Atypical Parkinsonian Syndromes

Slide 1 · Atypical Parkinsonian

Syndromes

Progressive supranuclear palsy • Corticobasal degeneration • Multiple system atrophy

Neuropathology and clinicopathologic correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define atypical parkinsonism relative to Parkinson disease (PD).

Differentiate PSP, CBD, and MSA by dominant clinical systems and protein aggregates.

Correlate pathologic distribution and affected cell types with clinical phenotypes.

Interpret representative clinicopathologic vignettes without treating them as definitive diagnoses.

Slide 3 · Parkinsonism begins with nigrostriatal dysfunction

Nigrostriatal dopaminergic pathway

Dopaminergic dysfunction

Bradykinesia and rigidity

The syndrome describes a motor phenotype, not a single disease.

Multiple neurodegenerative conditions share this motor phenotype.

Slide 4 · “Atypical” means additional neurologic systems

Parkinsonism is only part of the clinical picture in PSP, CBD, and MSA.

Prominent eye-movement, cortical, cerebellar, or autonomic findings extend beyond the core PD phenotype.

The “Parkinson-plus” designation captures these accompanying abnormalities.

Slide 5 · Levodopa response: A discriminating clue

Typical PD (source comparison)

Atypical parkinsonian syndromes

Dopamine replacement can improve motor symptoms, especially early

Generally minimally responsive to L-DOPA

Nigrostriatal dopamine deficit contributes strongly to motor features

Additional degenerating systems contribute non-dopaminergic deficits

Response is not a permanent arrest of degeneration

Limited response does not identify a particular atypical syndrome

Slide 6 · Three entities, two protein families

Atypical parkinsonian syndromes

Tauopathies

Progressive supranuclear palsy (PSP)

Corticobasal degeneration (CBD)

Synucleinopathy

Multiple system atrophy (MSA)

Slide 7 · Protein–cell–territory signature

Entity

Dominant aggregate

Topographic emphasis

PSP

Tau in neurons and glia

Brainstem and deep gray matter

CBD

Tau in neurons and glia

Cerebral cortex prominent

MSA

α-Synuclein in oligodendrocytes

White matter pathways and multiple circuits

Slide 8 · PSP and CBD overlap FTLD-tau

Both disorders combine parkinsonian features with frontotemporal degeneration.

PSP and CBD as subtypes of frontotemporal lobar degeneration with tau pathology (FTLD-tau).

Protein class alone cannot distinguish PSP from CBD; Distribution and lesion pattern matter.

Slide 9 · Clinicopathologic orientation map

Entity

Motor / ocular pattern

Cortical dysfunction

Autonomic / cerebellar

PSP

Truncal rigidity, falls, ocular difficulty

Progressive dementia

Not the defining pattern

CBD

Asymmetric rigidity and jerks

Apraxia; later cognitive decline

Not the defining pattern

MSA

Parkinsonism among presentations

Not emphasized in source

Ataxia and orthostatic hypotension

Slide 10 · Progressive supranuclear palsy

Slide 11 · PSP: Characteristic clinical constellation

Progressive truncal rigidity and disequilibrium produce frequent falls.

Voluntary eye movements become difficult.

Nuchal dystonia, pseudobulbar palsy, and progressive dementia may accompany the motor syndrome.

Slide 12 · From axial motor disturbance to falls

Progressive truncal rigidity

Impaired balance and postural control

Disequilibrium and frequent falls

Truncal rather than predominantly distal dysfunction is emphasized.

This constellation should redirect evaluation away from uncomplicated PD.

Slide 13 · PSP: Disturbance of voluntary eye movements

Difficulty with voluntary eye movements is a characteristic component of PSP.

Eye-movement involvement occurs alongside truncal rigidity and postural disequilibrium.

The combination carries greater discriminative value than parkinsonism alone.

Slide 14 · PSP: Associated bulbar and cervical findings

Nuchal dystonia adds a distinctive axial motor abnormality.

Pseudobulbar palsy reflects dysfunction affecting voluntary bulbar control.

These findings expand the phenotype beyond a pure nigrostriatal syndrome.

Slide 15 · PSP: Progressive cognitive impairment

Progressive dementia among the common clinical manifestations.

Cognition must be assessed together with motor and ocular deficits.

Combined motor and cognitive deficits are compatible with the FTLD-tau disease context.

Slide 16 · PSP: Clinical tempo

Typical onset is between the fifth and seventh decades.

Males affected approximately twice as frequently as females.

Death often occurring within 5–7 years of disease onset; This is a source-specific estimate.

Slide 17 · PSP: Tissue compartments with greatest burden

Tau-positive neuronal and glial inclusions

Brainstem

Substantia nigra

Colliculi

Periaqueductal gray

Deep gray and cerebellar nuclei

Globus pallidus

Subthalamic nucleus

Dentate nucleus

Slide 18 · PSP: Deep gray matter involvement

Regional involvement — conceptual map

Globus pallidus

Neuronal loss

Subthalamic nucleus

Neuronal loss

Substantia nigra

Neuronal loss

Multiple motor-associated deep gray structures are affected.

The lesion distribution is broader than isolated nigral dysfunction.

Source describes widespread neuronal loss rather than a single focal injury.

Slide 19 · PSP: Brainstem and cerebellar nuclei

Regional involvement — conceptual map

Colliculi

Neuronal loss

Periaqueductal gray

Neuronal loss

Dentate nucleus

Neuronal loss

Affected structures extend through brainstem and cerebellar circuitry.

Anatomic distribution helps explain the multisystem phenotype.

No precise one-region–one-symptom mapping is asserted by the textbook excerpt.

Slide 20 · PSP aggregates are not Alzheimer-type tangles

PSP tau tangles

Alzheimer disease tangles (textbook comparison)

Globular appearance

More filamentous appearance

Neurons and glia in affected regions

Compared morphologically; not asserted to have identical cell distribution

Regional emphasis: brainstem and deep gray

Different broader disease context

Slide 21 · PSP: Neuronal and glial tau pathology

Tau-containing inclusions involve both neurons and glial cells.

Inclusions concentrate most heavily in brainstem and deep gray matter.

The coexistence of aggregate pathology and neuronal loss is the morphologic core of PSP in this chapter.

Slide 22 · PSP genetic susceptibility: MAPT-linked risk

Polymorphisms near tau gene locus

Greater expression of aggregation-prone tau isoforms

Increased sporadic PSP susceptibility

The source describes a risk association, not a deterministic Mendelian rule.

Causative tau-gene mutations are identified in only a few PSP cases.

Slide 23 · PSP: Genetic evidence has distinct levels

Causative tau-gene mutations are uncommon among described PSP cases.

Common susceptibility is linked to tau-locus polymorphisms.

Additional genome-wide association risk alleles exist; Their mechanistic contributions remain uncertain.

Slide 24 · PSP: Clinical evidence versus morphologic evidence

Clinical observation

Pathologic observation

Truncal rigidity, falls

Neuronal loss across multiple motor-associated nuclei

Voluntary eye-movement difficulty

Brainstem/deep-gray involvement

Progressive cognitive symptoms

Tauopathy with frontotemporal degeneration context

Limited L-DOPA response (group-level)

Broader pathology beyond dopamine-specific circuitry

Slide 25 · Illustrative case: PSP pattern

Teaching vignette (illustrative)

A patient develops progressive trunk rigidity, repeated falls, impaired voluntary eye movements, and nuchal dystonia.

Which protein family and predominant anatomic compartment best fit this pattern?

Tauopathy; Highest aggregate burden in brainstem and deep gray matter.

Slide 26 · Corticobasal degeneration

Slide 27 · CBD: Key clinical features

Extrapyramidal rigidity and asymmetric motor disturbances characterize the disorder.

Jerking movements of limbs may be present.

Higher cortical function is impaired, commonly producing apraxia.

Slide 28 · CBD combines movement and cortical deficits

Motor component

Cortical component

Rigidity

Impaired higher cortical function

Asymmetric limb disturbances

Apraxia is particularly typical

Jerking movements

Cognitive decline may develop later

Slide 29 · CBD: Why asymmetry matters

Asymmetric motor disturbance in CBD.

Rigidity alone is nonspecific within the atypical-parkinsonism group.

A lateralized motor presentation coupled with apraxia is especially suggestive in a teaching comparison.

Slide 30 · CBD: Apraxia and cortical dysfunction

Cortical neurodegeneration

Impairment of higher cortical function

Apraxia

Apraxia is highlighted as the typical higher cortical deficit.

This link is clinicopathologic interpretation, not a claim of a uniquely localized lesion.

Slide 31 · CBD: Cognition across progression

Cognitive decline may occur during the illness.

Decline is typically later in CBD than the early motor phenotype.

Cognition should not be used in isolation to distinguish CBD from PSP.

Slide 32 · CBD: Selective cortical atrophy

Regional involvement — conceptual map

Motor cortex

Atrophy

Premotor cortex

Atrophy

Anterior parietal cortex

Atrophy

Cortical atrophy is concentrated in motor-associated and anterior parietal regions.

This distribution supports combined motor and higher-cortical deficits.

A schematic is used; No actual gross specimen is available for this deck.

Slide 33 · CBD: Cortex shows neuron loss and gliosis

Affected cerebral cortex undergoes severe neuronal depletion.

Gliosis accompanies neuronal loss.

Ballooned neurons are an additional conspicuous pathologic finding.

Slide 34 · CBD: Ballooned neurons in the cortex

Ballooned neurons in markedly affected cortical regions.

This feature is interpreted in the setting of neuronal loss and gliosis.

It does not, on its own, reproduce the full histopathologic diagnosis.

Slide 35 · CBD: Tau-positive cell populations

Cell / compartment

Textbook observation

Use in interpretation

Astroglia

Tau immunoreactivity

Glial involvement

Oligodendroglia

Coiled bodies

Glial tau accumulation

Basal ganglia neurons

Tau immunoreactivity

Extrapyramidal involvement

Cortical neurons

Variable positivity

Cortical disease association

Slide 36 · CBD: Astrocytic plaques and tau threads

Clusters of tau-positive processes surround astrocytes, forming astrocytic plaques.

Tau-positive threads occur in gray and white matter.

These findings as potentially the most specific pathologic features of CBD.

Slide 37 · CBD: Distinguish plaque from thread

Tau-positive processes around astrocyte

Astrocytic plaque

A plaque is a cluster of processes organized around an astrocyte.

Threads denote tau-positive processes distributed through gray and white matter.

These are conceptual definitions; Not replacements for microscopy.

Slide 38 · CBD: Additional subcortical neuronal injury

Substantia nigra and locus ceruleus show neuronal loss.

Ballooned neurons and tangles also occur in those structures.

Thus, cortical predominance does not imply disease restriction to cortex.

Slide 39 · CBD: Cortical predominance of tau inclusions

Tau accumulation in multiple structures

Larger fraction of inclusions in cerebral cortex

Cortical atrophy and higher cortical deficits

The relative cortical burden in CBD with PSP.

The final link is a clinicopathologic association, not proof of molecular causality.

Slide 40 · CBD and PSP share MAPT-linked susceptibility

Tau-gene variants associated with PSP are also strongly linked to CBD.

Shared genetic association reinforces their grouping among tauopathies.

Regional pathology and aggregate characteristics differentiate these related diseases.

Slide 41 · PSP versus CBD: Dominant distributions

PSP

CBD

Brainstem and deep gray matter: greatest burden

Greater relative cortical tau burden

Truncal rigidity, disequilibrium, eye-movement difficulty

Asymmetric limb motor signs and apraxia

Globular tau tangles in neurons and glia

Astrocytic plaques, tau threads, ballooned neurons

Both tauopathies within FTLD-tau

Both associated with tau-locus variants

Slide 42 · PSP and CBD have distinct tau folds

Tau aggregates in PSP and CBD adopt distinct molecular folds in vitro.

Shared tau protein does not imply identical aggregate conformation.

Molecular fold is presented as a pathologic property—not as a routine clinical diagnostic assay.

Slide 43 · Illustrative case: CBD pattern

Teaching vignette (illustrative)

A patient has progressive asymmetric rigidity and limb jerks accompanied by loss of a learned purposeful motor skill (apraxia).

Which pathology distribution is most strongly favored among the three syndromes?

Corticobasal degeneration; Prominent cortical atrophy and cortical tau pathology.

Slide 44 · Multiple system atrophy

Slide 45 · MSA: Defining histopathologic concept

MSA is described as a sporadic neurodegenerative disorder.

α-Synuclein aggregates accumulate in oligodendroglial cytoplasm.

White matter tract degeneration and accompanying neuronal loss coexist.

Slide 46 · “Multiple” refers to three systems

MSA: Multisystem circuit involvement

Motor circuits

Striatonigral → parkinsonism

Olivopontocerebellar → ataxia

Autonomic circuits

Central and peripheral autonomic involvement

Orthostatic hypotension prominent

Slide 47 · MSA: Striatonigral involvement

Striatonigral circuit degeneration

Dysfunction of motor circuitry

Parkinsonism

Substantia nigra and striatum are prominent in parkinsonian forms.

The putamen is highlighted within the striatum.

Slide 48 · MSA: Olivopontocerebellar involvement

Olivopontocerebellar degeneration

Disrupted cerebellar circuitry

Ataxia

Cerebellum, peduncles, pons, and inferior olive may be atrophic.

This is the characteristic anatomic distribution of cerebellar forms.

Slide 49 · MSA: Autonomic system involvement

Autonomic neural degeneration

Failure of autonomic regulation

Orthostatic hypotension

Robbins especially emphasizes orthostatic hypotension.

Central medullary and spinal autonomic structures are implicated.

Slide 50 · MSA phenotype evolves beyond the first system

One system may dominate at onset of illness.

Other involved circuits typically manifest as disease progresses.

Therefore, an initial parkinsonian, cerebellar, or autonomic phenotype can evolve into multisystem disease.

Slide 51 · MSA: Predominant onset versus later illness

At presentation

During progression

Parkinsonism may dominate

Ataxic and autonomic features may emerge

Ataxia may dominate

Parkinsonian and autonomic features may emerge

Autonomic symptoms may dominate

Additional motor systems often become affected

Patterns are not mutually exclusive

Anatomic overlap is central to the disease concept

Slide 52 · MSA: Glial pathology is the primary emphasis

The major histopathologic alterations are located in glial cells.

Oligodendrocytes contain characteristic glial cytoplasmic inclusions.

Unlike typical Lewy-body disorders, neuronal degeneration often occurs without neuronal inclusions.

Slide 53 · MSA: Inclusion burden and neuronal loss

Glial cytoplasmic inclusions

Increasing inclusion burden as disease advances

White matter and neuronal degeneration

The observations support an early or primary glial pathologic role.

The temporal sequence is suggested, not conclusively demonstrated, by the cited findings.

Slide 54 · MSA: Evidence for early glial involvement

Glial cytoplasmic inclusion burden increases with progression.

Inclusions may be seen where neuronal loss has not yet occurred.

Together, these observations suggest inclusions can be an early pathologic event.

Slide 55 · MSA: Origin of oligodendroglial α-synuclein is uncertain

α-Synuclein is normally associated with neuronal synaptic vesicles.

No up-regulation of α-synuclein expression in oligodendrocytes or white matter.

Transfer of aggregates from damaged neurons to oligodendrocytes is a proposed explanation, not established proof.

Slide 56 · MSA: Proposed intercellular protein transfer

Injured / degenerating neurons

Proposed acquisition of α-synuclein

Oligodendroglial inclusions

Dashed conceptual hypothesis: Cellular origin remains unresolved.

No mechanistic transport route is specified by the textbook.

Proposed mechanism; Cellular transfer remains unproven.

Slide 57 · MSA: Oligodendroglial stress responses

Oligodendrocytes containing α-synuclein show increased susceptibility to oxidative stress.

Their interaction with extracellular matrix is impaired.

These cellular effects offer a possible link to white matter tract damage.

Slide 58 · MSA: Genetic association is not causal proof

No causative α-synuclein gene mutation is identified in the cited textbook account of MSA.

Polymorphisms near the gene may influence susceptibility.

A risk association should not be misrepresented as a diagnostic genetic test.

Slide 59 · MSA cerebellar form: Gross atrophy

Regional involvement — conceptual map

Cerebellum

Atrophy

Cerebellar peduncles

Atrophy

Pons (base)

Atrophy

Inferior olive

Atrophy

Atrophy extends through the olivopontocerebellar network.

The pons, especially its base, is specifically highlighted.

Region labels are conceptual; No source photomicrograph is reproduced.

Slide 60 · MSA parkinsonian form: Gross atrophy

Regional involvement — conceptual map

Substantia nigra

Atrophy

Striatum

Atrophy

Putamen

Especially involved

This distribution corresponds to a dominant parkinsonian phenotype.

Putaminal injury is included within striatal pathology.

Affected regions also show neuronal loss.

Slide 61 · MSA autonomic form: Anatomic correlates

Regional involvement — conceptual map

Medullary catecholaminergic nuclei

Neuronal loss

Spinal intermediolateral column

Neuronal loss

These structures participate in autonomic regulation.

Loss correlates with autonomic dysfunction and orthostatic hypotension.

Atrophy may be distributed rather than confined to one isolated center.

Slide 62 · MSA: Direct morphology–clinical mapping

Circuit

Typical anatomic changes

Dominant feature

Striatonigral

Nigra and striatum, especially putamen

Parkinsonism

Olivopontocerebellar

Cerebellum, peduncles, pontine base, inferior olive

Ataxia

Autonomic

Medullary catecholaminergic nuclei; spinal intermediolateral column

Autonomic failure / orthostatic hypotension

Slide 63 · MSA: Inclusion composition and detection

The diagnostic glial cytoplasmic inclusions reside in oligodendrocytes.

They contain α-synuclein and ubiquitin.

They were originally demonstrated using silver impregnation methods.

Slide 64 · MSA versus PD: Same protein, different cell emphasis

PD / dementia with Lewy bodies

MSA

α-Synuclein inclusions predominantly neuronal

α-Synuclein inclusions characteristically oligodendroglial

Lewy bodies and Lewy neurites described

Glial cytoplasmic inclusions are diagnostic

Substantia nigra neuronal loss; additional distribution varies

White matter tract degeneration and multiple circuits

Robbins reports a distinct α-synuclein fold

Fold differs from PD/DLB in textbook account

Slide 65 · Illustrative case: MSA pattern

Teaching vignette (illustrative)

A patient develops parkinsonism with prominent orthostatic hypotension; Later, impaired coordination and gait ataxia appear.

Which primary aggregate protein and cell type best fit this multisystem pattern?

α-Synuclein in oligodendroglial cytoplasmic inclusions.

Slide 66 · Integrated clinicopathologic comparison

Slide 67 · Distinguishing clinical signatures

Disorder

Early or prominent clue

Additional feature

PSP

Truncal rigidity with falls

Difficulty with voluntary eye movements

CBD

Asymmetric rigidity / jerking limb movements

Apraxia

MSA

Parkinsonism, ataxia or autonomic failure

Other systems commonly become involved

Slide 68 · Distinguishing morphologic signatures

Disorder

Neural topography

Dominant inclusion

PSP

Brainstem and deep gray nuclei

Globular tau tangles; neuron and glia

CBD

Motor, premotor, anterior parietal cortex

Tau; astrocytic plaques and threads

MSA

White matter / striatonigral / olivopontocerebellar

Oligodendroglial α-synuclein inclusions

Slide 69 · A three-question interpretation framework

Which additional syndrome?

Which anatomic system?

Which protein and cell type?

Clinical presentation directs the likely entity.

Gross/neuroanatomic findings test that hypothesis.

Aggregate identity and cellular location strengthen neuropathologic classification.

Slide 70 · Avoid common classification errors

Tempting oversimplification

More accurate interpretation

“Parkinsonism means PD.”

Parkinsonism appears in multiple degenerative disorders.

“All α-synucleinopathies have neuronal Lewy bodies.”

MSA is characterized by oligodendroglial inclusions.

“All tauopathies share one morphologic pattern.”

PSP and CBD have different tissue distributions and folds.

“L-DOPA response alone identifies the syndrome.”

Group-level poor response is supportive, not individually specific.

Slide 71 · Integrated recognition exercise

Teaching vignette (illustrative)

A neuropathologic examination shows severe cortical neuronal loss, gliosis, ballooned neurons, and tau-positive astrocytic plaques in association with an asymmetric motor–apraxic syndrome.

Which entity is most concordant, and why?

CBD; Cortical-predominant degeneration and tau-positive astrocytic plaques match the described morphology.

Slide 72 · Integrated recognition: Contrasting example

Teaching vignette (illustrative)

A brain shows oligodendroglial α-synuclein/ubiquitin inclusions with degeneration of pontine and cerebellar structures in a patient with ataxia.

What syndrome and pathologic circuit are supported?

MSA; Olivopontocerebellar circuitry in the cerebellar phenotype.

Slide 73 · Synthesis: Three testable distinctions

PSP: Axial–ocular phenotype with brainstem and deep-gray tau pathology.

CBD: Asymmetric motor–apraxic phenotype with pronounced cortical tau pathology.

MSA: Oligodendroglial α-synuclein and combined parkinsonian, cerebellar, and autonomic systems.

Slide 74 · Primary source and editorial boundaries

Core reference

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 28: The Central Nervous System, pp. 1168–1170.

Scope and source caveats

The lecture is based on project-provided textbook Markdown and adjacent Parkinson disease context; this is not an external-guideline update.

Original chapter PDF and permission-cleared microscopy were not available; no authentic histology specimens or source figures are reproduced.