degenerative diseases of cns

1. DEGENERATIVE DISEASES of CNS
By
Dr. FARZAN ISLAM

2. NEURODEGENERATIVE DISEASES
• Characterized by cellular degeneration of
subsets of neurons that typically are related
by function rather than by any physical
location in the brain

3. CAUSES OF COGNITIVE IMPAIRMENT
A:PRIMARY NEURODEGENERATIVE DISEASES:
• Alzheimer disease
• Frontotemporal lobar degeneration
• Lewy body demantia
• Huntington disease
• Spinocerrebellar ataxia

4. B: INFECTIONS
• prion disease
• HIV associated neurocognitive disorder
• Viral encephalitis
• Neurosyphilis
• Chronic menengitis
C: VASCULAR AND TRAUMATIC DISEASES
D: METABOLIC AND NUTRITIONAL DISEASES
E: MISCELLANEOUS

5. PRION DISEASES
• Sporadic
• Familial
• Iatrogenic
• Variant forms of Creutzfeldt-Jakob disease(CJD)
• Animal diseases- Scrapie in sheep
• Bovine spongiform encephalopathy (mad cow
disease) in cattle

6. Mad cow

7. PATHOGENESIS
• PrP may undergo a conformational change
from its normal shape PrPc to an abnormal
shape called PrPsc
• When Prpsc physically interact with PrP
molecules it induces them to also adopt the
Prpsc conformation

10. Creutzfeldt-Jakob disease (CJD)
• Rapidly progressive dementing
illness
• Typical duration from onset of
subtle changes in memory and
behaviour to death is only 7
months
• Sporadic in approximately 85% of
cases
• Affecting persons older than 70
years of age
• Familial forms- mutations in PRNP
in younger

11. Morphology CJD
• Progression to death is so rapid, little evidence of
brain atrophy
• Microscopic pathogonomic finding is spongiform
transformation of cerebral cortex and deep gray
matter structures
• There is uneven formation of small, vacoules of
varying sizes within neuropil or perikaryon of
neurons
• In advanced cases, severe neuronal loss, gliosis,
expansion of vacoulated areas into cyst like
spaces status spongiosus

12. Prion disease. A, Spongiform change in the cerebral cortex. Inset, High
magnification of neuron with vacuoles. B, Cerebellar cortex showing kuru
plaques (PAS stain) representing aggregated PrPsc. C, Cortical plaques
surrounded by spongiform change in vCJD.

13. vCJD
• Neuropathologic and molecular features similar
to CJD but it differs
• Young adults
• Behavioural disorders in early disease stages
• Neurologic syndrome progress slowly
• Exposure to prion disease of cattle
• Transmission by blood transfusion
• Morphology is similar, but abundant amyloid
plaques surrounded by spongiform change

14. PRIMARY DISEASES OF MYELIN
MULTIPLE SCLEROSIS
• Primarily a white matter disease
• Most common demyelinating disorder
• Autoimmune, characterised by distinct
episodes of neurologic deficits, separated in
time, attributable to white matter lesions that
are separated in space
• Any age but rare in childhood and after 50
• Relapsing and remitting episodes of
neurologic impairment

18. Pathogenesis - MS
• Environmental and genetic factors result in loss
of tolerence to self protein (myelin antigens)
• Genetic risk for MS is attributable to HLA-DR
variants – DR2 allele being the one
• Polymorphisms in genes encoding receptors for
IL-2 & IL-7 which are known to control activation
and regulation of T cell mediated immune
responses
• CD4+ T cells – TH 17 TH 1  Injury to myelin
• CD8+ T cells and B cells

19. Morphology - MS
• Active Plaque: Ongoing myelin breakdown, abundant
macrophages with myelin debris
• Lymphocytes and macrophages- perivascular cuffs
• Axons are preserved
• 4 types:
• Type I: Macrophages with sharp margins
• Type II: Type 1 + complement deposition
• Type III: Less defined borders, oligodendrocyte
apoptosis
• Type IV: Nonapoptotic oligodendrocyte loss
• Inactive: No inflammation, no myelin, only gliosis

20. Multiple sclerosis. Section of brain showing brown
plaque around occipital horn of the lateral ventricle

21. MS. Unstained regions of demyelination (MS plaques)
around the fourth ventricle (Luxol fast blue PAS stain
for myelin).

22. MS. A, Myelin-stained section shows the sharp edge of a
demyelinated plaque and perivascular lymphocytic cuffs. B, The
same lesion stained for axons shows relative preservation.

23. Clinical Features - MS
• Relapses followed by remissions
• Gradual, stepwise accumulation of neurologic
deficits
• Changes in cognitive function
• CSF: Mild elevated protein level with an
increased proportion of immunoglobulins,
pleocytosis

24. Alzheimer Disease
• Most common cause of dementia in elderly
• Impaired higher intellectual function, altered
mood and behaviour
• Later disorientation, memory loss and aphasia
and after 5 – 10 yrs pt is disabled, mute and
immobile
• Death from intercurrent pneumonia

25. Pathogenesis – Alz D

26. Mechanisms of processing of amyloid precursor protein (APP). APP can be
processed by two pathways; sequential cleavage by β-secretase and γ-
secretase is the pathway that results in the generation of Aβ and the
formation of amyloid fibrils.

27. Morphology
• Gross: Cortical atrophy, widening of sulci
• With significant atrophyhydrocephalus ex
vacuo
• Microscopy: Plaques and neurofibrillary
tangles
• But diagnosis relies on clinical and
pathological features

28. β-amyloidPlaques
Immunocytochemical
staining of senile plaques
in the isocortex of a brain
of a human with AD (anti-
amyloid antibody)

29. NeurofibrillaryTangles
• Immunocytochemical
staining of neurofibrillary
tangles in the isocortex of
the brain of a human with
AD (anti-tau antibody)

30. • Neuritic plaques: spherical collections of
dilated, tortuous neuritic processes around a
central amyloid core which contains Aβ
• Neurofibrillary tangles: bundles of paired
helical filaments containing
hyperphosphorylated tau

31. Alzheimer disease with cortical atrophy most evident on the
right, where meninges have been removed

32. Alzheimer disease. A, Plaques with dystrophic neurites surrounding amyloid cores are visible
(arrows). B, Plaque core and surrounding neuropil are immunoreactive for Aβ. C,
Neurofibrillary tangle is present within one neuron, and several extracellular tangles are also
present (arrows). D, Silver stain showing a neurofibrillary tangle within the neuronal
cytoplasm. E, Tangle (upper left) and neurites around a plaque (lower right) contain tau,
demonstrated by immunohistochemistry.

33. PARKINSON DISEASE
• Tremer, rigidity, brady kinesia and instability
• Damage to dopaminergic neurons – From
substancia nigra and striatum
• Neurodegenerative diseases:
• Parkinson disease
• Multiple system atrophy (MSA)
• Progressive supranuclear palsy (PSP)
• Corticobasal degeneration (CBD)

34. Pathogenesis - PD
• May be sporadic
• Autosoma dominant and recessive forms
• Point mutations in gene encoding α-
synuclein (protein involved in synaptic
transmission)
• Mutations in protein kinase LRRK2
• Mutations in PARK7 or PINK1 gene

35. Morphology - PD
• Pallor of substantia nigra
• Microscopiy: Loss of pigmented ,
catecholaminergic neurons with gliosis
• Lewy bodies found in those neurons that
remain
• These are single or multiple, intracytoplasmic,
eosinophilic, round to elongated inclusions
that have a dense core surrounded by pale
halo

36. Parkinson disease. A, Normal substantia nigra. B, Depigmented substantia
nigra in idiopathic Parkinson disease. C, Lewy body in a substantia nigra
neuron, staining bright pink (arrow).

37. HUNTINGTON DISEASE
• Autosomal dominant movement disorder
• Degeneration of striatum (caudate and putamen)
• Choreic form (dance like) involuntary and jerky
movement of body
• Writhing movements of extremeties
• Progressive average course 15 years
• Forgetfulness and thought disorders,
dementia and depression; average age at
presentation is 40 years. Suicide is a common
cause of death.

38. PATHOGENESIS
• Autosomal dominant disorder (chromosome
4) characterized by expanded trinucleotide
repeats (CAG) in the huntingtin gene located
on 4p16.3
• Further expansion of repeats during
spermatogenesis leads to anticipation.

39. MORPHOLOGY
GROSS:
• Small brain and atrophy of caudate nucleus
and sometimes putamen
• Medial to lateral in cudate
• Dorsal to ventral in putamen
• Globus pallidus atrophied
• Lateral and 3rd ventricles are dilated

40. MICROSCOPIC EXAMINATION
• Severe loss of neurons affecting regions of
striatum
• Medium sized spiny neurons that release
neurotransmitter GABA, enkephalin,
dynorphin and substance p are disappeared
early in disease
• Ubiquinated huntington protein

41. Amyotrophic lateral sclerosis
• Degenerative disorder of upper and lower motor
neurons of the corticospinal tract
• Results from the death of lower motor neurons in
brain stem and upper motor neurons in motor
cortex
• Loss of lower motor neurons results in
denervation, muscular atrophy, weakness and
fassiculation, hyperreflexia and spasticity along
with a babinski sign
• Loss of upper motor neuron results in paresis

42. • Affects men more than women
• 5th decade
• As the disease progresses to involve more of the motor
system, muscle strength and bulk diminshes
• Mutation in SOD gene located on chromosomes 21
• Mutations lead to abormal misfolded protein which
may trigger apoptotic death of neurons
• TDP-43
• FUS

43. MORPHOLOGY
• GROSS:
• ANTERIOR ROOTS OF SPINAL CORD:THIN GRAY
• PRECENTAL GYRUS MILDLY ATROPHIC
• MICROSCOPIC:
• GLIOSIS
• CYTOPLASMIC INCLUSION

44. INFECTIONS OF CNS

45. INFECTIONS OF CNS
• Hematogenous
• Direct implantation
• Local extension
• Peripheral nerves

46. MENINGITIS
• Acute Pyogenic (usually bacterial)
• Aseptic (usually viral)
• Chronic (TB, spirochetal, cryptococcal)
• Examination of CSF is useful in distinguishing
various causes of meningitis

47. Acute Pyogenic Meningitis
• In neonates: E.coli, group B streptococci
• In adolescents: N meningitidis
• In older: Strep. Pneumoniae, Listeria
monocytogenes
• In all age gps, systemic signs of infection
meningeal irritation, Neurologic imp including
headache, photophobia, irritability, clouding of
consciousness and neck stiffness

48. Lumber Puncture
• Increased pressure
• Examination of CSF:
– Abundant neutrophils
– Elevated proteins
– Reduced glucose
• Bacteria may be seen on smear or can be
cultured

49. Morphology - Gross

50. Microscopy
• Neutrophilic infiltration
• Abscess in the brain

51. Aseptic (Viral Meningitis)
• Clinical course is less fulminent than bacterial
• Self limiting
• CSF Examination:
– Lymphocytosis
– Mod protein elevation
– Normal glucose
• Morphology: Either no change or mild
lymphocytic infiltration

52. Chronic Meningitis
• TB
• CSF Examination:
– Only moderate increase in CSF cellularity with
polymorphonuclear and mononuclear cells
– Protein level is elevated often strikingly
– Glucose is mod reduced or normal
• Morphology: Obliterative endarteritis of
arteries running through sub-arachnoid space
• Lympho plasmacytic infiltrate, granulomas

53. Characteristic findings of viral encephalitis include perivascular
cuffs of lymphocytes (A) and microglial nodules (B).

54. BRAIN ABSCESS
• Bacterial infections (direct implantation, local
extension, hematogenous spread.
Predisposing conditions ( acute bacterial
endocarditis, cyanotic congenital heart
disease, chronic pulmonary sepsis),
destructive leison, progressive deficits, inc.
intracranial pressure, inc. CSF protein & WBC,
glucose normal, lead to ventriculitis,
meningitis, thrombosis

55. MORPHOLOGY
• central liquefactive necrosis with fibrous capsule,
exuberant neovascularization, marked odema,
granulation tissue, outside is zone of reactive
gliosis.
• VIRAL ENCEPHALITIS: with meningeal
inflammation (meningoencephalitis), perivascular
& parenchymal mononuclear infiltrate, microglial
nodules & neuronophagia, inclusion bodies,
(rabies, polio & rubella_ congenital
malformations

56. DYSTONIA
• Neurological disorder characterized by
sustained muscle contractions that frequently
causes twisting , repetitive movements or
abnormal movements of body
• Dystonia can be classified by etiology
• Primary and 2ndary
• Age (early and late onset)
• Affected body region(focal, multifocal,
segmental, hemidystonia and generalized)

57. • When the cause is genetic or idiopathic it is
referred to as primary
• When there is an identifiable cause (stroke,
brain trauma or metabolic disease) it is
referred to as 2ndary

58. THANKS