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“NEURODEGENERATION”

“NEURODEGENERATION” . Lewis P. Rowland M.D. Neurological Institute of New York Columbia University Medical Center, NYC Neurobiology of Brain Dysfunction, MBL August 17, 2011.

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“NEURODEGENERATION”

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  1. “NEURODEGENERATION” Lewis P. Rowland M.D. Neurological Institute of New York Columbia University Medical Center, NYC Neurobiology of Brain Dysfunction, MBL August 17, 2011

  2. Neurodegeneration: What Is It and Where are We?Przedborski S, Vila M, Jackson-Lewis V. JCI 2003; 111:3-10.Rowland LP in Neurodegeneration, Hardiman O, ed, LWW, 2011. Clinical and histopathologic manifestations: • Specific subsets of neurons (selective vulnerability). • No clear explanation; genetic or acquired; few mutations identified; pathogenesis unknown. • Progression until death, relentless but slow; no effective drug or gene therapy. • Dementia common, may be FTD. • Parkinsonism common. • Chromosome 17-linked PD + lower motor neurons (Wilhelmsen). • Age-related, increasing frequency with advancing age. • Microscopic signs of 3 stages: (a) neuronal pathology; (b) neuronal cell death, and (c) glial proliferation. 9. Misfolded insoluble proteins in cytoplasm or nucleus. 10. RNA abnormalities in myotonic dystrophy, fragile X, SCAs.

  3. Neurodegeneration: What Is It and Where are We?Przedborski S, Vila M, Jackson-Lewis V. JCI 2003; 111:3-10. Examples (“Primary Diseases”): • Alzheimer disease. • Huntington disease. • Parkinson disease. • Amyotrophic lateral sclerosis (including PLS and PMA). • Synucleinopathies: PD-dementia, Lewy body dementia, multiple system atrophies. • Tauopathies: Progressive supranuclear palsy, corticobasal degeneration. ------------------------------------------------ • TDP-43opathies. • Spinocerebellar atrophies. • Spinal muscular atrophies (SMA). • Hereditary spinal paraplegias (HSP)

  4. Neurodegeneration: What Is It and Where are We?Przedborski S, Vila M, Jackson-Lewis V. JCI 2003; 111:3-10. Examples (“What it is not!”): • CNS tumors. • Vascular diseases of brain or spinal cord. • Acute trauma. • Chronic trauma (post-traumatic chronic encephalopathy; cervical spondylotic myelopathy).

  5. Neurodegeneration: Dementia HeterogeneityBarker WW et al. Alzheimer Dis AssocDisord 2002;16: 203-212 382 autopsy brains. • Alzheimer disease – 77% • Lewy body dementia – 26% • Vascular dementia - 18% • Hippocampal sclerosis - 13% • FTD 5%

  6. Neurodegeneration: Heterogeneity • Dementia: Multiple possible causes: ischemia, metabolic aberration, toxicity, infection, trauma. • Multiple system atrophy: clinical signs of olivopontocerebellar atrophy; orthostatic hypotension (Shy-Drager); • Progressive supranuclear palsy (PSP): impaired vertical eye movements. • Cerebellar Signs: Cerebellar cortical atrophy (Purkinje cells, inferior olives), pontocerebellar + brain stem pathology; Friedreich – spinal cord, peripheral nerves, heart.

  7. Motor and Multifocal NeuropathiesTraub R, Brannagan TH. Medlink, July 2011 • Diagnosis MMCB: a) clinical; b) NCS; c) anti-GM1. • Less typical: no conduction block, slowing or GM1 ab. • CSF protein may be normal or slightly increased. • Any of above may respond to IVIG Rx • Amyloid neuropathy differs clinically.

  8. Motor Neuropathies: ClinicalTraub R, Brannagan TH. Medlink, July 2011 • Limb weakness: one or more nerves; muscle atrophy, fasciculation common. • Bulbar, respiratory rare. • May be generalized or affect single large nerves. • Acute or slowly progressive. • Differs from Lewis-Sumner syndrome, which is sensorimotor. • If NCS normal, “multifocal acquired motor axonopathy” (MAMA neuropathy).

  9. Motor Neuropathies: GammopathyTraub R, Brannagan TH. Medlink, July 2011 • Monoclonal B-cells secrete IgM, IgA or IgG ab (Latov). Gammopathy usually benign but may have Waldenstrom macroglobulinemia,, B-cell lymphoma or CLL. • Evidence of axonal loss in 61% of all pts with MMN; disease not lethal, autopsies few. • CPMC pt showed normal number ant horn cells, with central chromatolysis and loss of anterior root fibers. Immunoglobulins may be deposited on myelin sheaths.

  10. ALS and ParkinsonismWolf-Gilbert R, Fahn S, Mitsumoto H, Rowland LP. Movement Dis 2010; 25: 1868-75. • From PD database 5,550 pts, find 27 with MND-PD. • PD+UMN and LMN signs (ALS-PD) 7 • ALS-PD-Dementia (3 of 7) • UMN, no LMN + Park (PLS-PD) 6 • PLS-PD-Dementia (4 of 6) • MND+PD+cerebellar, autonomic (MSA) 7 • Hereditary spastic paraplegia 3

  11. Familial Aggregation of ALS, Dementia, PDMajoor-Krakauer D, Ottman R, Johnson WG, Rowland LP. Neurology 1994;44:1872-7. • Compare 151 newly diagnosed pts with ALS to 140 controls. • Risk for dementia, ALS, PD, significantly higher in relatives of ALS pts than in relatives of controls (RR=1.9), similar in sporadic and familial ALS • Shared genetic susceptibility to these disorders? • Patients with 1 of 3 syndromes (ALS, Park, or dementia) are at higher risk for the others.

  12. Aggregation of neurodegenerative disease in ALS kindreds. Fallis BA, Hardiman O. ALS Journal 2009; 10:95-98. • ALS, PD, and dementia significantly more frequent in relatives of 181 ALS patients than in 233 non-ALS controls. • Not uniformly distributed across kindreds of ALS probandsbut clustered in few families. • 4 probands had multiple affected family members; 15 had 1 affected relative; 162 had no affected relatives. No relatives of controls had neurodegenerative disease. • Agree with shared susceptibility.

  13. ALS-PD-Dementia of Guam • Harry M. Zimmerman, neuropathologist, stationed on Guam during WWII and noted large number cases in Chamorros. • After war, US Navy followed and confirmed observation. • Asao Hirano, student of Zimmerman, noted Guamanian syndrome of ALS-PD-Dementia. • Similarly high incidence in Kii Peninsula, Japan.

  14. The ending of ALS on Guam John C. Steele, Shayna Jo Afaisen, Alexander Kerr Neurological Institute Columbia University Medical Center, New York March 8, 2011

  15. The ending of ALS on Guam Characteristics of ALS on Guam in 481 cases from 1945 to 2005 Long Latency John C. Steele, Shayna Jo Afaisen, Alexander Kerr Neurological Institute Columbia University Medical Center, New York March 8, 2011

  16. Characteristics of ALS on Guam in481 cases from 1945 to 2005Long Latency

  17. Characteristics of ALS on Guam: Association with tau NFTs Colocalization of TDP-43 and tau in hippocampus

  18. Hypotheses for the cause of ALS on Guam • Genetic • Environmental • Cycad toxins in flour • Cycad toxins in flying foxes • Infection by direct inoculation • Geochemistry • Linear retinal pigment epitheliopathy

  19. Causes of ALS on Guam:Genetic ALS PD PD PD ALS ALS ALS ALS PD PD PD PD “It is our impression at the moment that the familial aggregation of cases which we have noted there is basically due to some genetic mechanism.” Mulder & Kurland 1953

  20. Causes of ALS on Guam:The cycad flour hypothesis by Leonard Kurland 1953

  21. Cycad flour preparations and eating on Rota

  22. Causes of ALS on Guam:The cycad flour hypothesis “At this time there is insufficient evidence to link BMAA (or any other organotoxin) to ALS-PDC on Guam.” Duncan, Kopin, and Markey (1990)

  23. John Steele

  24. Causes of ALS on Guam:The flying fox hypothesis by Paul Cox(“ethnobotanist”)

  25. Link between ALS and short residence on GuamMajoor-Krakauer D, Mulder PG, Rowland LP, Ottman R. Neurology 2005; 64(10) 1815-20. • 83 pairs of men and 57 pairs of women, matched in demographics. • Dx of ALS in 1989-1991. • Significant association between short stay and ALS; OR 8.0. • No such association in Philippines, Central or South America. • 9 cases; 6/9 in military service; 1= 1 mo; 7 = 2mo; 1=15 mo. • Time from end exposure to symptom-onset 27-57 yrs; mean 47 yr.

  26. ALS Mimic Syndromes • Multifocal motor neuropathy with conduction block (MMNCB). • Multifocal acquired motor axonopathy (MAMA). • Brachial amyotrophic diplegia (BAD) • Cervical spondylotic myelopathy. • HIV-associated motor neuron disease (MND). • Reversible sporadic MND. • West Nile virus poliomyelitis.

  27. Gammopathy with Proximal Motor Axonopathy Simulating Motor Neuron DiseaseParry GJ et al Neurology 1986; 36: 273-6 • 38 yo man with pure motor syndrome and IgM gammopathy, culminated in flaccid quadriplegia. • Improved with dexamethasone, cyclophosphamide, and plasmapheresis. • ----”patients with motor neuron disease should be routinely screened for serum protein abnormalities.” • MAMA = multifocal acquired motor axonopathy.

  28. Subacute Reversible Motor Neuron DiseaseTucker T, Layzer RB, Miller RG, Chad D. Neurology 1991; 41: 1541-4. • 4 patients with ALS-like syndromes. • All 4 recovered without treatment 5-12 months after onset of symptoms. • CSF normal, no paraproteinemia; no heavy metal intoxication or systemic illness.

  29. Axonal Multifocal Motor Neuropathy Without Conduction BlockKatz JS, Barohn R, Kojan S, Wolfe GI, Nations SP, Saperstein DS, Amato AA. Neurology, 2002 • Conduction block (CB) considered hallmark of motor neuropathy. • 9 pts with motor neuropathy and no CB or other features of demyelination. • 6 treated with prednisone of IVIG. • 3 showed “convincing improvement”

  30. “Man-in-the-Barrel Syndrome; Brachial Amyotrophic DiplegiaOrsini et al Rev Assoc Med Bras 2009; 55: 712-5. • 9 patients with similar onset Sx, ages 38-73. • 6/9 pure LMN syndrome. All could walk. Duration 2-10 yrs. • TRs absent or depressed in arms. 3 pts developed brisk reflexes, Hoffmann, Babinski. • EMG denervation in most arm muscles. Normal or denervation in legs at first; appeared later in 3/9. • Cervical MRI normal. • Dx PMA in all, at first; changed to ALS in 3. • No deaths or autopsy.

  31. Bilateral cervical spondylotic amyotrophy.Gizaw S et al. J Neurol Sci 2010;290: 142-5. • 45 yo man several yrs wasting and weakness of arms, more severe proximally but involving distal muscles, too. • Abstract does not mention legs, fasciculation, TRs, UMN signs, CSF, or MRI.

  32. Surgery for Cervical Spondylotic; time for controlled trialRowland LP. Neurology 1992; 42:5-13. • Decompressive laminectomy standard Rx; billion-dollar market; about 5% all pts with ALS have surgery. • Improvement after surgery reported in about half cases but no comparison with natural history or conservative therapy (physical Rx or collar). • No guidelines for selection of pts; no outcomes assessment; no controlled trials. • MRI may show compression and high signal in people with no abnormality on clinical exam.

  33. CSM: conservative vs surgical Rx after 10 Years.Kadanka Z et al. Eur Spine J 2011; Apr 26 • 10-yr prospective study for mild or moderate severity, non-progressive or slowly progressive Sx. • 64 pts. = 2 groups of 32 for surgery or conservative; standard quantitative outcome measures. Ended with 22 pts in each group. No subjective or objective difference in outcomes. No difference in loss ability to walk. • Masaryk University, Prague.

  34. West Nile Virus PoliomyelitisCDC website, Feb 2010 • Most common cause of flaccid weakness; often asymmetric, may be one limb. • No loss of sensation or paresthesias but may be painful. • Less frequent than WN encephalitis or meningitis. • Most often after age 65 but also 30-50. • No data on outcome. Some recover, some left partially disabled. Mortality not given. E-MedTV states 3-15%.

  35. Reversible Dementias • Delirium • Dementia • Medications • Nutritional (Wernicke; Pellagra; B12 deficiency) • Thyroid disease • Posterior reversible encephalopathy syndrome (PRES) • Hashimoto encephalopathy. • CJD

  36. Reversible Dementias • Tauopathies: Dementia with parkinsonism. • Drug-Induced parkinsonism • Street-drugs-frozen addicts. • Vascular parkinsonism • Wilson disease (hepatolenticular degeneration); other hereditary movement disorders. • Fahr syndrome: idiopathic basal ganglia calcification. • Hallervorden-Spatz disease (pantothenate-kinase associated neurodegeneration).

  37. Parkinson-Dementia SyndromesFrom Possin LK, Kaufer DI • Degenerative: PDD, DLB; PSP; CBD; MSA-Cerebellar (OPCA); MSA-Park-cerebellum-IOH) • Prion disorders: rapidly progressing dementia, ataxia, PRES. • NPH • Mimics

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