1. Path: Nongenetic Degenerative Disorders Chris Pierson, MD, PhD Neuropathologist, Nationwide Children’s Hospital Associate Professor of Pathology christopher.pierson@nationwidechildrens.org

2. Learning Objectives  Describe the underlying pathology and symptoms of neurodegenerative diseases in the CNS.  Identify the location and describe the pathological findings, symptoms, and the appropriate intervention pharmacological, surgical, other) for Dementia, including Alzheimer’s disease.  Identify the location and describe the pathological findings, symptoms, and the appropriate intervention (pharmacological, surgical, other) for Movement disorders, including Parkinson's disease, Essential tremor, and Huntington’s disease.  Identify the location and describe the pathological findings, symptoms, and the appropriate intervention (pharmacological, surgical, other) for Motor neuron disorders, including amyotrophic lateral sclerosis.

3. Learning Objectives (continued)  Describe the difference of primary and secondary demyelination and the pathogenesis of multiple sclerosis and acute disseminated encephalomyelitis.  Describe the pathogenesis of neurodegenerative diseases including disorders affecting cerebral cortex (e.g. Alzheimer disease and frontotemporal dementias), basal ganglia (e.g. Parkinson’s disease and Parkinsonism, Huntington disease), spinocerebellar degenerations (e.g. Friedreich ataxia and spinocerebellar ataxia), and motor neuron degenerative diseases (e.g. amyotrophic lateral sclerosis).  Describe the impact of acquired metabolic, toxic and nutritional disorders on nervous system function and their clinicopathologic manifestations e.g., vitamin deficiencies, ethanol, and carbon dioxide.  Describe genetic metabolic diseases and their impact on the nervous system (e.g.mitochondrial encephalomyopathies, neuronal storage diseases, leukodystrophies).

4. Overview  Demyelinating disorders  Primary Myelinoclastic and leukodystrophies  Secondary - save for another day  Neurodegenerative disorders  Alzheimer disease, Diffuse Lewy body disease, Parkinson disease, Motor neuron disorders (Amyotrophic lateral sclerosis), Chronic traumatic leukoencephalopathy, Dementia pugilistica

5. DEMYELINATING DISEASES

6. Demyelinating Diseases  Primary demyelination - intrinsic defect in or injury to oligodendrocytes (Schwann cells)  Myelinoclastic disorders - Autoimmune (multiple sclerosis, ADEM), nutritional deficiency (SACD), toxins (CPM), infectious (PML)  Leukodystrophies - due to mutations in genes responsible for myelin metabolism or maintenance Metachromatic leukodystrophy, Krabbe’s disease, Adrenal leukodystrophy  Secondary demyelination - myelin loss and/or destruction following axonal injury

7. Multiple Sclerosis Gray discoloration in WM “plaques” Vary in size and shape Plaques often around angles of lateral ventricle, optic nerve, can occur in gray matter A B

8. Multiple Sclerosis MS plaques have discrete boarders optic nerve

9. Multiple Sclerosis – Active Plaques Cellular with lots of lymphocytes (T cells), foamy macrophages astrocytes are sparse Oil red O Luxol fast blue

10. Multiple Sclerosis – Inactive Plaques Paucicellular Densely gliotic Decreased oligodendrocytes Decreased axons May cavitate then axons are lost

11. Multiple Sclerosis – Shadow Plaques Myelin is reduced, but not absent Remyelination starts weeks after injury Myelin sheath is thin

12. Multiple Sclerosis - Axons are relatively spared

13. Acute Disseminated Encephalomyelitis (ADEM) Small distended veins Petechial hemorrhages Herniation due to edema may occur Small veins surrounded by foamy macrophages and lymphocytes So-called “sleeve” of demyelination Luxol fast blue

14. Subacute Combined Degeneration Parasthesiae of lower limbs, loss of fine touch, vibration and position sense Later spastic paraparesis

15. Central Pontine Myelinolysis Active demyelination, reactive astrocytes, foamy macrophages Lymphocytes are rare May show islands of preserved myelin

16. Progressive Multifocal Leukoencephalopathy (PML) White matter shows small focal gray areas that can become large and confluent may even become necrotic Foamy macrophages, but few lymphocytes Bizarre reactive astrocytes Oligos have nuclear inclusions

17. NEURODEGENERATIVE DISEASES

18. Concepts in dementia neuropathology  Accumulation of intracellular proteins as inclusion bodies  Characteristic of many disease  e.g. Lewy bodies in Parkinson disease; neurofibrillary tangles in Alzheimer disease  Lead to concept of proteinopathies: abnormal proteins are produced, improperly folded or fail to be eliminated leading to their accumulation followed by neuronal (and/or glial) dysfunction and cell death  Classified in part based on the main protein that accumulates, so if alpha-synuclein accumulates then disease part of synucleinopathy family; if tau accumulates then the disease is part of the tauopathy family  Specifically how protein accumulations lead to disease remains largely unclear

19. Concepts in dementia neuropathology  Accumulation of extracellular proteins is characteristic of several neurodegenerative diseases  Proteins with high content of beta-pleated sheet secondary structures can accumulate under certain (unknown) conditions  Amyloid is detected by various tissue stains, such as Congo red and thioflavin S, which intercalate with the deposited amyloid  The intercalation of the stain results in birefringence (with Congo red) or fluorescence (with thioflavin S) and this property defines a protein as amyloid  Disorders with amyloid accumulation are known as amyloidosis and Alzheimer disease is the most common type  In Alzheimer disease the extracellular accumulation of beta-amyloid peptide is due to the proteolytic cleavage of amyloid precursor protein

20. Concepts in dementia neuropathology  Neuronal loss involving certain neuronal populations is a defining feature  Believed to be due to cell death in the form of apoptosis  Abnormal protein accumulation in inclusion bodies may initiate cell death possibly via harmful effects on mitochondria  Neuroinflammation & cell stress  Abnormal protein accumulations and neuronal death increase: The brain’s inflammatory response Neuronal cell stress response Oxidative stress

21. Alzheimer’s Disease Cortical atrophy Wide sulci and thin gyri Temporal, frontal, parietal > occipital

22. Alzheimer’s Disease Age-matched non-demented AD

23. Alzheimer’s Disease Extracellular amyloid (A  peptide) plaques Intracellular tau aggregates

24. Frontotemporal lobar degeneration (FTLD)  FTLD is a term used to describe a clinically and pathologically heterogenous group of tauopathies that are non-Alzheimer neurodegenerative disorders that preferentially involve the frontal and temporal lobes  This is an evolving concept in neuropathology and clinical-neuropathologic correlations are still being established  This group is believed to represent 10-20% of all neurodegenerative dementia  FTLD patients progress to death more rapidly than Alzheimer disease patients

25. Pick’s disease an example of FTLD  Gross: Severe atrophy of frontal and anterior temporal lobes; note characteristic sparing of posterior superior temporal gyrus (arrow), and precentral & postcentral gyri  Microscopic sections of cortex show:  Neuronal loss and gliosis  Pick bodies may be seen in remaining neurons, swollen cytoplasm contain tau

26. Dementia with Lewy Bodies Mild to moderate atrophy of frontal, temporal and parietal cortex Severe atrophy of limbic areas Lewy bodies A B C

27. Dementia with Lewy Bodies Neuronal loss in substantia nigra and locus ceruleus Lewy bodies present

28. Pathologic Overlap of Dementia with Lewy Bodies & Alzheimer’s Disease Numerous plaques are seen in some DLB cases

29. Parkinson’s Disease  Need 2 of 3 cardinal features  Bradykinesia, resting tremor, rigidity  Can have autonomic dysfunction, dysphagia  Age of onset about 60 years Normal PD

30. Amyotrophic Lateral Sclerosis A B

31. Chronic Traumatic Encephalopathy (CTE)  Due to repetitive mild traumatic brain injury  Affects athletes in contact sports, military veterans, victims of domestic abuse  Symptoms: Memory loss, depression, suicidal thoughts, explosive/ aggressive behavior, may have difficulty ambulating or talking http://www.popsci.com/sites/popsci.com/files/psc0216_nx_decoded_0.jpg

32. Chronic Traumatic Encephalopathy (CTE)  Tau protein tangles accumulate in cortex and around blood vessels and deep in cortical sulci; distinguishing it from Alzheimer disease  Amyloid plaques may be seen, but not consistently and they are far less numerous than the tangles http://www.dailymail.co.uk/news/article-2242643/Head-injury-study-33- NFL-football-players-brain-disease-deaths.html Tau staining

33. Dementia Pugilistica  Refers to chronic effects of boxing- related brain injury  Patients show speech difficulties, unsteady gait, progressive ataxia, spasticity, dementia, parkinsonian movement disorder  Due to cumulative damage of repeated blows to the head  Gross: cerebral atrophy, large ventricles  Microscopic exam shows diffuse neuronal loss (cerebellum, substantia nigra, cortex, hippocampus) and gliosis  Tau accumulates in neurons and extracellular amyloid A  (same type as in Alzheimer disease) is present

35. Summary  In this module we have examined the neuropathology of a number of demyelinating and neurodegenerative disorders of the central nervous system with particular attention to the more common diseases  We have distinguished myelinoclastic processes from the leukodystrophies and provided a number of examples of each  Finally, we studied the neuropathology of some common neurodegenerative disorders and correlated the neuropathology with clinical features exhibit by affected patients

36. Thank you for completing this module Questions? Contact me at: christopher.pierson@nationwidechildrens.org