General pathology slides for study purpose

1. Neurodegenerative Disorders
By- Dr. Nekta Anand
Guide- Dr. Y.R Goteker

3. • Neurodegenerative diseases are disorders characterized by the progressive
loss of neurons, typically affecting groups of neurons with functional
relationships even if they are not immediately involved.
• The pathologic process that is common across most of the neurodegenerative
diseases is the accumulation of protein aggregates, which can be used as a
morphologic hallmark of the disease (hence the occasional use of the term
“proteinopathy”).

4. Degenerative diseases
Affecting the
Cerebral cortex
Affecting the
Basal ganglia
and brain stem
Spinocerebellar
degeneration
Degenerative
disease affecting
The Motor Neurons
1. Alzheimer
disease
2. Frontotemporal
disease
3. Vascular
dementia
1.Parkinsonism
2. Dementia with
Lewy bodies
3. Multiple system
atrophy
4.Huntington
disease.
Spinocerebellar Ataxia 1. Amyotrophic Lateral
Sclerosis
(ALS)= motor neuron
disease
2. Bulbospinal
Atrophy(KENNEDY
SYNDROM)
3. Spinal Muscular Atrophy

5. CNS Degenerations: Classification
• Neuronal Degenerations:
• ¨Primary Degenerations:
• Global – Alzheimer, Lewy body, Fronto-temporal
• Selective/System – Parkinson's, Huntington's, MND
• Secondary Degenerations:
• Toxins, metabolic(storage), infections, nutritional, Alcohol & B12 def.
• Disorders of Myelin:
• Demyelinating Disorders - Multiple sclerosis
• Dysmyelinating disorders – Leukodystrophies.

6. Alzheimer’s disease
• Commonest cause of dementia in elderly.
• Insidious with mood and behavior change.
Pathology:
• Significant cortical atrophy
• Secondary ventricular enlargement
• Neurofibrillary tangles
• ¨Neuritic plaques (Aβ amyloid)

7. AD Morphology -Mild to Moderate
• Involves cerebral cortex
• Mild signs: Memory loss, confusion, mood changes, and anxiety.
• Moderate signs: increased memory loss and confusion, problems
recognizing people,
• Severe AD :-Extreme shrinkage of brain.
Patients are completely dependent on others for care.
Other Symptoms: weight loss, seizures, skin infections,
loss of bladder and bowel control
• Death usually occurs from aspiration pneumonia or other infections.

9. Alzheimer’s disease: Genetics
• Autosomal dominant genetic pattern – rare
• 4 genes on chromosomes 1, 14, 19, and 21, influence initiation and
progression.
• Chromosome 21 generates the precursor protein for the amyloid protein
(APP).
• Chromosome 19 encodes APoE which has strong risk for developing AD.
• Trisomy 21 produces early Alzheimer's disease in persons with Down
syndrome

10. Normal
Generation of
A- beta plaque

11. Pathogenesis:-
• Deposition of neurotoxic amyloid protein (peptide Aβ derived from APP) around
blood vessels & neurons – extracellular plaques.
• Abnormal forms of axonal microtubule protein (protein tau) in neurons
neurofibrillary intracellular tangles.
• Leading to Atrophy of neurons, gliosis.

12. Neurons have an internal support structure partly made up of
microtubules. A protein called tau helps stabilize microtubules In AD,
tau changes, causing microtubules to collapse, and tau proteins
clump together to form neurofibrillary tangles.

13. CNS Morphology in Alzheimer's:
A-Neuritic Plaque,
B-Amyloid

15. Neurofibrillary Tangles in AD: Tau protein
C-Neurofibrillary (tau) tangles within the neurons (H & E).
D-Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm

16. Other components includes:-
• MAP2 and Ubiquitin
• Cerebral amyloid angiopathy
• Vascular amyloid
• Granulovacuolar degeneration
• Hirano bodies.

17. Neuron degeneration-Granulovcuolar:-
A. Several neurons display granulovacuolar degeneration of the cytoplasm.
B. A neuron (center) contains an eosinophilic Hirano body (arrow).

18. Fronto-Temporal Dementia:-
• Second common, group of dementia, progressive deterioration of personality,
behavior & speech.
• Memory is not affected until late.
• Accumulation of TAU containing deposits so aka Taupathy.
• FTD includes-
• FTD with parkinsonism linked tau mutation.(MAPT gene mutation)
• Pick disease
• Progressive supranuclear palsy.( no mutation in MAPT)
• Corticobasal degeneration.(Neuronal achromasia= Ballooned neurons)
• FTD without Tau pathology.(ubiquitin containing inclusion )

19. Pick’s Disease:- Lobar atrophy
• Severe 40-65y ,Rare.
• Selective Frontal & temporal lobe atrophy.
• Progressive aphasia /language dysfunction.
• Behavior & personality change.
• Preserved memory.
• Gross- Atrophy of gyri to WAFER thin (knife edge) appearance.
• Micro: Neurons with round intracytoplasmic Pick’s bodies (tau
protein)

20. Vascular Dementia:-
• Cognitive decline to vasculitis.
• Progressive cognitive disorder associated with vascular injury to the brain.
Different pathophysiological types.
• ¨Mild vascular cognitive impairment – arteriosclerosis.
• ¨Multi-infarct / single large infarct ¨Hypertensive lacunar lesions.
• ¨Binswanger disease – subcortical leukoencephalopathy - boxers, trauma.
• ¨Mixed – AD+vascular.

21. Parkinson’s disease:-
• “Shaking palsy"
• Parkinsonism: Clinical syndrome.( due to damage in Dopaminergic system.)
• dopamine antagonists, post encephalitis.
• Toxins: MPTP(heroin),
• Parkinson’s disease – Primary atrophy of substantia nigra. Dopaminergic system
• Clinical features:
• Diminished facial expressions, stooped posture,
• Slow voluntary movements, festinating gait, rigidity & fine rolling tremors.
• Tremor, bradykinesia and rigidity (45-60 years)
• Inhibition of movement & dementia in some cases

22. Pathogenesis :-
• Destruction of dopaminergic neuronal cells in the substantia nigra and the basal ganglia
• Degeneration of dopaminergic nigrostriatal pathway.
• Depletion of dopamine store
• Imbalance in excitatory (Ach) and inhibitory (dopamine) neurotransmitters in the corpus striatum
• Impairment of extrapyramidal tracts controlling body movements
• Tremers , rigidity, bradykinesia

23. Genetics
• 5 genes are associated with the PD-
• Alpha- synuclein
• LRRK2
• PARKIN
• DJ-1
• KINASE PINK-1
AD
AR

24. Pathology of Parkinson's disease:-
• Gross: Loss of pigment in substantia nigra.
• Neuronal loss, degeneration.
• Loss of neurons replaced , by gliosis (microglia)
• Lewy bodies (α-synuclein) in neurons

25. Lewy-body dementia:-
• 10-15% of Parkinson's with dementia (Alzheimer's).
• Impaired memory of recent events, confusion, language
problems.
• Dementia + Visual Hallucinations
• Lewy bodies (α-synuclein) in many part of cortex &
substantia nigra
• Pathological finding – depigmentation of substantia nigra and
locus ceruleus.
• Atrophy of cortex like AD.
Cortical Lewy bodies (α-synuclein)
special stain

26. Multiple System Atrophy:-
• Characterized by glial cytoplasmic inclusions.
• It can have different pattern of clinical presentation-(due to MSA protein
mutation)
• MSA-P= Striatonigral degeneration or Cerebellar dysfunction.
• MSP-C= Olivopontocerebral atrophy.(least frequent)
• MSP-A= Shy-Drager syndrome
• Atrophy of cerebellum , cerebellar peduncle, pons .

27. Huntington’s Disease:-
• Dementia, depression, Choreioform movements(jerking dementia).
• Common after 5th decade
• Autosomal Dominant.
• Huntington gene on 4p called –Huntingtin.
• Excess CAG tandem repeat.
• repeats = severity
• Atrophy of caudate & putamen (striatum)
• Compensatory hydrocephalus of lateral ventricles.
• Neuronal loss + fibrillary gliosis

28. Normal - Huntington’s
Atrophy

29. Spinocerebellar Ataxias:-
• Sign and symptoms referable to cerebellum, brain stem, spinal cord, peripheral
nerve.
• Pathologically characterized by Neuronal loss.
• Genetics :- Expansion in CAG repeat.
• Expansion in polygutamic disease affecting six different type of
proteins.
• SCA1,2,3= Machado –joseph disease and SCA six,7,17.
• Intranuclear inclusions can be found in these form of SCA.

30. Friedreich Ataxia:-
• AR spinocerebellar degeneration.
• Seen in 1st decade of life.
• It id due to expansion of GAA trinucleotide repeat in 1st intron of gene on
chr. 9q13 that encodes FRATAXIN gene.
• Axonal loss , gliosis
• Cardiomegaly and pericardial adhesions may also be seen.

31. Ataxia Telangiectasia:-
• Characterized by Ataxia –dyskinetic syndrome in early childhood.
• Telangiectasia in skin, conjunctiva .
• AR disorder.
• Mutation of ATM gene on chr.11q22q23.
• Loss of purkinje and granule cells in cerebellum.
• Unsteadiness in walking
• Relentlessly progressive to death.

32. Amyotrophic Lateral Sclerosis
(ALS)= motor neuron disease:-
• Loss of motor neurons in spinal cord and brain stem and upper motor neurons.
• Men > women
• Autosomal dominant inheritance.
• Genetics:- ALS are by mutation in gene ; encoding copper- zinc superoxide dismutase(SOD1) on
chr.21.
• Microscopy:- Reduction in number of neuron of number of anterior horn neurons through out the
length of spinal cord.
• Associated reactive gliosis
• Loss of anterior root- myelinated fibers.
• PAS positive cytoplasmic inclusions, called BUNINA bodied, that appear to be remnant of autophagic
vacuoles.

33. B, Spinal cord
showing loss of myelinated
fibers (lack of stain) in
corticospinal tracts as well
as degeneration of anterior
roots.

34. • Bulbospinal Atrophy (Kennedy syndrome)-
• X linked adult onset ds.
• C/F – androgen insensitivity ,gynecomastia, testicular atrophy,
oligospermia.
• Degeneration of LMN in the spinal cord and brain stem.
• Gene defect is expansion of a CAG /polyglutamine repeat in the androgen
receptors.
• Spinal muscular Atrophy:-
• These group of disease affects mainly the LMNs in the children's.

35. Demyelinating Disorders:-
• Selective myelin damage - axon sparing.
• Defective transmission of impulse.
• Prognosis à repair & axon damage.
• Types & Classification
• Immune – Multiple sclerosis
• Genetic – Metabolic, Leukodystrophies.
• Vitamin deficiency – Vit. B12
• Infections – JC virus

36. Multiple Sclerosis:-
• Autoimmune .
• Limb Weakness, paresthesia
• Relapsing & remitting.
• Progressive -death in years.
• Multiple soft pink plaques of demyelination periventricular.
• Inflammation, perivascular T lymphocytes & plasma cells.
• Radiological sign- Dawson’s fingers(plaques of demyelination periventricular)
• CSF -oligoclonal IgG.

39. Like patches of grey matter within white
matter…!
MS- PERIVENTRICULAR PLAQUE

40. Multiple Sclerosis -Chronic plaque
• Plaque contains fibrillary astrocytes, few lymphocytes and macrophages present
around the blood vessels.
• Normal myelin area appears blue and myelin loss area appears white in myelin
stain.

41. Leukodystrophies:-
• Characterized by myelin abnormalities.
• Also defects peroxisome enzymes.
• c/f:-
• deterioration of motor skills
• Spasticity
• Hypotonia
• Ataxia
• AR – most common
• Adrenoleukodystrophy
• X-linked type - rare

42. Metabolic CNS Disorders:-
• Alcoholism induced CNS disorders.
• Wernicke syndrome (Vit B1 def.)
• Central pontine myelinosis.
• Cortical atrophy.
• Atrophy of vermis of the cerebellum.

43. Vitamin Def & Neuropathy:-
• A- benign intracranial hypertension.
• B1- Wernicke's Korsakoff's syndrome
• B2- peripheral neuropathy ,Ataxia , Dementia.
• B -Convulsions in infants
• B12- Weakness in paresthesia in the lower limb
(1 And 2)
• C- Scurvy
• E- weakness , sensory loss, Ataxia, nystagmus,.
6

44. Wernicke's encephalopathy:-
Recurrent petechial hemorrhages in the hypothalamus, mamillary bodies with
atrophy.
Wernicke's syndrome Altered Thermal regulation & consciousness,
ophthalmoplegia, nystagmus
Korsokoff Psychosis- Loss of recent memory compensated by confabulation

45. Korsakoff's disease:
• Note: Shrunken, bodies brown mammillary bodies
indicating chronic stage or Korsakoff's disease.
• Central pontine myelinolysis:-
Demyelination of the center of the basis pontis. Cause is
unknown but is usually seen in chronic alcoholics and is
often associated with rapid over correction of hyponatremia.
• Alcoholic cerebellar atrophy:-
Shrunken folia and widened fissures of the anterior, superior
vermis of the cerebellum. Another change which may be
found in chronic alcoholics

46. Kernicterus -Neonatal hyperbilirubinemia:-
• Kern+Ictirus =yellow nuclei.
• Complication of Neonatal jaundice.
• Polycythemia
• Hemolytic disease of new born
• Hemolytic anemia

47. Summary of Pathology of CNS degenerations:
Disease Lesion Components Location
Alzheimer disease Plaques & NF
tangles
β-Amyloid & tau Extracellular
Intracytoplasmic
Frontotemporal
dementias
(eg. Picks)
NF tangles tau Intracytoplasmic
Dementia with Lewy
bodies
Lewy bodies
α- - Synuclein
Intracytoplasmic
Parkinson disease Lewy bodies α-Synuclein Intracytoplasmic
Amyotrophic
lateral sclerosis
Spheroids Neurofilament
subunits/super-oxide
dismutase (SOD-1)
Intracytoplasmic
Multi system atrophy Glial inclusions tau Intracytoplasmic
Spinocerebellar Ataxia Protein inclusions SCA Intranuclear