Neurodegenerative Diseases

Slide 1 · Neurodegenerative Diseases

Pathology of selective neuronal loss and protein accumulation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain selective degeneration of neural systems and its clinical consequences.

Distinguish protein misfolding, aggregation, and impaired clearance.

Classify disorders by phenotype, neuroanatomy, and aggregate identity.

Relate representative pathological inclusions to major disease groups.

Slide 3 · Selective neuronal loss defines the group

Neurodegeneration involves progressive loss of populations of neurons.

Vulnerable neuronal populations commonly share related functions.

The distribution of neuronal loss helps determine presenting symptoms.

Vulnerable neuronal population

Progressive neuronal loss

Characteristic clinical syndrome

Slide 4 · Disease patterns reflect neural systems

Involvement is not uniformly distributed throughout the CNS.

Each syndrome typically targets a recognizable network or circuit.

Localization is clinically informative, but not uniquely diagnostic.

Anatomic distribution

Shared function affected

Stereotyped symptom pattern

Slide 5 · Progression and presentation are distinct

Focal system injury

→

Dominant initial syndrome

→

More widespread dysfunction

Gradual tissue damage may precede the first recognizable symptom. • A recognizable presenting phenotype reflects the initially affected system. • Additional systems may become involved as disease progresses.

Slide 6 · Major clinical entry points

Cognitive / behavioral

Movement

Cerebellar / autonomic

Motor neuron

Cognitive decline and dementia • Behavior or language impairment • Hypokinetic or hyperkinetic movement disorders

Slide 7 · Protein aggregation is a unifying process

Many neurodegenerative diseases accumulate abnormal protein aggregates.

These conditions are sometimes grouped as proteinopathies.

Aggregate identity and regional distribution help distinguish disease families.

Abnormal protein accumulation

Histologic inclusion

Molecular disease family

Slide 8 · Altered protein conformation can initiate aggregation

Pathogenic sequence change

→

Protein misfolding

→

Aggregation

Inherited mutations may alter the conformation of an affected protein. • Some altered proteins become prone to misfolding and accumulation. • Huntingtin with expanded polyglutamine repeats is one example.

Slide 9 · Defective protein handling is another route

Processing / clearance defect

→

Protein persistence

→

Aggregate accumulation

Mutations may instead disrupt processing of otherwise normal proteins. • Mutations may also interfere with clearance pathways. • The result can be excessive retention of aggregation-prone proteins.

Slide 10 · Synthesis–clearance imbalance can be acquired

Proteins are continually produced and removed within cells.

An imbalance can permit gradual accumulation without a specific change in the protein sequence.

Genetic, environmental, and unknown influences may contribute.

Protein synthesis

Reduced net clearance

Accumulation over time

Slide 11 · Three routes converge on the same endpoint

Entry mechanism

Shared endpoint

Altered protein conformation

Aggregated protein

Defective processing / clearance

Aggregated protein

Synthesis–clearance imbalance

Aggregated protein

Slide 12 · Aggregates are often resistant to degradation

Accumulated proteins may persist despite normal degradation mechanisms.

Intracellular deposition commonly occurs in abnormal locations.

The resulting structures can be recognized as microscopic inclusions.

Misfolded protein

Degradation resistance

Persistent inclusion

Slide 13 · Inclusions provide pathological signatures

An inclusion is an observable deposit of aggregated cellular material.

Different disorders have characteristic proteins and inclusion patterns.

The deposit is often a diagnostic hallmark rather than a complete explanation of toxicity.

Protein identity

Aggregate location

Histologic recognition

Slide 14 · Soluble oligomers may contribute to toxicity

Misfolded monomers

→

Small oligomeric aggregates

→

Neuronal injury / apoptosis

Small aggregates of misfolded protein may injure neurons. • an association with activation of apoptosis. • Visible end-stage inclusions should not automatically be assumed to be the sole toxic species.

Slide 15 · Aggregation can deplete normal protein function

Mechanism

Potential effect

Toxic gain of function

Injury from abnormal aggregate species

Loss of normal function

Functional protein unavailable

Slide 16 · Two injury mechanisms can coexist

Aggregate-related injury

Misfolded species → neuronal stress

Loss of normal function

Functional protein → aggregate pool

Misfolded protein species may trigger cellular death pathways. • Sequestration may reduce availability of functional protein. • The relative contribution varies across disease mechanisms.

Slide 17 · Cell-to-cell spread is a qualified hypothesis

Disease-associated aggregates have been observed to spread between cells in experimental settings.

Much supporting evidence comes from animal studies.

Prion disease provides a clear pathogenic example; Broader generalization requires caution.

Aggregate in one cell

Possible intercellular transfer

New aggregate burden

Slide 18 · Protein origins differ across diseases

Illustrative disease

Protein origin

Huntington disease

Mutant huntingtin with polyglutamine expansion

Alzheimer disease

Amyloid-β from precursor processing

Parkinson disease

Aggregation of α-synuclein

Slide 19 · Polyglutamine expansions favor aggregation

Expanded CAG repeat

→

Polyglutamine-rich protein

→

Intracellular inclusion

An expanded repeat changes the encoded polyglutamine tract. • Huntingtin is a disease-defining example. • Related polyglutamine proteins accumulate in several ataxias and motor neuron disorders.

Slide 20 · Amyloid-β is derived from a precursor

Amyloid-β (Aβ) is a peptide cleaved from a larger protein.

Its aggregation is central to the pathological signature of Alzheimer disease.

Alzheimer disease also features tau-containing neurofibrillary tangles.

Precursor protein

Aβ peptide

Extracellular plaque

Slide 21 · α-Synuclein is a major aggregate protein

Condition

Characteristic inclusion location

Parkinson / Lewy body spectrum

Neuronal Lewy bodies

Multiple system atrophy

Oligodendroglial cytoplasmic inclusions

Slide 22 · Biology and histology must be linked

Protein identity

→

Cellular pathology

→

Network failure

→

Clinical phenotype

An aggregate protein suggests a molecular mechanism. • Its microscopic location provides the pathologic pattern. • The affected neural system explains the dominant clinical deficits.

Slide 23 · Two complementary classification systems

Symptom / anatomy

Pathology / molecule

Dementia, parkinsonism, ataxia

Aβ, tau, α-synuclein

Behavior / language deficits

TDP-43, FUS

Motor neuron weakness

SOD1, TDP-43, FUS

Slide 24 · Clinical classifications emphasize location

Anatomic system

→

Functional deficit

→

Clinical syndrome

Neocortical damage can present with cognitive impairment. • Striatonigral dysfunction may present with parkinsonism. • Motor neuron dysfunction can cause progressive weakness.

Slide 25 · Molecular classes emphasize deposit identity

Tau

α-Synuclein

TDP-43 / FUS

PrP / polyglutamine

Tauopathies are linked by tau-positive abnormalities. • Synucleinopathies contain disease-associated α-synuclein deposits. • Other major protein families include Aβ, TDP-43, FUS, PrP, and polyglutamine proteins.

Slide 26 · Topography and molecular class can cross

Clinical syndrome

Different molecular associations

Dementia

Aβ/tau; FTLD proteins; prion protein

Parkinsonism

α-Synuclein; tau

Motor neuron disease

TDP-43; SOD1; FUS

Slide 27 · Cognitive-predominant neurodegeneration

Higher cortical dysfunction is a common presentation.

Alzheimer disease is typically associated with progressive cognitive decline.

Prion disease provides an example of unusually rapid progression.

Cortical involvement

Impaired cognition

Dementia syndrome

Slide 28 · Behavioral and language syndromes

Frontal and temporal lobe dysfunction alters behavior or language.

These deficits can precede substantial memory impairment in FTLD.

The molecular substrate of FTLD is heterogeneous.

Frontal / temporal systems

Behavior / language change

Progressive functional impairment

Slide 29 · Hypokinetic movement disorders

Parkinson disease is associated with loss of substantia nigra dopaminergic neurons.

Slowness of movement, rigidity, and tremor occur in the clinical syndrome.

Similar clinical motor deficits can arise through several distinct diseases.

Nigrostriatal circuit dysfunction

Impaired movement initiation

Parkinsonian syndrome

Slide 30 · Hyperkinetic movement disorders

Huntington disease typically presents with hyperkinetic movement abnormalities.

The striatum is a major site of degeneration.

An inherited expansion in HTT provides a molecular anchor for diagnosis.

Striatal degeneration

Disrupted movement control

Hyperkinetic phenotype

Slide 31 · Cerebellar and spinocerebellar syndromes

Degeneration of cerebellar pathways often produces progressive ataxia.

Several inherited spinocerebellar ataxias involve repeat expansions.

The clinical category is molecularly heterogeneous.

Cerebellar circuits

Coordination failure

Progressive ataxia

Slide 32 · Motor neuron–predominant syndromes

ALS affects both upper and lower motor neuron systems.

Weakness develops through progressive denervation and motor pathway damage.

Pathology may include distinct disease-linked protein inclusions.

Cortical / spinal motor neurons

Denervation / tract loss

Progressive weakness

Slide 33 · Autonomic involvement identifies another axis

Multiple system atrophy often involves autonomic circuits.

Orthostatic hypotension is an important clinical manifestation.

Parkinsonism and/or cerebellar ataxia may accompany autonomic dysfunction.

Autonomic system

Orthostatic symptoms

Multisystem syndrome

Slide 34 · Clinical syndrome does not define the deposit

Clinical examination

→

Topographic evidence

→

Molecular / tissue findings

→

Integrated diagnosis

A similar movement phenotype may reflect different aggregates. • Identical proteins may appear in anatomically different syndromes. • Final interpretation integrates clinical and pathological evidence.

Slide 35 · Major proteinopathy families

Molecule

Illustrative disease group

Aβ + tau

Alzheimer disease

Tau

FTLD-tau; PSP; CBD

α-Synuclein

PD / DLB; MSA

TDP-43 / FUS

FTLD; ALS

Slide 36 · Prion proteinopathy is mechanistically distinctive

Abnormal PrP conformation

→

Template-like conversion

→

Aggregation / spongiform change

Misfolded PrP can promote conformational conversion of additional PrP. • Propagation of the altered conformation explains transmissibility. • Prion diseases classically produce spongiform neural tissue change.

Slide 37 · Tau appears across distinct syndromes

Alzheimer disease

FTLD-tau

PSP

CBD

Tau occurs in Alzheimer neurofibrillary tangles. • Tau also characterizes PSP, corticobasal degeneration, and some FTLD. • A common protein does not imply identical lesion distribution or symptoms.

Slide 38 · Synucleinopathies differ by cellular compartment

Neuronal inclusions

Oligodendroglial inclusions

PD / dementia with Lewy bodies

MSA

Lewy bodies

Glial cytoplasmic inclusions

Slide 39 · TDP-43 and FUS link clinical categories

FTLD phenotype

Shared protein pathology

ALS phenotype

Both proteins occur in some FTLD disorders. • Both also occur in subsets of ALS. • This molecular overlap supports an FTLD–motor neuron disease spectrum.

Slide 40 · Polyglutamine disorders share a mutation motif

Disorder

Expanded protein

Huntington disease

Huntingtin

Selected SCAs

Several distinct proteins

Spinal and bulbar muscular atrophy

Androgen receptor

Slide 41 · Neuron versus glia: Localization matters

Many diseases feature neuronal inclusions.

MSA prominently contains α-synuclein inclusions in oligodendrocytes.

The affected cell type changes interpretation of apparently similar aggregates.

Neuronal inclusion

Glial inclusion

Different pathologic patterns

Slide 42 · Microscopic structures have distinct names

Pattern

Illustrative association

Plaques / tangles

Alzheimer disease

Lewy bodies

Parkinson / Lewy body spectrum

Spongiform change

Prion disease

Slide 43 · Prion disease: Rapid clinical course

Prion disorders can be sporadic, familial, or acquired.

Rapidly progressive dementia is a key clinical pattern.

Misfolded PrP is central to pathogenesis.

PrP conformational change

Propagation

Rapidly progressive disorder

Slide 44 · Prion disease: Spongiform morphology

Microscopic tissue shows vacuoles within gray matter neuropil.

Neuronal loss and reactive gliosis may occur in advanced disease.

Inflammation is characteristically absent in the described pattern.

Slide 45 · Alzheimer disease: Dual protein signature

Lesion

Principal protein

Amyloid plaque

Aβ

Neurofibrillary tangle

Tau

Slide 46 · Alzheimer disease: Clinical–anatomic link

Insidious higher cognitive impairment is characteristic.

The neocortex is critical to the progressive dementia syndrome.

AD is distinguished from rapidly progressive prion-associated dementia by clinical course.

Cortical neural dysfunction

Cognitive impairment

Progressive dementia

Slide 47 · FTLD: Predominantly frontal–temporal degeneration

Anatomic pattern

Molecular possibilities

Frontal / temporal degeneration

Tau

Behavior / language impairment

TDP-43 or FUS

Slide 48 · FTLD: One syndrome, multiple proteins

A shared clinical family encompasses heterogeneous pathology.

Molecular categories cannot be assigned from symptoms alone.

Motor neuron disease can coexist in part of the FTLD spectrum.

Clinical FTLD phenotype

Tau / TDP-43 / FUS

Molecular subclassification

Slide 49 · Parkinson disease: Selective nigral injury

Substantia nigra degeneration

→

Dopamine system dysfunction

→

Hypokinetic syndrome

Loss of dopaminergic neurons in substantia nigra drives hypokinetic abnormalities. • Typical features include slowed movement, rigidity, tremor, and altered gait. • Parkinsonism describes a syndrome, not a single histological diagnosis.

Slide 50 · Parkinson disease: Lewy body association

Parkinsonian group

Molecular pattern

PD / DLB spectrum

α-Synuclein Lewy bodies

PSP / CBD

Tau

MSA

Glial α-synuclein

Slide 51 · Dementia with Lewy bodies

Diffuse Lewy body deposition includes cortex and brainstem.

Fluctuating cognitive impairment and visual hallucinations are described features.

Clinical and pathological boundaries with PD dementia can overlap.

Widespread neuronal Lewy bodies

Cortical dysfunction

Dementia phenotype

Slide 52 · Progressive supranuclear palsy

PSP is a tauopathy with parkinsonism.

Postural instability, falls, and voluntary eye movement abnormalities are typical.

Tau inclusions affect neurons and glia, prominently in deep regions and brainstem.

Tau deposition

Brainstem / deep gray injury

Gaze and balance disturbance

Slide 53 · Corticobasal degeneration

CBD belongs to the tauopathy group.

Asymmetric motor impairment, rigidity, and apraxia are important clues.

The cerebral cortex is particularly affected by the disease process.

Cortical tau pathology

Asymmetric cortical / motor dysfunction

Apraxia and rigidity

Slide 54 · Multiple system atrophy: Unusual glial pathology

MSA

Lewy body spectrum

Oligodendroglial α-synuclein

Neuronal α-synuclein

White matter tract pathology prominent

Lewy body neuronal pathology prominent

Slide 55 · Multiple system atrophy: Three circuits

Striatonigral

Parkinsonism

Olivopontocerebellar

Ataxia

Autonomic

Autonomic failure

Striatonigral involvement contributes to parkinsonism. • Olivopontocerebellar involvement contributes to ataxia. • Autonomic system involvement contributes to orthostatic dysfunction.

Slide 56 · Huntington disease: Inherited polyglutamine

HTT CAG expansion

→

Mutant huntingtin

→

Polyglutamine inclusions

An expanded CAG repeat in HTT encodes mutant huntingtin. • Mutant protein is associated with intranuclear inclusions. • This is a clear genotype–proteinopathy association.

Slide 57 · Huntington disease: Striatal degeneration

The disease strongly affects the striatum.

Loss of striatal neurons contributes to hyperkinetic motor abnormalities.

Macroscopic striatal atrophy and ventricular enlargement are described.

Striatal atrophy

Motor circuit dysfunction

Hyperkinetic movements

Slide 58 · Spinocerebellar ataxias are heterogeneous

CAG / polyglutamine

Noncoding repeats

Conventional variants

Different SCAs share progressive impairment of coordination. • Several subtypes reflect expanded polyglutamine tracts. • Other subtypes involve noncoding repeat expansions or conventional mutations.

Slide 59 · Three genetic routes in spinocerebellar ataxia

Genetic class

Interpretation

Coding CAG expansion

Polyglutamine protein

Noncoding repeat expansion

Mechanism variable / incompletely understood

Other sequence / dosage variants

Diverse protein functions

Slide 60 · ALS: Upper and lower motor neuron disease

Upper motor neuron loss

→

Lower motor neuron loss

→

Progressive weakness

ALS affects cortical upper motor neurons and spinal/brainstem lower motor neurons. • Degeneration causes denervation and progressive muscle weakness. • Both motor neuron compartments help define the disorder.

Slide 61 · ALS: Several aggregate proteins

Protein

Associated example

SOD1

SOD1-associated ALS

TDP-43

Many sporadic / selected inherited ALS forms

FUS

FUS-associated ALS

Slide 62 · ALS and FTLD form an overlapping spectrum

FTLD and ALS share some genetic and protein abnormalities.

C9orf72 repeat expansion is an important shared genetic association.

Motor and cognitive / behavioral phenotypes can overlap.

Shared genetic / protein substrate

FTLD phenotype

ALS phenotype

Slide 63 · Inherited causes provide molecular anchors

Genetic change

Illustrative disorder

HTT CAG expansion

Huntington disease

PRNP variant

Familial prion disease

C9orf72 repeat expansion

ALS / FTLD

SNCA variants

Inherited PD forms

Slide 64 · A practical clinical-first interpretive sequence

Syndrome

→

Localization

→

Differential

→

Pathological subtype

Recognize the dominant neurological syndrome. • Localize the most affected functional system. • Construct a differential that includes different molecular pathologies.

Slide 65 · A practical pathology-first interpretive sequence

Morphology / cell type

→

Protein identity

→

Topography

→

Clinicopathologic integration

Identify the inclusion morphology and affected cell type. • Determine the major aggregated protein where pathology permits. • Evaluate anatomical distribution and clinical information.

Slide 66 · Potential diagnostic confusion: Overlapping pathways

Observation

Diagnostic implication

Same protein; different phenotypes

Topography matters

Same phenotype; different proteins

Protein studies matter

Mixed disease processes

Integrative evaluation required

Slide 67 · Apply the framework: Four short vignettes

Rapidly progressive dementia with spongiform change.

Insidious dementia with plaques and tangles.

Parkinsonism with oligodendroglial α-synuclein inclusions.

Progressive weakness with upper and lower motor neuron loss.

Slide 68 · Vignette solutions: Match the defining feature

Defining observation

Best-fitting group

Spongiform change / PrP

Prion disease

Aβ plaques + tau tangles

Alzheimer disease

Glial α-synuclein

MSA

Upper + lower motor neuron loss

ALS

Slide 69 · Integrative matrix: Phenotype to pathology

Presentation

Illustrative pathology

Dementia

AD: Aβ/tau; FTLD: tau/TDP-43/FUS

Parkinsonism

PD: Lewy bodies; PSP: tau; MSA: glial α-synuclein

Hyperkinesia

HD: expanded huntingtin

Weakness

ALS: motor neuron degeneration

Slide 70 · Foundational principles to retain

Neurodegeneration is selective, progressive neuronal loss.

Proteostasis failure and protein accumulation recur across most of these disorders.

Oligomer toxicity, loss of normal protein function, and possibly intercellular transfer are distinct concepts.

Clinical localization and molecular pathology are complementary but imperfect classification axes.

Slide 71 · Primary reference and source boundaries

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026).

Chapter 28: Neurodegenerative Diseases, p. 1159; Tables 28.3–28.4.

Adjacent disease sections through motor neuron disorders inform brief comparisons.

Schematic diagrams are original editable representations, not diagnostic specimens.