NEUROPATHOLOGY IV

PRIMARY CNS LYMPHOMA.PRIMARY CNS LYMPHOMA. NEUROCUTANEOUS SYNDROMENEUROCUTANEOUS SYNDROME NEURODEGENERATIVE DISORDERSNEURODEGENERATIVE DISORDERS

AMS07AMS07

NEUROPATHOLOGY IV PRIMARY CNS LYMPHOMA.PRIMARY CNS LYMPHOMA.*Most are Non-Hodgkin lymphomas of B cell origin:*Most are Non-Hodgkin lymphomas of B cell origin:

-Frequently are high grade large immuno- blastic or -Frequently are high grade large immuno- blastic or small non-cleaved(Burkit´s type) cell lymphomasmall non-cleaved(Burkit´s type) cell lymphoma-T cell lymphomas are rare-T cell lymphomas are rare-Primary Hodgkin´s lymphoma is very uncommon-Primary Hodgkin´s lymphoma is very uncommon

*Sporadic(non-AIDS) form is seen in the elderly and*Sporadic(non-AIDS) form is seen in the elderly andimmunosuppresion states after renal transplants.immunosuppresion states after renal transplants.

NEUROPATHOLOGY IV

PRIMARY CNS LYMPHOMA...PRIMARY CNS LYMPHOMA...

*Epidemic form associated with AIDS*Epidemic form associated with AIDS

*Usually located deep in the brain hemisph.*Usually located deep in the brain hemisph.

-frequently multicentric and asymmetric-frequently multicentric and asymmetric

*Does not tend to metastasize to systemic organs*Does not tend to metastasize to systemic organs

*Sensitive to radiation therapy*Sensitive to radiation therapy

*Survival longer than 2 yrs is rare*Survival longer than 2 yrs is rare

NEUROPATHOLOGY IV PRIMARY CNS LYMPHOMA...PRIMARY CNS LYMPHOMA...

NEUROPATHOLGY IV

NEUROCUTANEOUS SYNDROMES.NEUROCUTANEOUS SYNDROMES.

*Neurofibromatosis (NF)*Neurofibromatosis (NF)

-NF type 1-NF type 1

-NF type 2 -NF type 2

*Tuberous sclerosis*Tuberous sclerosis

*Von-Hippel-Lindau syndrome*Von-Hippel-Lindau syndrome

*Sturge-Weber syndrome*Sturge-Weber syndrome

NEUROPATHOLOGY IV

NEUROCUTANEOUS SYNDROMES...NEUROCUTANEOUS SYNDROMES...COMMON FEATURES.COMMON FEATURES. *Inherited disorders*Inherited disorders

-AD pattern of inheritance-AD pattern of inheritance *Characterized by hamartomas involving *Characterized by hamartomas involving the nervous system and skin the nervous system and skin

-Other body sites may be involved less -Other body sites may be involved less frequentlyfrequently *Often associated with neoplasms*Often associated with neoplasms

NEUROPATHOLOGY IV

NEUROFIBROMATOSIS TYPE 1(NF 1).NEUROFIBROMATOSIS TYPE 1(NF 1).

*Characterized by neurofibromas,acoustic *Characterized by neurofibromas,acoustic schwanoma,gliomas of the optic nerve, schwanoma,gliomas of the optic nerve, Lisch nodules and café-au-lait spots. Lisch nodules and café-au-lait spots.

*Gene located on 17q11.2*Gene located on 17q11.2

-neurofibromin-GTPase activating protein-neurofibromin-GTPase activating protein

-plexiform neurofibroma is classic of NF 1-plexiform neurofibroma is classic of NF 1

*High frequency of malignant transformation*High frequency of malignant transformation

NEUROPATHOLOGY IV

NEUROFIBROMATOSIS TYPE II(NF 2).NEUROFIBROMATOSIS TYPE II(NF 2).

*Gene located on chromosome 22q12*Gene located on chromosome 22q12

-Tumor suppressor gene-Tumor suppressor gene

-Codes for merlin – a cytoskeletal protein-Codes for merlin – a cytoskeletal protein

probably involved in membrane organiza probably involved in membrane organiza tion tion

-Associated w/bilateral acoustic Schwannoma-Associated w/bilateral acoustic Schwannoma

and frequent multiple meningiomasand frequent multiple meningiomas

NEUROPATHOLOGY IV

TUBEROUS SCLEROSIS.TUBEROUS SCLEROSIS.*AD with variable penetrance *AD with variable penetrance

-TSC1 gene(9q34)-hamartin and TSC2 -TSC1 gene(9q34)-hamartin and TSC2 gene(16p13.3)-tuberin, a GTPase acti- gene(16p13.3)-tuberin, a GTPase acti-

vating protein specific for vating protein specific for rap rap 1(mem- 1(mem- ver of ver of ras ras superfamily)superfamily)*Characterized by:*Characterized by:

-Cutaneous angiofibroma,seizures,mental-Cutaneous angiofibroma,seizures,mental retardation and behavioral problems, CNSretardation and behavioral problems, CNS hamartomas.hamartomas.

NEUROPATHOLOGY IV

TUBEROUS SCLEROSIS...TUBEROUS SCLEROSIS...

*Characteristics....*Characteristics....

-Cortical tubers(potato-like)- firm roun- -Cortical tubers(potato-like)- firm roun- ded pale or wart-like ded pale or wart-like protrusions of gyriprotrusions of gyri

-Collection of large bizarre cells w/neu- -Collection of large bizarre cells w/neu- ronal and astrocytic features ronal and astrocytic features

-Subependymal nodules - hamartomas-Subependymal nodules - hamartomas

NEUROPATHOLOGY IV

TUBEROUS SCLEROSIS...TUBEROUS SCLEROSIS...*It may be associated with:*It may be associated with:

-Renal angiomyolipoma/renal cysts-Renal angiomyolipoma/renal cysts-Retinal glial hamartoma, hypopigmen--Retinal glial hamartoma, hypopigmen- ted iris spot, white eyelashes, conjunti-ted iris spot, white eyelashes, conjunti- val hamartomasval hamartomas-Pulmonary/cardiac rhabdomyomas-Pulmonary/cardiac rhabdomyomas

*Frequently develop subependymal giant cell *Frequently develop subependymal giant cell astrocytomas(SEGCA)astrocytomas(SEGCA)

NEUROPATHOLOGY IV STURGE – WEBER SYNDROME.STURGE – WEBER SYNDROME.

*Also known as Encephalofacial angiomato *Also known as Encephalofacial angiomato sis is characterized by: sis is characterized by:

-Port wine stain of the face(facial nevi) -Port wine stain of the face(facial nevi) (distribution in the region of the 5th cra- (distribution in the region of the 5th cra-

nial nerve)nial nerve)-Ocular angioma-Ocular angioma-Venous angioma of the meninges(calci- -Venous angioma of the meninges(calci-

fication of outer cortical layers and meningeal fication of outer cortical layers and meningeal vesselsvessels*Familial cases reported but no clear evidence of *Familial cases reported but no clear evidence of hereditary transmission hereditary transmission

NEUROPATHOLOGY IV VON-HIPPEL LINDAU´S DISEASE.VON-HIPPEL LINDAU´S DISEASE.

*AD pattern of inheritance*AD pattern of inheritance-Gene located on 3p25-26-Gene located on 3p25-26

*Associated with:*Associated with:-Capillary hemangioblastoma(65%)-Capillary hemangioblastoma(65%)-High incidence in cerebellum and retina-High incidence in cerebellum and retina-Cysts of pancreas, liver and kidney-Cysts of pancreas, liver and kidney-High risk of renal cell carcinoma(45%) -High risk of renal cell carcinoma(45%) -Bilateral pheochromocytomas(26%) -Bilateral pheochromocytomas(26%)

NEUROPATHOLOGY IV VON-HIPPEL LINDAU´S....VON-HIPPEL LINDAU´S....

NEUROPATHOLOGY IV VON-HIPPEL LINDAU´S....VON-HIPPEL LINDAU´S....

NEUROPATHOLOGY IV

NEURODEGENERATIVE DISEASE.NEURODEGENERATIVE DISEASE.

*Category of disorders w/uncertain etiology*Category of disorders w/uncertain etiology

*Classified as:*Classified as:

-Movement disorders-Movement disorders

-Cognitive disorders(dementia)-Cognitive disorders(dementia)

NEUROPATHOLOGY IV

NEURODEGENERATIVE DIS.......NEURODEGENERATIVE DIS....... MOVEMENT DISORDERS. MOVEMENT DISORDERS.

*Akinetic and rigid *Akinetic and rigid -predominantly extrapyramidal deficits -predominantly extrapyramidal deficits

-degeneration involves -degeneration involves substantia nigra/ substantia nigra/ basal gangliabasal ganglia*Hyperkinetic *Hyperkinetic -dysregulation of movement -dysregulation of movement -basal ganglia degeneration-basal ganglia degeneration

NEUROPATHOLGY IV NEURODEGENERATIVE DIS....NEURODEGENERATIVE DIS.... MOVEMENT DISORDERS...MOVEMENT DISORDERS...

*Ataxic *Ataxic -cerebellar ataxia -cerebellar ataxia -degeneration of -degeneration of cerebellum/connecting cerebellum/connecting

tractstracts *Motor neuron disorders *Motor neuron disorders

-motor weakness -motor weakness -degeneration of motor systems-degeneration of motor systems

NEUROPATHOLOGY IV

NEURODEGENERATIVE....NEURODEGENERATIVE.... COGNITIVE DISORDERS.COGNITIVE DISORDERS.

DEMENTIA. DEMENTIA. *Descriptive term for *Descriptive term for deterioration of deterioration of

intellectual/cognitive intellectual/cognitive abilities of su abilities of su fficient severity to interfere with fficient severity to interfere with normal social functioning.normal social functioning.

NEUROPATHOLOGY IV

DEMENTIA...DEMENTIA...

*Temporal and parietal degenerations *Temporal and parietal degenerations -memory disturbance w/parietal lobe dis. -memory disturbance w/parietal lobe dis.

-degeneration of hyppocampal/cortical -degeneration of hyppocampal/cortical neurons neurons

*Frontotemporal degenerations *Frontotemporal degenerations -apathy, disinhibition,depression,loss of -apathy, disinhibition,depression,loss of memory memory -degeneration of cortical/subcortical functions -degeneration of cortical/subcortical functions

NEUROPATHOLOGY IV

DEMENTIA....DEMENTIA....

*Multifocal degenerations*Multifocal degenerations

-variable cortical and subcortical -variable cortical and subcortical deficitsdeficits

-degeneration of cortical and -degeneration of cortical and subcortical subcortical neurons neurons

NEUROPATHOLOGY IV

DEMENTIA....DEMENTIA....

*Signs of dementia: *Signs of dementia: -Confusion -Confusion -Memory disturbances -Memory disturbances -Difficulties w/problem solving and abs- -Difficulties w/problem solving and abs- tract thinking tract thinking -Impaired jugdment -Impaired jugdment -Personality changes -Personality changes -Emotional lability-Emotional lability

NEUROPATHOLOGY IV

DEMENTIA.....DEMENTIA.....

*50% - Treatable or reversible dementia*50% - Treatable or reversible dementia

*50% - Neurodegenerative disorder*50% - Neurodegenerative disorder

-2/3 – Alzheimer´s disease-2/3 – Alzheimer´s disease

-1/3 – Other disorders-1/3 – Other disorders

NEUROPATHOLOGY IV REVERSIBLE DEMENTIA. *Vitamin REVERSIBLE DEMENTIA. *Vitamin

deficiencies(B12,folate,niacin,etc) deficiencies(B12,folate,niacin,etc) *Endocrine disorders(thyroid,parathyroids) *Endocrine disorders(thyroid,parathyroids) *Neuroshyphilis,Borrelia infect.,HIV infec. *Neuroshyphilis,Borrelia infect.,HIV infec. *Hypoglycemia, electrolyte umbalance *Hypoglycemia, electrolyte umbalance *Hydrocephalus(normal pressure) *Hydrocephalus(normal pressure) *Cerebrovascular dis(multi-infarcts demen.) *Cerebrovascular dis(multi-infarcts demen.) *Renal/hepatic failure *Renal/hepatic failure *Chronic hypoxia/hypercarbia(COPD) *Chronic hypoxia/hypercarbia(COPD) *Drug/medication induced mental disorders *Drug/medication induced mental disorders *Neoplasms(primary or secondary,paraneoplastic) *Neoplasms(primary or secondary,paraneoplastic) *Affective disorders(depression) *Affective disorders(depression) *Epilepsy *Epilepsy *Subdural hematoma*Toxic(Pb,Hg,As,Mn,COOH*Subdural hematoma*Toxic(Pb,Hg,As,Mn,COOH

NEUROPATHOLOGY IV

NEURODEGENERATIONS.NEURODEGENERATIONS.

*Alzheimer´s disease *Alzheimer´s disease *Diffuse Lewy body disease *Diffuse Lewy body disease *Pick´s disease *Pick´s disease *Parkinson´s disease *Parkinson´s disease *Huntington´s disease *Huntington´s disease *Multiple systemic *Multiple systemic atrophy atrophy *Progressive *Progressive supranuclear palsy supranuclear palsy *Spinocerebellar degeneration*Spinocerebellar degeneration

NEUROPATHOLOGY IV

ALZHEIMER´S DISEASE.ALZHEIMER´S DISEASE.

Most common neurodegenerative dementiaMost common neurodegenerative dementia

-10% of surviving population over 65 yrs.-10% of surviving population over 65 yrs.

-50% of surviving population over 85 yrs.-50% of surviving population over 85 yrs.

NEUROPATHOLOGY IV

ALZHEIMER´S.... ALZHEIMER´S.... *Risk factors: *Risk factors: -Aging -Aging -Head trauma -Head trauma -Chronic ingestion of some -Chronic ingestion of some metals(Al) *Etiopathogenesis: metals(Al) *Etiopathogenesis: -Genetic -Genetic factors(about 5-10% are heredi factors(about 5-10% are heredi tary, early onset, and transmitted as tary, early onset, and transmitted as AD AD trait trait

NEUROPATHOLOGY IV

ALZHEIMER´S....ALZHEIMER´S....

*Dx.: *Dx.: - -Probable Probable Alzheimer´s disease –evidence of Alzheimer´s disease –evidence of progressive dementia w/no disturbance of progressive dementia w/no disturbance of consciousness and abscence of consciousness and abscence of systemic or other brain diseases that cause dementia. systemic or other brain diseases that cause dementia. - -Definite Definite Alzheimer´s disease-Alzheimer´s disease-pathological confirmation of clinical pathological confirmation of clinical Dx(biopsy/autopsy) Dx(biopsy/autopsy)

NEUROPATHOLOGY IV

ALZHEIMER´S.... ALZHEIMER´S.... *Pathology: *Pathology: Neurofibrillary tanglesNeurofibrillary tangles. . ---Intracell.clumps of 10 nm filaments in dou- ---Intracell.clumps of 10 nm filaments in dou- ble helical arrangement ble helical arrangement -Occupy cerebral cortical neuronal -Occupy cerebral cortical neuronal cell bo- dy/axonal and dendritic cell bo- dy/axonal and dendritic processes -Argyrophilic processes -Argyrophilic staining properties(special dyes) staining properties(special dyes) -Immunopositive for ubiquitin and -Immunopositive for ubiquitin and tau(microtubu- le binding protein)tau(microtubu- le binding protein)

NEUROPATHOLOGY IV

ALZHEIMER´S.... ALZHEIMER´S.... Pathology... Pathology... Neurofibrillary tangles...Neurofibrillary tangles... -Non specific since they can be found in -Non specific since they can be found in other disorders, vgr.: dementia pugilistica, other disorders, vgr.: dementia pugilistica, progressive supranuclear palsy, parkinso- progressive supranuclear palsy, parkinso- nism-dementia-ALS complex(Guam nism-dementia-ALS complex(Guam syndr.) Down´s syndrome, SSP,post-encephalitic syndr.) Down´s syndrome, SSP,post-encephalitic parkinsonism, Nieman-Pick´s disease type Cparkinsonism, Nieman-Pick´s disease type C

NEUROPATHOLOGY IV

ALZHEIMER´S.... ALZHEIMER´S.... Pathology...... Pathology...... Neuritic(senile) plaques.Neuritic(senile) plaques. -Peripheral clumps of abnormal neuronal -Peripheral clumps of abnormal neuronal processes processes -Central(extracellular) amyloid core -Central(extracellular) amyloid core *Beta/A4-amyloid *Beta/A4-amyloid *Derived from *Derived from APP(amyloid precursor protein) in axonal APP(amyloid precursor protein) in axonal membrane -membrane -Specific for Specific for Alzheimer´s diseaseAlzheimer´s disease

NEUROPATHOLOGY IV ALZHEIMER´S... ALZHEIMER´S...

Pathology..... Pathology..... Generalized cerebral cortical/subcortical nerve cell Generalized cerebral cortical/subcortical nerve cell lossloss(explains dementia) -Marked (explains dementia) -Marked loss in hippocampus/amygdala -Loss in loss in hippocampus/amygdala -Loss in specific nuclei: specific nuclei: *Memory disturbances(cholinergic neurons of *Memory disturbances(cholinergic neurons of nucleus basalis of Meynert nucleus basalis of Meynertprocesses to hippo.) processes to hippo.) *Emotional(depressive) symptoms- *Emotional(depressive) symptoms-noradrenergic neurons of locus noradrenergic neurons of locus ceruleus/serotoninergic neurons of raphe nuclei(processes ceruleus/serotoninergic neurons of raphe nuclei(processes to cerebral cortex)to cerebral cortex)

NEUROPATHOLOGY IV

ALZHEIMER´S.... ALZHEIMER´S.... Genetics. Genetics. *Amyloid precursor protein(APP) *Amyloid precursor protein(APP) -Chromosome 21q -Chromosome 21q -Normal neuronal membrtane -Normal neuronal membrtane protein protein -Mutations cause early -Mutations cause early onset of disease onset of disease -Down´s syndrome -Down´s syndrome patients develop disease patients develop disease after 30 yrs of age after 30 yrs of age *AB-42/43 peptide result *AB-42/43 peptide result from abnormal proce- ssing of APPfrom abnormal proce- ssing of APP

NEUROPATHOLOGY IV

ALZHEIMER´S.... ALZHEIMER´S.... Genetics.... Genetics.... *Presenilins 1(PS-1) *Presenilins 1(PS-1) -Chromosome 14q -Chromosome 14q -Involved in metabolism of APP -Involved in metabolism of APP -Mutation associated w/early--Mutation associated w/early-onset AD *Presenilin 2(PS-2) onset AD *Presenilin 2(PS-2) -Chromosome 1q -Chromosome 1q -Defined from -Defined from Volga Germans in W.Ok. Volga Germans in W.Ok. --Mutations cause late-onset diseaseMutations cause late-onset disease

NEUROPATHOLOGY IV

ALZHEIMER´S..... ALZHEIMER´S..... Genetics... Genetics... *Apolipoprotein E(APOE) *Apolipoprotein E(APOE) --Polymorphic serum protein Polymorphic serum protein -Interacts with APP and promotes -Interacts with APP and promotes deposi deposi tion of beta/A4-amyloid tion of beta/A4-amyloid -Associated -Associated with late-onset diseasewith late-onset disease

NEUROPATHOLOGY IV

PICK´S DISEASE. PICK´S DISEASE. *Corticobasal ganglionic degeneration *Corticobasal ganglionic degeneration *Familial frontotemporal *Familial frontotemporal dementia(chromo- some 17-dementia(chromo- some 17-linked dementia) linked dementia) *Progressive subcortical gliosis(DFT) *Progressive subcortical gliosis(DFT) *Primary progressive aphasia *Primary progressive aphasia *Dementia w/motor neuron *Dementia w/motor neuron disease inclusionsdisease inclusions

NEUROPATHOLOGY IV PICK´S DISEASE...PICK´S DISEASE...

NEUROPATHOLOGY IV

PARKINSON´S DISEASE. PARKINSON´S DISEASE. *Parkinsonism is characterized by: *Parkinsonism is characterized by: -Bradykinesia -Bradykinesia -Resting tremor -Resting tremor --Rigidity Rigidity *Parkinsonism is commonly due to *Parkinsonism is commonly due to Parkin- son´s diseaseParkin- son´s disease

NEUROPATHOLOGY IV

PARKINSON´S DISEASE... PARKINSON´S DISEASE... *It is also characterized by: *It is also characterized by: -Gross depigmentation of -Gross depigmentation of substantia substantia nigra and nigra and locus ceruleus locus ceruleus --Loss of pigmented neurons(collections Loss of pigmented neurons(collections of of melanin-containing macrophages) melanin-containing macrophages) --Loss of dopaminergic nerve fibers in Loss of dopaminergic nerve fibers in striatum striatum w/80% reduction in basal w/80% reduction in basal ganglia dopamine ganglia dopamine concentrationconcentration

NEUROPATHOLOGY IV

DIFFUSE LEWY BODY DISEASE. DIFFUSE LEWY BODY DISEASE. *Dementia mimicking Alzheimer´s *Dementia mimicking Alzheimer´s dis. and associated with Parkinsonism dis. and associated with Parkinsonism *Lewy bodies in cerebral *Lewy bodies in cerebral cortical neurons and substantia nigra cortical neurons and substantia nigra *Most be *Most be differentiated from concurrent differentiated from concurrent Parkinson´s disease and Alzheimer´s dis. Parkinson´s disease and Alzheimer´s dis.

NEUROPATHOLOGY IV

PROGRESSIVE SUPRANUCLEAR PALSY(Steele-PROGRESSIVE SUPRANUCLEAR PALSY(Steele-Richardson-Olszewski syndrome) Richardson-Olszewski syndrome) *Parkinsonism w/supranuclear gaze *Parkinsonism w/supranuclear gaze palsy *Atrophy/neuronal loss in superior palsy *Atrophy/neuronal loss in superior colliculi and subthalamic nuclei colliculi and subthalamic nuclei *Depigmentation/neuronal loss in *Depigmentation/neuronal loss in substantia nigra substantia nigra *Neurofibrillary tangles in *Neurofibrillary tangles in substantia nigra. No Lewy bodies seen substantia nigra. No Lewy bodies seen