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

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

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

Dementia Beginning mostly inapparent Course reversible stationary progredient

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

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.)

Prionoses - morphology v neuronal loss v spongiosis v gliosis ATROPHY

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

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

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

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

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

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

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

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

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

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

M. Alzheimeri- genetic factors

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

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

Arnold Pick Head of the Prague Psychiatry Clinic Prager medizinische Wochenschrift 1882 – case report of a dementia patient Pick disease

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

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)

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

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 …

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….

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

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)

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

Neurodegenerative Diseases genetic abnormality modified protein pathologic structures loss of neurons

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)

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

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

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

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

Sclerosis cerebrospinalis multiplex disseminata MS Pathogenesis u genetic predisposition u viruses

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)

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