1. CNS Pathology - II Pathology of Dementia Jaroslava Dušková Inst. Pathol.,1st Med. Faculty, Charles Univ. Prague

2. Dementia Def. decrease of individual intelectual abilities under the formerly reached niveau

3. Dementia Clinical features Disturbances of v memory (mnestic) v cognitive functions (gnostic) v adaptative behaviour (practice)

4. Dementia Beginning mostly inapparent Course reversible stationary progredient

5. Dementia - causes (1) v THERAPY v INTOXICATION v INFECTION v METABOLIC DISORDERS v PROGRESSIVE DEGENERATIVE DISEASES v MALNUTRITION v VASCULAR v EXPANSION v AFFECTIVE DISORDERS

6. Dementia - causes (2) v THERAPY polypragmasia v INTOXICATION Mn, Cu, Pb, CO, CS2, Hg, etanol….. v INFECTION viral, bacterial protozoan, mycotic (HIV, PME, Whipple disease, Lues, toxoplasmosis, cryptococcosis, prion dis.)

7. Prionoses - morphology v neuronal loss v spongiosis v gliosis ATROPHY

8. Dementia - causes (3) v METABOLIC DISORDERS chron. liver or kidney failure, thesaurismoses hepatolenticular degeneration v MALNUTRITION v avitaminosis B1 v Wernicke-Korsakoff encephalopathy with dementia

9. Storage Diseases Def.: inborn errors of metabolism (mostly single gene abnormality) leading to an v enzyme defect with subsequent v accumulation of the substrate (& v lack of the product) in tissues or organs

10. Lipid Storage Diseases -1. DiseaseE- defAccum. Lipid Tissues Involved Tay-SachsHexos aminidase A GM2 ganglioside Brain, retina Gaucher  - Glucosidase Gluco cerebrosid Liver, spleen, bone marrow, brain Niemann- Pick Sphingo myelinase Sphingo myelin Brain, liver spleen

11. Lipid Storage Diseases – 2. DiseaseE- defAccum. Lipid Tissues Involved Metachro matic Leuco dystrophy Arylsulfat ase A SulfatidBrain, kidney, liver, peripheral nerves Fabry´s  -galactosid ase Ceramid trihexosid Skin, kidney Krabbe´sGalactosyl ceramidase Galactol cerebroside Brain

12. Mucopolysaccharidoses Disease, inheritance course E- defAccum. Mucopoly saccharide Tissues Involved Hurler AR, severe  -l- iduronidase Heparan sulfate, dermatan sulfate Skin, cornea, bone heart, Brain, liver spleen Hunter X, rec. moderate l- iduronosulf ate sulfatase Heparan sulfate, dermatan sulfate Skin, bone, heart, ear, retina SanfilippoMany typesHeparan sulfate Brain, skin

13. Dementia – causes (4) v VASCULAR hypertensive encephalopathy, MID v EXPANSION subdural hematoma, hygroma, neoplasia, hydrocephalus v AFFECTIVE DISORDERS depression

14. Dementia - causes (5) PROGRESSIVE DEGENERATIVE DISEASES v dementia – the only one symptome: m. Alzheimer, m. Pick v dementia – combined with neurology symptomes: m. Parkinson, m. Huntington, ALS, PP

15. M. Alzheimeri - incidence  65 yrs 5% population  80 yrs 20%

16. M. Alzheimeri Extracellular   -amyloid plaques u dystrophic dendrites u axons u activated microglia u reactive astrocytes diffuse plaques - A  42 mature plaques - A  42 and A  40

17. M. Alzheimeri Intracellular u neurofibrillary deposits hyperphosphorylated proteins (pair helical filaments) glycosaminoglycans admixture (heparin)

18. M. Alzheimeri- genetic factors

19. M. Alzheimeri - diagnosis age matched neuritic plaques quantity Khachaturyan, Mirra et al.

20. Dementia - causes (5) PROGRESSIVE DEGENERATIVE DISEASES v dementia – the only one symptome: m. Alzheimer, m. Pick v dementia – combined with neurology symptomes: m. Parkinson, m. Huntington, ALS, PP

21. Arnold Pick 1851-1924 Head of the Prague Psychiatry Clinic 1886-1924 Prager medizinische Wochenschrift 1882 – case report of a dementia patient Pick disease

22. Dementia - causes (5) PROGRESSIVE DEGENERATIVE DISEASES v dementia – the only one symptome: m. Alzheimer, m. Pick v dementia – combined with neurology symptomes: m. Parkinson, m. Huntington, ALS, PP

23. Paralysis agitans – m. Parkinsoni (1817) Clinical features v Start 40–60 years v Early stage v dysesthesias v discrete tremor v hypertonia–hypokinesis syndrome v resting tremor v rigidity v bradykinesia & loss of automatic movements v prognosis: quoad vitam good, quoad sanationem  (L-DOPA, transpl., nicotine)

24. Paralysis agitans – m. Parkinsoni (1817) Morphology v macroscopy depigmentation of substantia nigra mesencephali v microscopy Lewy bodies, loss of pigmented neurons

25. Parkinson´s dis. - etiology u genetic factors recently described: –PARK1 – α-synuclein- autos. dom., Lewy bodies –PARK2 – Parkin, autos. rec. juv.-no LB –PARK3 –late onset –….. –PARK 11 …

26. Causes of Parkinsonism u common –Parkinson´s dis. u less common –drug induced –multiple system atrophy –progressive supranuclear palsy –vascular u rare – Alzheimer´s dis., Huntington´s dis., Wilson´s dis., toxins, dementia pugilistica, hydrocephalus, space ocupying lesions….

27. Chorea chronica progressiva Huntington v Autosomally dominant (!) 4th chromosome v Manifestation 25 – 45 years (juvenile form prior to 20 years of age) v Duration 15 years

28. Chorea chronica progressiva Huntington Clinical features v contravolitional uncontrolled dance–like motions v schizophrenic and depressive personality features v death from intercurrent infection (bronchpneumonia, cachexia)

29. Chorea chronica progressiva Huntington Morphology v macroscopy striatum atrophy (ncl. caudatus + putamen) v microscopy loss of small GABA neurons (norm. 80% of population)

30. Neurodegenerative Diseases genetic abnormality modified protein pathologic structures loss of neurons

31. Neurodegenerative Diseases I. Polyglutamine diseases (multiple Cytosin– Adenin–Guanin CAG complexes) m. Huntington (+ family of other triplet repeat expansion dis.) II.  – pathies,  –synucleinopathies m. Alzheimeri, m. Parkinsoni (Lewy bodies)

32. Sclerosis cerebrospinalis multiplex disseminata MS Def. chronic autoimmune disease with myelin breakdown

33. Multiple sclerosis – classif. u classic (Charcot type) u acute (Marburg type) u neuromyelitis optica (Devic´s dis.) u concentric sclerosis (Baló ´s dis.)

34. Sclerosis cerebrospinalis multiplex disseminata MS Clinical features Disorders of Course v sight v sensation v motorics v cont. progressive v saw-like

35. Sclerosis cerebrospinalis multiplex disseminata MS Morphological features –myelinic plaques v acute v chronic

36. Sclerosis cerebrospinalis multiplex disseminata MS Pathogenesis u genetic predisposition u viruses

37. MS – viral influence (morbilli, herpes,…) Pathogenesis v interaction macroorganism x virus limited production of Ig (only 10-20% produced viruses are virulent) v virus mutation & immunosuppression (age, pregnancy, stress, other disease)

38. MS – viral influence (2) Pathogenesis v infection of endothelia – microangiitis v hematoencephalic barier disorder v serum and CSF CD4, CD8 (mirror image to AIDS)