Amyotrophic Lateral Sclerosis

Slide 1 · Amyotrophic Lateral Sclerosis

Motor neuron degeneration · proteinopathy · neuropathology · clinical correlation

Pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish upper- from lower-motor-neuron tissue injury in ALS.

Explain how SOD1, C9orf72, RNA-binding proteins and autophagy genes implicate distinct molecular pathways.

Relate spinal cord, brainstem and muscle pathology to the clinical phenotype.

Interpret ALS–frontotemporal lobar degeneration overlap and key neighboring motor neuron diseases.

Slide 3 · ALS among neurodegenerative diseases

Category

Predominant functional system

Characteristic disease pattern

Motor neuron diseases

Voluntary motor pathways

ALS: cortical and lower motor neuron loss

Dementing neurodegeneration

Cortical association circuits

FTLD: frontotemporal dysfunction

Overlap spectrum

Motor + frontotemporal networks

ALS can coexist with FTLD-associated clinical features

Slide 4 · Defining pathologic lesion in ALS

Upper motor neurons

Degeneration in motor cortex

Lower motor neurons

Degeneration in cord and brainstem

Motor units

Denervation of skeletal muscle

Clinical outcome

Progressive and severe weakness

ALS is defined by distributed motor neuronal loss, not by a single muscle lesion.

Slide 5 · Two motor-neuron populations

Upper motor neurons

Cell bodies in motor cerebral cortex

Descending axons in corticospinal tracts

Degeneration is linked to tract fiber loss

Lower motor neurons

Cell bodies in anterior horns and motor cranial nuclei

Axons reach skeletal muscles through motor nerves

Degeneration causes loss of motor axons and denervation

Slide 6 · The motor pathway as an anatomical sequence

Motor system (schematic)

Cortex → descending corticospinal pathway → spinal motor neuron → muscle

Motor cortex

Corticospinal tract

Anterior horn / brainstem motor nucleus

Motor axon → skeletal muscle

Pathologic interpretation

The cortex, descending tract, lower motor neuron and muscle form a functional chain.

ALS injures more than one station in this sequence.

A motor pathway schematic does not substitute for actual histology.

Slide 7 · Why motor neuron loss weakens muscle

Neuron injury

Upper and lower motor neuronal degeneration

Axonal attrition

Fewer lower motor axons reach muscle

Denervation

Motor units lose neuronal drive

Muscle effect

Atrophy and progressive weakness

The muscle lesion in ALS is primarily neurogenic: Pathology begins in the motor neural system.

Slide 8 · Complementary clinical consequences

Predominant upper motor injury

Impaired descending motor control

Spasticity may accompany weakness

Corticospinal tract degeneration provides anatomical substrate

Predominant lower motor injury

Motor unit loss and denervation

Loss of muscle bulk and fasciculations

Anterior horn and cranial motor neuron loss provides substrate

Slide 9 · Epidemiology: What Robbins reports

The overall incidence is approximately 2 per 100,000 people.

Symptoms commonly begin in the fifth decade of life or later.

The clinical course is progressive, with substantial motor disability developing over time.

The epidemiologic figures here follow Robbins 11e; No independent population re-estimation was performed.

Slide 10 · Sporadic and familial ALS are both important

Sporadic disease is more common than familial ALS.

Familial cases may account for as many as 20% of cases.

Both forms share degeneration of upper and lower motor neurons, often with toxic protein accumulation.

Slide 11 · The ALS–FTLD disease spectrum

ALS

Motor neuron predominant

Overlap

Motor + cortical disease

FTLD

Frontotemporal cortical predominant

Genetic, pathologic and clinical overlap supports a shared disease spectrum, not identity of all ALS and FTLD cases.

Slide 12 · Why familial ALS informs sporadic disease

More than two dozen genetic loci were recognized as causes of familial ALS in the source.

Nearly all identified familial forms are described as autosomal dominant.

Genetic mechanisms reveal pathways potentially relevant to broader ALS pathobiology.

Slide 13 · Major pathogenic themes from the source

Molecular theme

Examples

Proposed consequence

Protein misfolding

Mutant SOD1

Aggregation and proteostasis stress

Repeat expansion

C9orf72

Repeat-associated translation / neuronal peptide deposits

RNA biology

TDP-43, FUS

Altered RNA processing and stress granule biology

Clearance pathways

SQSTM1, OPTN, ubiquilin-1

Impaired selective autophagy

Cytoskeleton

TUBA4A, PFN1

Altered structural/transport processes

Slide 14 · A common pathological endpoint

Genetic or sporadic stress

Multiple initiating insults

Cellular dysfunction

Protein / RNA handling and organellar injury

Motor neuron loss

Cortical + spinal / bulbar populations

Motor impairment

Denervation and progressive weakness

These are converging themes, not proof that every molecular mechanism occurs in every ALS subtype.

Slide 15 · SOD1-associated ALS: Genetic context

SOD1 encodes copper–zinc superoxide dismutase.

The locus is on chromosome 21.

SOD1 mutations account for about 20% of familial ALS cases.

Slide 16 · SOD1: Initial model versus current interpretation

Earlier hypothesis

Reduced detoxification of free radicals was initially suspected.

This followed recognition of mutations in an antioxidant enzyme.

Interpretation

Mutations are understood primarily as an adverse gain of function.

Misfolded mutant protein and toxic aggregation are emphasized.

Slide 17 · SOD1 protein misfolding

SOD1 mutation

Mutant protein structure

Protein misfolding

Unstable or abnormal conformers

Aggregation

Mutant ± wild-type SOD1

Cell injury

Several proposed toxic mechanisms

Aggregates may include normally encoded SOD1; Toxic gain of function is not equivalent to simple enzyme deficiency.

Slide 18 · Proposed downstream effects of mutant SOD1

Cellular process

Source-described disturbance

Neuropathologic implication

Protein turnover

Proteasomal and autophagic dysregulation

Accumulation of abnormal proteins

Axonal transport

Disrupted intracellular transport

Injury to long neuronal processes

Mitochondria

Disrupted mitochondrial function

Metabolic stress

Protein interactions

Sequestration of other proteins

Additional proteostasis impairment

Slide 19 · Proteostasis as a vulnerable node

Abnormal protein

Mutant protein misfolds

Clearance burden

Proteasome and autophagy stressed

Aggregate persistence

Misfolded material accumulates

Cellular injury

Motor neuron dysfunction

Clearance dysfunction as a proposed contributor, supported by genetic links to autophagy proteins.

Slide 20 · Axonal transport: Why long motor neurons are susceptible

Motor neuron cell body

Axonal transport apparatus

Distal axon and muscle contact

Interpretation

SOD1-mutant aggregates are postulated to disrupt axonal transport.

The anatomic length of motor axons makes transport a conceptually important vulnerability.

The source does not quantify how much transport failure explains ALS.

Slide 21 · Mitochondrial dysfunction in SOD1 disease

Disruption of mitochondrial function is listed among proposed aggregate-mediated injuries.

This mechanism may contribute to the loss of motor neuron cellular resilience.

Its relative contribution versus other mechanisms is not resolved by the textbook excerpt.

Slide 22 · Protein sequestration and cellular stress

Protein aggregates

Abnormal assembly

Sequestration

Other cellular proteins recruited

Impaired pathways

Normal proteostasis becomes disturbed

Neuronal injury

Functional decline and cell loss

Protein aggregates can be both a pathological marker and a potential source of toxic interactions; Causality varies by mechanism.

Slide 23 · Unfolded protein response and apoptosis

Aggregate persistence

Persistent abnormal proteins

Proteostasis stress

Unfolded protein response

Failure of adaptation

Cell injury progresses

Cell death

Apoptotic pathways may be initiated

The source describes this as a possible downstream sequence, not an exclusive neuronal death pathway.

Slide 24 · C9orf72 expansion: Recurrent familial lesion

A hexanucleotide repeat expansion in the 5′ untranslated region of C9orf72 is strongly linked to familial ALS and FTLD.

That this mutation causes up to 40% of familial ALS.

The combined ALS–FTLD phenotype illustrates shared genetic pathogenesis.

Slide 25 · Repeat-associated translation in C9orf72

Repeat expansion

Hexanucleotide repeat in C9orf72

Non–AUG translation

Translation across repeat reading frames

Peptide generation

Repeat-derived proteins produced

Tissue finding

Neuronal peptide deposits observed

Repeat-associated peptide deposits are demonstrated in individuals carrying the mutation; Their causal importance remains uncertain.

Slide 26 · C9orf72: Established and unresolved

Supported observations

Repeat expansion occurs in ALS and FTLD

Non–AUG-initiated translation may occur

Repeat-derived peptide deposits occur in brain

Uncertainty expressly stated

Whether deposited peptides contribute to disease is unknown in the source.

Do not portray a repeat-derived deposit as a proven single pathogenic cause.

Slide 27 · RNA-binding proteins implicated in ALS

TDP-43 and FUS are RNA-binding proteins linked genetically to ALS and FTLD.

The source associates both with stress granule biology.

Altered RNA processing and aberrant protein accumulation are implicated in pathogenesis.

Slide 28 · TDP-43 and FUS: Overlapping functional themes

Normal functional context

RNA binding and regulation

Association with stress granules

Maintenance of orderly transcript processing

Pathologic context

Disease-associated protein aggregation

Abnormal RNA processing

Defective protein homeostasis and autophagy

Slide 29 · RNA processing as a pathologic mechanism

RNA-binding protein dysfunction

Altered TDP-43/FUS-related biology

Processing defects

Abnormal RNA maturation

Aberrant exon expression

Cryptogenic exon-related transcript disruption

Neuronal dysfunction

Altered protein expression / homeostasis

The mechanistic connection is incomplete: The source explicitly avoids reducing ALS to one RNA lesion.

Slide 30 · Aberrant exon expression matters

Aberrant RNA processing and expression of cryptogenic exons as candidate mechanisms.

This links RNA-binding protein dysfunction to changes in the expressed neuronal transcriptome.

The magnitude of its contribution to motor neuron death is not established in the excerpt.

Slide 31 · Stress granules and RNA-binding proteins

Cellular stress

Temporary changes in translation

Stress granules

RNA–protein material assembled

TDP-43 / FUS biology

RNA-binding proteins participate

ALS-linked disturbance

RNA handling and proteostasis become abnormal

Stress-granule involvement is a mechanistic theme rather than a stand-alone diagnostic criterion.

Slide 32 · Genes related to selective autophagy

SQSTM1 (p62), OPTN (optineurin) and ubiquilin-1 are among genes highlighted by Robbins.

Their association with ALS strengthens the link between neurodegeneration and protein-clearance pathways.

Specific mutant effects are not detailed in the supplied ALS passage.

Slide 33 · Cytoskeletal genes in the ALS landscape

Source examples

TUBA4A: Tubulin α4A

PFN1: Profilin 1

Both are assigned to the cytoskeletal category

Interpretive scope

Structural integrity and intracellular transport are plausible vulnerable pathways.

The source lists these genes but does not specify a detailed mutation-to-phenotype cascade.

Slide 34 · Gene–protein–pathway correspondence

Gene / locus

Encoded product or lesion

Source-linked theme

SOD1

Cu/Zn superoxide dismutase

Misfolding; toxic gain of function

C9orf72

Hexanucleotide repeat expansion

Repeat-derived peptide deposits; ALS–FTLD

TARDBP

TDP-43

RNA processing; inclusions

FUS

FUS

RNA binding / stress-granule pathway

SQSTM1, OPTN

p62, optineurin

Selective autophagy

TUBA4A, PFN1

Tubulin α4A, profilin 1

Cytoskeletal processes

Slide 35 · Convergence without assuming a single cause

Molecular diversity

Misfolding · repeats · RNA · autophagy

Vulnerable processes

Proteostasis · transport · cell stress

Selective pathology

Motor neuron degeneration

Final phenotype

Muscle denervation and weakness

Convergence is a teaching synthesis of pathways, not a claim that their relative causal weights are known.

Slide 36 · Do not overgeneralize TDP-43 pathology

Many ALS cases

Cytoplasmic TDP-43-positive inclusions are described in sporadic ALS.

Also occur in familial C9orf72- and TARDBP-linked cases.

Important exceptions

TDP-43 inclusions are absent in SOD1-mutant ALS in this description.

They are also absent in FUS-mutant ALS in this description.

Slide 37 · Anatomic distribution of lesions

Site

Primary microscopic / gross change

Why it matters

Motor cortex

Possible precentral gyrus atrophy

Upper motor neuron loss

Corticospinal tracts

Loss of myelinated axons; reduced volume

Descending motor pathway degeneration

Spinal anterior horns

Neuron loss + reactive gliosis

Lower motor neuron loss

Brainstem motor nuclei

Neuronal loss

Bulbar motor dysfunction

Anterior spinal roots

Attenuated motor roots

Loss of lower motor axons

Skeletal muscle

Neurogenic atrophy

Motor unit denervation

Slide 38 · Gross finding: Attenuated anterior motor roots

Schematic — not a histologic specimen

Posterior (sensory) root

Anterior (motor) root: Attenuated

Relative representation only

What the source establishes

Anterior roots become thin because motor axons are lost.

The posterior sensory roots provide a useful anatomic comparison in Fig. 28.43.

The original Robbins photograph is not reproduced here.

Slide 39 · Precentral motor cortex may become atrophic

In especially severe ALS, the precentral motor gyrus may show atrophy.

This parallels upper motor neuron loss in the cerebral cortex.

Gross cortical atrophy need not be evident in every affected individual.

Slide 40 · Spinal anterior horns: Neuron loss

Schematic — not a histologic specimen

Reduced motor neuron population

What the source establishes

Motor neurons are reduced along the spinal cord.

Reactive gliosis accompanies the neuronal loss.

This drawing is conceptual and does not reproduce an H&E micrograph.

Slide 41 · Reactive gliosis accompanies anterior horn injury

Gliosis is a tissue response to neuronal loss in the spinal anterior horns.

Loss of lower motor neurons translates into fewer motor axons leaving the cord.

Together, these changes explain anterior root thinning and muscle denervation.

Slide 42 · Bulbar motor nuclei are also affected

Similar degenerative findings occur in the hypoglossal nucleus.

The nucleus ambiguus and motor trigeminal nucleus may also be involved.

This anatomic distribution provides the pathologic substrate for bulbar symptoms.

Slide 43 · Intracytoplasmic inclusions in surviving neurons

Schematic — not a histologic specimen

Intracytoplasmic inclusions

What the source establishes

Bunina bodies are described as PAS-positive cytoplasmic inclusions.

They may represent remnants of autophagic vacuoles.

Many cases also contain TDP-43-positive cytoplasmic inclusions.

Slide 44 · Two inclusion types emphasized in ALS

Bunina bodies

Cytoplasmic structures in surviving motor neurons

PAS-positive in the source description

Interpreted as probable autophagic-vacuole remnants

TDP-43-positive inclusions

Cytoplasmic neuronal aggregates

Seen in many sporadic and selected familial cases

Not universal across molecular subtypes

Slide 45 · TDP-43 inclusions require molecular context

TDP-43-positive inclusions in sporadic ALS and C9orf72- or TARDBP-linked familial ALS.

SOD1- and FUS-mutant cases are specified as exceptions.

Consequently, TDP-43-positive pathology should not be asserted for all ALS cases.

Slide 46 · Corticospinal tract degeneration

Schematic — not a histologic specimen

Degenerated corticospinal fibers

What the source establishes

Upper motor neuron injury causes loss of corticospinal axons.

The tract becomes reduced in volume and loses myelinated fibers.

The original textbook image is described as showing a lack of myelin staining.

Slide 47 · Corticospinal fiber loss can be level-dependent

The source notes that descending tract abnormalities may be especially evident at lower spinal segmental levels.

The pattern reflects degeneration of long descending motor pathways.

The image Figure 28.43 uses loss of staining to demonstrate this abnormality.

Slide 48 · Neurogenic atrophy in skeletal muscle

Schematic — not a histologic specimen

Unequal, diminished myofiber caliber

What the source establishes

Muscles innervated by the degenerated lower motor neurons become atrophic.

The primary lesion is loss of neural input rather than primary myofiber degeneration.

This is an abstract caliber comparison, not a patient biopsy.

Slide 49 · Correlating pathology with observed findings

Anterior horn loss

Motor axon depletion

Muscle denervation

Neurogenic atrophy

Motor unit failure

Reduced muscle bulk and strength

Clinical progression

Worsening disability

The cellular lesion predicts changes in both movement and muscle morphology.

Slide 50 · Clinical signs linked to anatomical compartments

Feature

Anatomic interpretation

Pathologic substrate

Spasticity

Upper motor neuron dysfunction

Motor cortex/corticospinal tract degeneration

Atrophy

Lower motor neuron denervation

Anterior horn/cranial motor neuron loss

Fasciculations

Motor unit involvement

Lower motor neuron pathology

Bulbar impairment

Cranial motor system dysfunction

Brainstem motor nuclei involvement

Respiratory weakness

Progressive motor system failure

Respiratory muscle denervation

Slide 51 · Early hand weakness may be asymmetric

Difficulty with fine motor tasks may be an early manifestation.

Patients may report repeatedly dropping objects.

The source specifically highlights asymmetric hand weakness at presentation.

Slide 52 · Cramping and spasticity in ALS

Cramping

May appear in early disease along with limb weakness

Reflects disturbed motor unit function

Spasticity

Can involve the arms and legs

Is consistent with upper motor neuron dysfunction

Slide 53 · Progressive loss of muscle bulk and strength

As the disease advances, skeletal muscle power and bulk diminish.

Fasciculations are involuntary contractions of individual motor units.

The mixture of weakness, atrophy and fasciculations corresponds to ongoing lower motor neuron loss.

Slide 54 · Why respiratory complications develop

Motor neuron degeneration

Progression beyond limb motor pools

Respiratory muscle involvement

Loss of ventilatory muscle function

Reduced effective ventilation / cough

Greater respiratory vulnerability

Clinical complication

Recurrent pneumonia is described

Respiratory involvement is central to advanced ALS, although the textbook excerpt does not prescribe management algorithms.

Slide 55 · Recognized patterns of motor neuron involvement

Clinical pattern

Motor neuron emphasis

Terminology used in Robbins

Typical ALS

Upper + lower motor neurons

Mixed motor neuron disease

Progressive muscular atrophy

Predominantly lower motor neurons

LMN-predominant pattern

Primary lateral sclerosis

Predominantly upper motor neurons

UMN-predominant pattern

Progressive bulbar palsy / bulbar ALS

Early lower brainstem motor nuclei

Bulbar-predominant pattern

Slide 56 · Progressive muscular atrophy: An LMN-predominant pattern

This term is used for uncommon cases in which lower motor neuron involvement predominates.

Wasting and denervation-related weakness are conceptually prominent.

The distinction describes a different distribution of motor pathology within the source framework.

Slide 57 · Primary lateral sclerosis: An UMN-predominant pattern

This term for cases with mostly upper motor neuron involvement.

Spastic motor impairment is the corresponding clinical pattern.

This is an anatomic phenotype distinction, not evidence that every case shares identical molecular pathology.

Slide 58 · Progressive bulbar palsy / bulbar ALS

Early degeneration affects lower brainstem cranial motor nuclei.

Swallowing and speech abnormalities dominate the presentation.

The source describes a rapidly progressive course in this subgroup.

Slide 59 · Bulbar dysfunction has a direct anatomical basis

Hypoglossal / other bulbar nuclei

Lower motor neuron degeneration

Bulbar muscle denervation

Impaired motor coordination and strength

Clinical presentation

Speech and swallowing abnormalities

Course

Can progress rapidly

Bulbar symptoms follow injury to motor nuclei supplying oropharyngeal functions; No clinical criteria were imported.

Slide 60 · Clinical course: Bulbar versus less severe bulbar disease

Early severe bulbar involvement

The source describes progression over approximately 1–2 years.

Speech and swallowing impairment dominates.

Less severe bulbar involvement

Roughly half alive 2 years after diagnosis.

This is a textbook description, not a contemporary pooled survival estimate.

Slide 61 · Extraocular motor function is relatively late to fail

Motor neurons supplying extraocular muscles are among the last motor groups involved.

With prolonged survival, often associated with ventilatory support, extraocular motor output may eventually fail.

“Relative preservation” should not be interpreted as absolute immunity.

Slide 62 · Familial and sporadic presentations differ in onset

Familial ALS is described as developing symptoms earlier than most sporadic ALS.

The textbook characterizes overall clinical courses as comparable.

These are group-level patterns; The excerpt does not provide genotype-specific natural-history predictions.

Slide 63 · ALS–FTLD: Clinical and pathological continuum

Motor-dominant

Weakness / denervation

Combined

Motor + cognitive / behavioral

Cortex-dominant

Frontotemporal dysfunction

Many patients with ALS show cortical disease; Overlap is particularly clear for TDP-43-related pathology.

Slide 64 · Frontotemporal dementia may accompany ALS

Some individuals with ALS develop clinically important frontotemporal cerebral disease.

A common presentation is frontotemporal dementia.

Pathology frequently corresponds to FTLD with TDP-43 inclusions.

Slide 65 · Shared genetic and proteopathic features

ALS side

Motor neuron loss and denervation

TDP-43 inclusions in many molecular subtypes

C9orf72 and TARDBP among overlapping genes

FTLD side

Frontotemporal cortical degeneration

TDP-43-associated inclusions in relevant FTLD

Genetic overlap with C9orf72 and TARDBP

Slide 66 · ALS versus Kennedy disease

Dimension

ALS

Kennedy disease

Motor neuron pattern

Often upper + lower

Lower motor neuron degeneration

Genetic principle

Usually sporadic; diverse familial genes

X-linked CAG repeat in androgen receptor

Other features

Frontotemporal overlap may occur

Androgen-insensitivity features

Course

Progressive and often rapidly disabling

Usually slow; lifespan reported as normal

Slide 67 · ALS versus 5q spinal muscular atrophy

Dimension

ALS

5q spinal muscular atrophy

Typical onset

Fifth decade or later

Usually a disorder of childhood

Motor neuron target

Upper + lower motor neurons

Lower motor neurons

Genetic basis

Multiple genes / many sporadic cases

SMN1 loss of function; SMN2 copy count modifies severity

Pathobiologic clue

Protein aggregation and RNA / autophagy

Reduced survival motor neuron protein

Slide 68 · Differential discrimination by pattern

Finding

ALS

Alternative disease suggested

UMN + LMN findings

Characteristic combined pattern

Pure LMN disease is less typical

Androgen-insensitivity phenotype

Not an ALS-defining feature

Kennedy disease

Childhood-onset LMN syndrome

Unusual for typical ALS

5q-SMA

Frontotemporal cortical symptoms

Possible within ALS spectrum

ALS–FTLD overlap

Slide 69 · Case application: Mixed motor neuron pathology

Clinical vignette

An adult develops progressively asymmetric hand weakness, loss of muscle bulk, fasciculations and leg spasticity. The presentation subsequently involves swallowing difficulty.

Which upper- and lower-motor-neuron sites account for these findings?

Slide 70 · Case explanation: Mixed motor neuron pathology

Motor cortex / tract

Spasticity and upper motor signs

Anterior horn

Atrophy and fasciculations

Bulbar motor nuclei

Dysphagia / speech problems

Integration

Combined ALS-type distribution

The pathology-based interpretation is an application of the source; It is not a standalone clinical diagnostic rule.

Slide 71 · Case application: Molecular pathological inference

Clinical vignette

A familial motor neuron disease specimen shows motor neuron loss with cytoplasmic TDP-43-positive inclusions. A second affected family has a known pathogenic SOD1 variant.

Should TDP-43-positive inclusions automatically be expected in both families?

Slide 72 · Case explanation: Molecular subtype matters

TDP-43-positive family

The inclusion pattern is compatible with many ALS settings.

It to sporadic, C9orf72- and TARDBP-associated ALS.

SOD1-mutant family

A different proteinopathy pattern.

TDP-43 cytoplasmic inclusions are not expected in SOD1-mutant ALS in the cited discussion.

Slide 73 · Synthesis: Clinical and anatomical map

Pathological compartment

Microscopic / gross lesion

Clinical expression

Motor cortex / descending tract

Upper motor neuron and myelinated-fiber loss

Spasticity; weakness

Spinal anterior horn

Motor neuron loss; gliosis

Atrophy; fasciculations; weakness

Bulbar motor nuclei

Loss of motor neurons

Dysarthria / dysphagia

Skeletal muscle

Denervation atrophy

Loss of muscle bulk and function

Frontotemporal cortex (subset)

FTLD-type cerebral pathology

Dementia / cortical features

Slide 74 · Five conclusions supported by Robbins

ALS is a progressive disorder involving upper and lower motor neurons.

Sporadic disease predominates; Familial forms reveal several mechanistic pathways.

Protein misfolding, RNA dysfunction and impaired proteostasis converge on neuronal injury.

Anterior horn, corticospinal tract, brainstem and muscle findings explain clinical manifestations.

ALS and FTLD overlap in genetics, neuropathology and, in some patients, clinical presentation.

Slide 75 · Important limits of this lecture’s source

No complete contemporary diagnostic criteria or EMG diagnostic algorithm appear in the supplied ALS passage.

The quoted textbook estimates are not independently updated or reanalyzed here.

Robbins Figure 28.43 was described from its caption; Its copyrighted specimen photographs were not reproduced.

Mechanisms explicitly described as uncertain remain tentative in these slides.

Slide 76 · Primary reference and source scope

Robbins, Cotran & Kumar

Pathologic Basis of Disease, 11th edition (2026)

Chapter 28 · The Central Nervous System · Amyotrophic Lateral Sclerosis · pp. 1172–1173

Parent context: Neurodegenerative Diseases; adjacent comparison: Other Motor Neuron Diseases.

All diagrams are native, editable educational schematics; no histologic specimen images are represented.