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NEURODEGENERATIVE
HUMAN DISEASES
Gavino Faa
Department of Pathology
University of Cagliari
NEURONS = 100 mld
• Up to150.000 sinaps/neuron
GLIAL CELLS = 10.000 MLD
• Proliferation
• Migration
• Elongation of cell processes
SEL = STRATO SUBEPENDIMALE
• Neuroblasti = cellule staminali
FATTORI NEUROTROFICI NEUROTROPICI
• Glia radiale
HUMAN
BRAIN
CORTEX
1. Definition of neurodegenerative
diseases
2. Alzheimer disease
3. Pathogenesis (hypotheses)
4. Macroscopy
5. Microscopy
6. Sister NUN
NEURODEGENERATION OF THE CNS
DEFINITION: Group of different diseases,with in common similar clinical-pathological
features, but with different pathogenesis
COMMON CLINICAL AND PATHOLOGICAL FINDINGS 1. Neurons: the main target
2. Selective diseases: one functional system affected, others
completely spared
PARKINSON: affected the dopaminergic-striatal system
3. simmetrical diseases
4. progressive diseases
REGIONS OF THE CNS MAINLY DAMAGED 1. Cortex Alzheimer
2. Basal ganglia and trunk ganglai Parkinson, Hungtington
3. Spinal cord and cerebellum Spino-cerebellar Degeneration
4. Motoneurons ALS
NEURODEGENERATIVE DISEASES
OF THE CNS
1. Alzheimer’s disease
2. Parkinson disease
3. Huntington Chorea
4. Amyotrophic lateral sclerosis
5. Spinocerebellar degeneration
(ataxia)
6. Pick disease
ALZHEIMER’S DISEASE
DEFINITION
Progressive neurological disorder characterized by disturbances of
affectivity, loss of memory, and evolution towards dementia
ALZHEIMER’S DISEASE Senile Dementia
Dementia presenile
EPIDEMIOLOGY 400.000 cases
2% < 65 years
> 10% > 85 years
Frequence: 50% of dementia
M/F: ½
Italy 1980
CLINICAL VARIANTS
PATHOGENESIS
ALZHEIMER’S DISEASE
1. Sporadic
2. Familial
3. Down syndrome > 45 years
1. β amiloid Protein
2. Neurofibrillary tangles
3. Senile plaques
4. amyloid congofilic angiopathy
5. granulo-vacuolar degeneration
6. Hirano bodies
PROTEIN β
AMYLOID
ALZHEIMER’S Disease
40 aa, deposition inside neuritic plaques
Precursor proteic of amyloid, of about 695 aa
CNS normal
Down
syndrome
Alzaheimer’s
disease β AP
AMYLOID β PROTEIN
ALZHEIMER’S DISEASE
Neurofibrillary
tangles
Fibrils of
amyloid Plaques
senile
Congofilic
Angiopaty
Genes involved in AD
• Cytoskeleton reorganization:
– APOE, MAP2, MAPT, PKP4, PRKCI
• Synaptic formation
– ACHE, APBA1, APBB1, APBB2, APOE,
BDNF
• Lipid metabolism
– ABCA1, APOA1, APOE, CLU, HSD17B10
Genes involved in AD
• Apoptosis
– APLP1, APP, CASP3, CASP4, CLU, EP300,
ERN1, IL1A, MAPT, MPO, NAE1, PRHCA,
PRKCE, PRKCZ, PSEN1, PSEN2, SNCA
Cell cycle
APBB1, APBB2, CDK1, CDK5, CDKL1,
ERN1, EP300, IL1A, PRKCA
Cell Siganling molecules involved in
Beta-amyloid generation
• WNT signaling: • GSK3A, GSK3B, LRP6
• NOTCH signaling: • ADAM10, APH1A, NCSTN
• G-protein coupled receptor signaling: • APLP2, GNAO1, GNAZ, GNB1
• Intracellular signaling: • APBA3, APBB2, PRKCA, PRKCB, PRKCD,
PSEN1
ALZHEIMER’S DISEASE CHROMOSOME 21
1. In subjects with Down syndrome, Alzheimer’s disease is
characterized by precocius insurgence
2. The gene encoding for APP (amyloid proteic precursos) is
localized to chromosome 21
3. Subjects affectd by the familiar form of AD carry a
mutation (val-ile) in exon 17 of the APP gene (early
presenting Alzheimer)
4. Pazients with late Alzheimer do not carry any mutation in
chromosome 21
5. Hereditary cerebral hemorrhagic disease with
amyloidosis- Ducth type (HCWA - D) is characterized by a
point mutation in the APP gene, with βAP deposits in brain
Munoz FJ, J Neurosci 2002, 22, 3081-3089
Neurofibrillary tangles
ALZHEIMER’S DISEASE
DEFINIZIONE
Abnormal tau protein causes collapse of the
microtubule structure, leading to neuronal
necrosis/apoptosis
Insoluble twisted fibers inside the
cytoplasm of neurons, surrounding nuclei
ME 9 nm-thick filaments/microtubules
IPOTESI
Silver stain H&E
SENILE (neuritic) PLAQUES
ALZHEIMER’S DISEASE
Cras P, PNAS 1991, 88, 7552-7556
Polymorphous β-A protein deposition
including dystrophic fragmented
neurites (100 μm in Diameter)
Amigdala
Hyppocampus Localization
AMYLOID ANGIOPATY
ALZHEIMER’S DISEASE
DEFINITION Congo red-positive (specific for amyloid)
material, birifrangent at polarized light.
IHC: immunoreactive to β-Amyloid peptide
LOCALIZATION
Artery and vein wall in the
subrachnoid space
Penetranting arteries of
the gry matter (segmental
angiopaty (but never in the
brain deep structures!)
VACUOLAR DEGENERATION
ALZHEIMER’S DISEASE
DEFINITION Small clear vacuols (5
μm) with a central
argirophilic granule
HIRANO BODIES
DEFINITION
Eosinophilic rod-like
structures consisting in
abnormal filaments
LOCALIZATION Restricted to the
pyramidal layer of
hippocampus
TAU PROTEIN
Amyloid angiopathy
Amiloid plaques
Granzotto A, Zatta P. Metal ions in neurological systems, Springer2012
Ghost neurons NEUROFIBRILLARY TANGLES
SENILE (neuritic) PLAQUES
IHC: TAU PROTEIN SILVER STAIN
Degenerated dendritic processes (Silver stain)
H%E
IHC: β-Amyloid
Senile plaques
Congo Red
SENILE PLAQUES
Silver stain
DIFFERENTIAL DIAGNOSIS WITH OTHER
DEMENTIAS
1. Vitamin deficiency (alcool-related)
2. Cerebral tumors
3. Adverse drug reaction
4. Intossication by toxics/pollutants
5. Chronic infections
6. Depression (pseudodementia)
7. Cerebral infarction
8. White matter disease (Binswanger)
9. Creutzfelt – Jacob
10.Fronto – temporal Dementia (FTD)
Pick disease
• A rare and permanent form of dementia,
affecting only certain areas of the brain
• Average age of presentation: 54 y
• Memory loss, personality changes
• Increased muscle tone (rigidity)
IHC: Tau protein
IHC: Neurofilament
Siler stain
PICK BODIES
PICK BODIES: Tau protein IHC
Hippocampal dentate gyrus cells
New episodic memories
IHC: Ubiquitin
Iseki E, J Neurol Sci 1998,159, 194-201
DEMYELINATING BRAIN DISEASES
1. Leucodistrophy
2. Krabbe disease
3. Adrenoleucodistrophy
4. Alexander’s disease
5. Multiple Sclerosis
6. Inflammatory/Post-infectious
encephalomyelitis
7. Central pontine Myelinolysis
MULTIPLE SCLEROSIS (MS) DEFINITION Inflammatory disease characterized by damage to the insulating covers of
nerve cells in brain and spinal cord, resulting in a wide range of symptoms:
•Physical, neurological
•Mental and psychiatric
EPIDEMIOLOGY Young adults
Tipica del clima TEMPERATO, rara in vicinanza delle alte quote
I soggetti che cambiano stato in età infantile acquisiscono il rischio della
nuova sede
PRESENTATION Mean age: 30 y: rare < 14 y and > 60 aa
PATHOGENESIS 1. Genetic predisposition?
2. Infantile viral infection ? (< 15 aa)
3. Autoimmunity
GENETIC FACTORS •Familiar history (fino al 2° e 3° grado)
•Homozigous twins 25%
•HLA-DR2
IMMUNOLOGICAL FACTORS •Perivascolar lymphocytes (CD4+ and CD8+)
•Experimental allergic encephalitis(EAE) by introducing myelin protein
in the brain of experimental animals: A SUITABLE MODEL OF MS?
•Siriam S, Steiner I. Ann Neurol 2005, 58, 939-945
INFECTIOUS AGENTS •VIRUS: Measles (Alter M. Neurol Neurochir Psichiatr 1977, 18, 341-355)
•, German measles
• Herpes virus HHV6
MULTIPLE SCLEROSIS
Early phases 1. Selective loss of myelin at the periphery of plaque
2. Axons trespassing the plaque maintain their integrity, even when
myelin-deprived (naked axons)
3. Limphocyte aggregates surrounding small arteries
LATE PHASES 1. Cerebral oedema first decreases disppears
2. plaqueS become harder
3. Axons loose their structural integrity
4. Apoptosis of oligodendrocytes
5. Neuronal death
6. Astrocyte reaction
Plaque development
MS PLAQUES Ø variable (< 2 cm)
Roundish,
sharp borders
1. Presentation: 20-30 years
2. Acute presentation with relapses and long free intervals
3. Symptoms at presentation
a. Strabismus (squint)
b. Loss of eyesight
c. Dizziness
d. Diplopia
e. Numbness of legs
f. Weakness of legs
g. Paresis of legs
CLINICAL FEATURES
Relapse = new plaques’ insurgence
Spinal Nerves affected
Optical nerves affected
Sequential lesions of the myelin sheet
Woelcke myelin stain shows multiple plaques
Chronic plaque of demyelination, evidenced by myelin stain
Plaques of demyelination with astrocyte reaction
Spielmayer stain Holzer stain
GFAP showh astrocytic hyperplasia at he margins
of a demyelinating plaque
The center of tha plaque is occupied by CD68+ macrophages/microglia
On the right, GFAP+ astrocytes (arrows)
CD3+ T-lymphocytes surrounding a vessel
Vascular
lumen
Active plaque: perivascular lymphocytic infiltrates
V
Myelin loss in the center of an active plaque
T.E.M
Myelin
Loss
PARKINSON DISEASE
Hypocinetic rigid syndrome (HRS)
• James Parkinson: the shaking palsy, 1817
• Degenerative disorder of the CNS
• Death of dopamine-generating cells in the
substantia nigra
• Causes of neuronal death: unknown
• Movement-related symptoms
• Thinking and behavioral later symptoms
• Dementia and depression in advances stages
PARKINSON DISEASE
• Increased risk: exposition to pesticides
• Tobacco smokers: protected against PD?
• Pathology:
• 1. accumulation of alpha-synuclein into
inclusion called “Lewy bodies” in
dopaminergic neurons of the midbrain
• 2.
Genes putatively involved in Parkinson disease
Mesencephalon: loss of pigmentation in substantia nigra
Parkinson disease: Lewy bodies in pigmented neurons of substantia nigra
Lewy bodies, immunostained for sinuclein
SCLEROSI LATERALE AMIOTROFICA
DEFINIZIONE
Malattia degenerativa dei motoneuroni ad eziologia sconosciuta. Sono
colpiti i motoneuroni di alcuni distretti specifici (vulnerabilità selettiva di
sistemi neuronali specifici)
EPIDEMIOLOGIA
1 caso ogni 100.000 abitanti in tutto il mondo
Età media di insorgenza 40-50 aa
M/F = 1,5-2/1
5% dei casi forma familiare
•cromosoma 21q (braccio lungo)
•Associato a mutazione “non sense”
del gene che codifica per SOD
SEDE Motoneuroni delle corna anteriori del midollo spinale
Motoneuroni della corteccia cerebrale (area motoria)
Motoneuroni dell’ipoglosso
ANATOMIA PATOLOGICA
1. Perdita dei grossi motoneuroni
2. Lieve gliosi reattiva
3. Perdita (secondaria) di fibre mieliniche nei fasci laterali del midollo
spinale (pallidi)
4. Muscoli colpiti pallidi e coartati
CLINICA
1. Indebolimento e deperimento dei muscoli di una mano
2. Crampi muscolari al braccio
3. Fascicolazioni al braccio
4. Difficoltà nel parlare (linguaggio non comprensibile)
5. Indbolimento arti inabilità totale
6. Coinvolgimento dei musccoli respitatori morte
7. Attività intelletuale sempre mantenuta
10
an
ni cir
ca
DEGENERAZIONE SPINO-
CEREBELLARE
DEFINIZIONE
Sotto questa definizione sono comprese diverse entità, tutte caratterizzate
da:
1. Perdita neuronale
• Cervelletto
• Tronco
• Midollo spinale
2. Base genetica autosomica
La sintomatologia riflette la topografia delle lesioni
1. Cervelletto atassia e tremori
2. Tronco rigidità e tremori
3. Midollo spinale assenza riflessi tendinei
DEGENERAZIONE CEREBELLO-
OLIVARE
ATASSSIA DI FRIEDREICH
ENCEFALOPATIA ALCOLICA
ATROFIA CORTICALE
Effetto tossico diretto dell’alcol?
Carenze vitaminiche?
Malnutrizione?
ATROFIA DELLE CELLULE DI PURKINJE
Atassia
MIELINOSI PONTINA
Forse iatrogena
Carenza di vitamina B12 (anche in non alcolisti), reversibile dopo
somministrazione di vitamina B12
Sede
1. Corpi mamillari
2. Iptalamo
3. Ponte tetto e regioni periventricolari
Clinica: esordio acuto
1. Alterato stato di coscienza
2. Alterata regolazione termica
3. Oftalmoplegia - nistagmo
SDR di Wernicke
ENCEFALOPATIA ALCOLICA
1. Perdita della memoria recente
2. Confabulazioni
SDR di Wernicke-korsakoff
ANATOMIA PATOLOGICA
Cromatolisi dei neuroni del nucleo medio-dorsale
del talamo
ENCEFALOPATIA ALCOLICA
