This document summarizes various demyelinating and degenerative disorders of the central nervous system (CNS). It discusses diseases that involve preferential damage to myelin such as multiple sclerosis and various leukodystrophies including metachromatic leukodystrophy and Krabbe disease. It also covers degenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease that are characterized by selective neuronal loss in specific brain regions. The morphology, pathogenesis, clinical features of each disease are described.

1. Demyelinating and Degenerative Disorders of the CNS By Noel C. Santos, M.D.

2. DEMYELINATING DISEASES Acquired conditions Preferential damage to myelin Relative preservation of axons Clinical neurologic deficits Effect of myelin loss on the transmission of electrical impulses along axons Natural History Limited capacity of CNS to regenerate normal myelin Degree of secondary damage to axons

4. Infection: oligodendrocytes, ex. JC virus

5. Autoimmune: MULTIPLE SCLEROSIS

6. Inherited disorders:

7. affect myelin synthesis and turnover

8. LOSS OF MYELIN LEUKODYSTROPHIES

10. Metachromatic Leukodystrophy most common, autosomal recessive accumulation of a cerebroside (galactosyl sulfatide) in the white matter predominates in infancy, but rare juvenile or adult cases have been described lethal within several year deficiency in the activity of arylsulfatase A, a lysosomal enzyme involved in the degradation of myelin sulfatides. progressive accumulation of sulfatides within the lysosomes of myelin-forming cells

11. A coronal section of the brain reveals conspicuous loss of myelin in the superior half of the white matter of the parietal lobe.

12. Krabbe Disease rapidly progressive, invariably fatal, autosomal recessive neurologic disorder deficiency of galactocerebroside-galactosidase infants and progresses to death within 1 to 2 years perivascular aggregates of mononuclear and multinucleated “globoid cells” in the white matter – “globoid cell leukodystrophy”: macrophages that contain undigested galactocerebroside (galactosylceramide) Severe motor, sensory, and cognitive impairment almost complete loss of oligodendroglia and myelin the enzyme deficiency results in toxic, alternative metabolites that destroy oligodendroglia

13. Krabbe Disease Small brain, diffuse loss of myelin, but the cerebral cortex is normal Marbled areas of partial and total demyelination, astrogliosis is typically severe As demyelination proceeds, clusters of globoid cells are found around blood vessels measure up to 50 µm in diameter and contain as many as 20 peripherally located nuclei In end-stage disease, the number of globoid cells decreases, and in areas of severe myelin loss, only scattered globoid cells remain By electron microscopy, the globoid cells contain crystalloid-like inclusions with straight or tubular profiles.

14. Adrenoleukodystrophy X-linked (Xq28), inherited disorder dysfunction of the adrenal cortex & demyelination associated with high levels of saturated very-long-chain fatty acids (VLCFAs) in tissue and body fluids children between the ages of 3 and 10 years neurologic symptoms precede the signs of adrenal insufficiency progresses rapidly, quickly reduced to a vegetative state, which may persist for several years before death

15. Adrenoleukodystrophy enzyme mutation that impairs the capacity to degrade VLCFAs defect in the peroxisomal membrane prevents the normal activation of free VLCFAs by the addition of coenzyme A (CoA) unable to degrade VLCFAs, the fatty acids accumulate in gangliosides and myelin accumulation of abnormal cholesterol esters and the toxic effects of VLCFAs.

16. A coronal section of the brain discloses extensive degenerative changes throughout the white matter.

17. MULTIPLE SCLEROSIS Autoimmune demyelinating disorder Distinct episodes of neurologic deficits separated in time due to white matter lesions separated in space Most common, F>M, any age Clinical course evolves as relapsing and remitting episodes of neurologic deficit during variable intervals of time followed by gradual and partial recovery of neurologic functions Frequency of relapses decreases over course of time Steady neurologic deterioration

18. Multiple Sclerosis Pathogenesis: Cellular immune response directed against components of myelin sheaths – AUTOIMMUNE PROCESS Genetic (susceptibility) and Environmental (initiator) Factors

19. Multiple Sclerosis Morphology: White matter disease: multiple, well-circumscribed, depressed, glassy, gray-tan, irregularly shaped plaques, firm (sclerotic) commonly beside ventricles, follow the course of paraventricular veins; optic nerves and chiasm, brain stem, fiber tracts, cerebellum and spinal cord

22. Multiple Sclerosis MICROSCOPIC: ACTIVE PLAQUE Ongoing myelin breakdown: lipid-rich macrophages, PAS(+) debris, perivascular cuffs of inflammatory cells (lymphocytes, monocytes) Relative preservation of axons Depletion of oligodendrocytes In time, reactive astrocytes

25. Multiple Sclerosis INACTIVE PLAQUE Become quiescent – diminution of inflammatory cells At the center – no myelin, reduced nuclei of oligodendrocytes; astrocytic proliferation and gliosis Depleted myelin in axons

26. Multiple Sclerosis SHADOW PLAQUE Border between normal and affected white matter – not sharply circumscribed Abnormally thinned-out myelin sheaths (partial or incomplete loss of myelin OR remyelinization of surviving oligodendrocytes)

28. Unilateral visual impairment – optic neuritis or retrobulbar neuritis

29. Brain stem – cranial nerve signs, ataxia, nystagmus, ophthalmoplegia

30. Spinal cord – motor/sensory impairment, spasticity, difficulties in voluntary control of bladder function

32. Rapidly and relentlessly progressive or as single episode

36. ALZHEIMER DISEASE DEMENTIA – progressive loss of cognitive function independent of the state of attention Insidious impairment of higher intellectual function, mood and behavioral alterations Progressive disorientation, memory loss, aphasia 5 to 10 yrs – disabled, mute, immobile Mostly sporadic, elderly – major medical, social and economic problems

37. ALZHEIMER DISEASE Grossly: Cortical atrophy: wide sulci (frontal, temporal, parietal lobes), narrowed gyri, compensatory ventricular enlargement (hydrocephalus ex vacuo)

39. ALZHEIMER DISEASE Microscopic: Neuritic (senile) plaques: dystrophic neurites, amyloid core of Aβ from APP (amyloid precursor protein) Neurofibrillary tangles: cytoplasmic filaments (protein tau) Amyloid angiopathy, granulovacuolar degeneration, Hirano bodies Pattern: Earliest in the entorhinal cortex Spread to hippocampal formation and isocortex Extend to the neocortex

46. ALZHEIMER DISEASE Clinical Features: Progression is slow (> 10 yrs) but relentless Initial symptoms – forgetfulness Language deficits, loss of mathematical skills, loss of learned motor skills Final stage: incontinent, mute, unable to walk with intercurrent disease, ex. Pneumonia

47. DEGENERATIVE DISEASES OF BASAL GANGLIA AND BRAINSTEM Movement disorders: rigidity, abnormal posturing, chorea Reduction of voluntary movement or abundance of involuntary movement Parkinson disease Multiple System Atrophy (cerebellar ataxia, autonomic dysfunction) Huntington disease Progressive Supranuclear Palsy (PSP) Corticobasal Degeneration (CBD) with cognitive impairment

48. PARKINSONISM CLINICAL SYNDROME of MOTOR DISTURBANCE Diminished facial expression Rigidity with stooped posture Slowness of voluntary movement Festinating gait: progressively shortened, accelerated steps “pill-rolling” tremor Damage to nigrostriatal dopaminergic system

49. PARKINSON DISEASE Parkinsonism in the absence of toxic or other known underlying etiology Changes in mental function – dementia Morphology Pallor of the substantia nigra and locus ceruleus Loss of pigmented, catecholaminergic neurons with gliosis Lewy bodies: cytoplasmic inclusions with dense core and pale halo – fine filaments composed of α-synuclein

53. PARKINSON DISEASE Pathogenesis: Degeneration of dopaminergic neurons with reduction of striatal dopamine content Severity of motor syndrome is proportional to the dopamine deficiency correctable by L-DOPA Clinical Features: Motor disturbance, dementia Fluctuating course, hallucinations, prominent frontal signs Symptomatic response to L-DOPA which become less effective in time

54. HUNTINGTON DISEASE Inherited autosomal dominant Progressive movement disorders and dementia CHOREA: jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body Later develop parkinsonism with bradykinesia and rigidity Relentlessly progressive Degeneration of striatal neurons

55. HUNTINGTON DISEASE Morphology: Small brain, atrophy of caudate nucleus and putamen Secondarily atrophic globus pallidus and dilated ventricles Frontal and less often parietal Severe loss of striatal neurons with fibrillary gliosis

57. HUNTINGTON DISEASE Clinical Features: 4th to 5th decades Direct relationship between the degree of degeneration in the striatum and severity of clinical symptoms Motor symptoms precede cognitive impairment Increased risk of suicide, intercurrent infection