Ppt

• Demyelinating diseases are acquired conditions characterized by preferential damage to myelin with relative preservation of axons
• Demyelinating diseases


  The clinical deficits, at least initially, are due to the effect of myelin loss on the transmission of electrical impulses along axons
• Demyelinating diseases


  • The natural history is determined by the limited capacity of the CNS to regenerate normal myelin and the degree of secondary damage to axons that occurs as the disease runs its course
• Causes of demyelination


  • Immune-mediated destruction of myelin (as in multiple sclerosis [MS])
  • Infections (as in PML)
  • Inherited disorders (leukodystrophies)
• Multiple Sclerosis (MS)


  An autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits that are separated in time and attributable to patchy white matter lesions that are separated in space
• MS is the most common of the demyelinating disorders
• Onset of MS


  May become clinically apparent at any age, but onset in childhood or after 50 years of age is relatively rare
• Gender distribution of MS

  Women are affected twice as often as are men
• Clinical course of MS

  Relapsing and remitting episodes of variable duration, neurologic defects, followed by gradual and partial recovery of neurologic function
• Pathogenesis of MS


  • Involves both genetic and environmental factors, with a strong association with a DR haplotype of the major histocompatibility complex and IL-2 and IL-7 receptor genes. There is geographic variation in the prevalence of MS, with a higher number of cases diagnosed away from the equator and low level of vitamin D. The disease is initiated by Th1 and Th17 T cells that react against myelin antigens and secrete cytokines
• Morphology of MS lesions

  White matter disease, firm ("sclerosis") and appear as well circumscribed, somewhat depressed, glassy, gray-tan, irregularly shaped plaques. Plaques commonly occur adjacent to the lateral ventricles and can extend into gray matter
• Active MS plaque


  • Ongoing myelin breakdown associated with abundant foamy macrophages, lymphocytes as perivascular cuffs
• Inactive MS plaque


  • No macrophage-rich infiltrate, little to no myelin is found
• Clinical features of MS

  Unilateral visual impairment due to involvement of the optic nerve (optic neuritis) is a frequent initial manifestation. Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia. Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and loss of bladder control. CSF shows mildly elevated protein level, moderate pleocytosis, and raised IgG levels
• Treatment of MS


  Immunosuppressive or immunomodulatory agents
• Neuromyelitis Optica


  A syndrome with synchronous (or near-synchronous) bilateral optic neuritis and spinal cord demyelination, more commonly associated with poor recovery from the first attack, often characterized by the presence of aquaporin-4 antibodies. Within the damaged areas of white matter, there is typically necrosis, inflammatory infiltrate including neutrophils and eosinophils, and vascular immunoglobulin and complement deposition
• Acute Disseminated Encephalomyelitis


  A diffuse, monophasic demyelinating disease that follows a viral infection or, rarely, a viral immunization. Symptoms typically develop 1 or 2 weeks after the antecedent event and include headache, lethargy, and coma. The clinical course is rapid, and as many as 20% of those affected die, but the remaining patients usually recover completely
• Acute necrotizing hemorrhagic encephalomyelitis


  A fulminant syndrome of CNS demyelination that typically affects young adults and children, with illness preceded by a recent episode of upper respiratory infection. The disease is fatal in many patients
• Central Pontine Myelinolysis


  An acute disorder characterized by loss of myelin in the base of the pons and portions of the pontine tegmentum in a roughly symmetric pattern, most commonly arising 2 to 6 days after rapid correction of hyponatremia (clinically known as osmotic demyelination syndrome). Rapid increases in osmolality damage oligodendrocytes through uncertain mechanisms. The clinical presentation is a rapidly evolving quadriplegia, which may be fatal or lead to severe long-term deficits, including the "locked-in" syndrome
• Neurodegenerative diseases


  • Disorders characterized by the progressive loss of particular groups of neurons, which often have shared functions. Different diseases tend to involve particular neural systems and have relatively stereotypic presenting signs and symptoms. The common pathologic process across most of the diseases is the accumulation of protein aggregates (proteinopathy)
• Protein aggregates in neurodegenerative diseases

  May arise because of mutations that alter the affected protein's conformation or disrupt the pathways that are involved in the processing or clearance of an otherwise normal protein. Protein aggregates typically are resistant to degradation and show aberrant localization within neurons, recognized histologically as inclusions
• Approaches to classify neurodegenerative diseases

  • Symptomatic/anatomic - based on the anatomic regions that are most affected, typically reflected in the clinical symptoms
  • Pathologic - based on the types of inclusions or abnormal structures observed
• There is remarkable overlap in terms of characteristic neurologic deficits, functional/anatomic distribution of lesions, and cellular pathology across neurodegenerative diseases
• Prion diseases


  Rapidly progressive neurodegenerative disorders caused by aggregation and intercellular spread of a mis-folded prion protein (PrP). They may be sporadic, familial, or transmitted. All of these diseases are characterized morphologically by "spongiform change" caused by intracellular vacuoles in neurons and glia, and clinically by a rapidly progressive dementia
• Pathogenesis of prion diseases

  • Normal PrP is a cytoplasmic protein of unknown function. Disease occurs when PrP undergoes a conformational change from its normal α-helix–containing isoform (PrPc) to an abnormal β-pleated sheet isoform(PrPsc). PrPsc facilitates the conversion of other PrPc molecules to PrPsc molecules, and PrP acquires resistance to digestion with proteases. IHC staining demonstrates the presence of proteinase K–resistant PrPsc in tissue
• Alzheimer's Disease (AD)


  The most common cause of dementia in older adults, with an increasing incidence as a function of age. The disease usually becomes clinically apparent as insidious impairment of higher cognitive functions, and as the disease progresses, deficits in memory, visuospatial orientation, judgment, personality, and language gradually emerge. Over a course of 5 to 10 years, the affected individual becomes profoundly disabled, mute, and immobile. Patients rarely become symptomatic before 50 years of age, and about 5% to 10% of cases are familial
• Pathogenesis of Alzheimer's Disease

  • The fundamental abnormality is the accumulation of two proteins (Aβ and tau) in specific brain regions as a result of excessive production and defective removal. The two pathologic hallmarks are amyloid plaques (deposits of aggregated Aβ peptides in the neuropil that elicit an inflammatory response) and neurofibrillary tangles (aggregates of the microtubule binding protein tau that elicit a stress response and destabilize microtubules). Aβ generation is the critical initiating event, and the number of neurofibrillary tangles correlates better with the degree of dementia
• Morphology of Alzheimer's Disease

  Gross: Variable cortical atrophy, most pronounced in the frontal, temporal, and parietal lobes, with compensatory ventricular enlargement. Microscopic: Neuritic (senile) plaques (focal, spherical collections of dilated, tortuous, axonal or dendritic processes around a central amyloid core), neurofibrillary tangles (tau-containing bundles of filaments in the cytoplasm of the neurons), progressive neuronal loss and reactive gliosis, and cerebral amyloid angiopathy
• Pathologic examination of brain tissue obtained at autopsy remains necessary for definitive diagnosis of Alzheimer's Disease
• The progression of Alzheimer's Disease is slow but relentless
• Reduced Aβ


  Reduced amyloid-beta in the cerebrospinal fluid
• Elevated tau


  Increased tau protein in the cerebrospinal fluid
• Alzheimer Disease (AD)


  • Variable cortical atrophy marked by gyral narrowing and sulcal widening, most pronounced in the frontal, temporal, and parietal lobes
  • Hippocampus, entorhinal cortex, and amygdala involved early in the disease course, usually severely atrophied in the later stages
  • Compensatory ventricular enlargement (hydrocephalus ex vacuo) secondary to reduced brain volume
  • Neuritic (senile) plaques: focal, spherical collections of dilated, tortuous, axonal or dendritic processes around a central amyloid core
  • Neurofibrillary tangles: tau-containing bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus
  • Progressive, eventually severe, neuronal loss and reactive gliosis
  • Cerebral amyloid angiopathy (CAA)
• Clinical Features of Alzheimer Disease (AD)

  • Slow but relentless progression, with a symptomatic course often running more than 10 years
  • Initial symptoms are forgetfulness and other memory disturbances
  • With progression, other symptoms emerge, including language deficits, loss of mathematical skills, and loss of learned motor skills
  • In the final stages, affected individuals may become incontinent, mute, and unable to walk
  • Intercurrent disease, often pneumonia, is usually the terminal event
• Frontotemporal Lobar Degenerations (FTLDs)

  • Focal degeneration of frontal and/or temporal lobes
  • Clinically distinguished from AD by the pattern of involvement: alterations in personality and behavior, language (aphasias) preceding memory loss
  • Global dementia occurs with progressive disease, and a subset of patients develops extrapyramidal motor loss
  • Associated with cellular inclusions comprised of specific proteins: tau inclusions (FTLD-tau) or TDP-43 inclusions (FTLD-TDP)
• Parkinson Disease (PD)


  • Hypokinetic movement disorder
  • Caused by loss of dopaminergic neurons from the substantia nigra
  • Clinical syndrome of parkinsonism combines diminished facial expression (masked facies), stooped posture, slowing of voluntary movement, festinating gait (progressively shortened, accelerated steps), rigidity, and a "pill-rolling" tremor
• Clinical diagnosis of Parkinson Disease (PD)

  Triad of parkinsonism: tremor, rigidity, and bradykinesia in the absence of a toxic or other known underlying etiology
• Pathogenesis of Parkinson Disease (PD)


  • Protein accumulation and aggregation
  • Mitochondrial abnormalities
  • Neuronal loss in the substantia nigra and elsewhere in the brain
• SNCA gene


  Encodes α-synuclein, a lipid-binding protein normally localized to synapses and a major component of the Lewy body (the diagnostic hallmark of PD)
• Morphology of Parkinson Disease (PD)

  • Pallor of the substantia nigra and locus ceruleus due to loss of the pigmented, catecholaminergic neurons
  • Lewy bodies: single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo
  • Areas of neuronal loss also typically show gliosis
  • Lewy neurites: dystrophic processes that contain aggregated α-synuclein