Neurol 1964; 23:584-608Dégénérescences nigro-striées et cérébello-nigro-striées.R.D. Adams, L. van Bogaert, H. van der EeckenPsychiatria et Neurologia 1961; 142:219

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Con

trol

Olivo-P

onto-Cerebellar A

.

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19

20

18

16

6

2

8

2

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A neurological syndrome associated with orthostatic

hypotension.

G.M. Shy & G.A. Drager

Arch Neurol 1960, 2, 511

Orthostatic hypotension and nicotine sensitivity in a case of 

Multiple System AtrophyJ. Graham & D.R. OppenheimerJ Neurol Neurosurg Psychiat 1969; 32:28

Shy & Drager

OPCASND

MSA

PC

A

Papp M.I., Kahn J.E., Lantos P.L. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellaratrophy and Shy-Drager syndrome). J. Neurol. Sci., 1989,94, 79-100.

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Oligodendroglial inclusionsWhere ?

Spino-reticularSpino-olivarySpino-cerebellar

Cortico-pontineCortico-bulbarCortico-spinal

Ponto-cerebellarOlivo-cerebellarReticulo-cerebellar

Data from Braak et al., 2003

Alpha-synuclein in glial inclusions of MSA

Arima et al. Acta Neuropathol 1998; 96:439-444Gai et al. Lancet 1998; 352: 547-548

Spillantini et al. Neurosci Lett 1998; 251:205-208Tu et al. Ann Neurol 1998; 44:415-422

Wakabayashi et al. Neurosci Lett 1998; 249: 180-182

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Progressive supranuclear palsy : a heterogeneous degeneration involving the brainstem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuclear dystonia and dementia

Steele JC, Richardson JC, Olzewski J

Arch Neurol 1964 ; 10:333‐359

Rev Neurol (Paris) 1926; 2: 410-418.PAGF=Pure Akinesia with Gait Freezing

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Pallidum Tau Pallidum

Neuron(NFT)

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Coiled body

Putamen

Astrocytes(Tufted astrocytes)

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Normal

Affected

The common view in the 70s

Cortical NFT

Brain 1996 119: 1123‐1136.

The significance of cortical pathology in 

progressive supranuclearpalsy.

Verny M., Duyckaerts C., Agid Y., Hauw J.‐J.

Tau IHC

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Rebeiz J J, Kolodny E H and Richardson E P (1968). Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18: 20‐33.

Gibb WR, Luthert PJ, Marsden CD. Corticobasal degeneration. Brain. 1989 Oct;112 ( Pt 5):1171‐92. 

pTau AT8 pTau AT8

pTau AT8

Cortico-basal degeneration

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PSP DCBM. Tolnay & A. Probst Neuropathol Appl Neurobiol 1999; 25:171-187

Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration:tau pathologies with exclusively "exon 10" isoforms.

Sergeant N, Wattez A, Delacourte A

J Neurochem 1999 72:1243‐1249

Tau 4 répétitions avec exon 10

Tau 3 répétitions sans exon 10

Conclusions

Parkinson disease

GlialNeuronal

MSA

+

+Synucleinopathy

PSP

DCB

(+)

(+)

+

+

+

+

4R‐ tauopathy

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Dorsal nucleus of the vagus nerve

Locus coeruleus : noradrenalin.coeruleus - subcoeruleus complex : sleep regulation Substantia nigra - Alphasynuclein immunohistochemistry

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Lewy body disease

Brainstem type

Transitional type 

Diffuse type

Clinical data Neuropathology(Kosaka classification)

• Motor symptoms• RBD• Vegetative symptoms

Parkinson diseasedementia

Lewy body dementia

The question of genetic « Parkinson’s disease »

Parkin (homozygous) mutation: generally without Lewy body

LRRK2 mutation: frequently with Lewy bodies

JAMA Neurology, 2014:

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Pédoncule cérébelleuxsupérieur

1) Glial cytoplasmic inclusions

2) Neuronal cytoplasmic inclusions

3) Neuronal nuclear inclusions

4) Glial nuclear inclusions

5) Neuropil threads

J. Lowe & N. Leigh in Greenfield ’s Neuropathology, 2002

Nishimura et al.Neurosci Lett 1992; 143:35-38

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Criteria for the diagnosis of probable MSA

A sporadic, progressive, adult‐onset (>50 years) disease characterized by:

• Autonomic failure involving urinary incontinence […] or an orthostatic decrease of blood pressure […]

• Poorly levo‐dopa responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or

• A cerebellar syndrome 

Second consensus statement on the diagnosis of multiple system atrophyS Gilman, G K. Wenning,  P A. Low, et al.Neurology. 2008 Aug 26; 71(9): 670–676

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