patoloji-ders-notlari

Title

Serdar Balcı

Degenerative Diseases of CNS

Serdar BALCI, MD

Neurodegenerative Diseases

• Cellular degeneration of subsets of neurons
• These subsets are related by function, rather than by physical location in the brain
• Cause is accumulation of abnormal proteins
  • also histologic hallmarks of specific disorders
• ??Why these abnormal proteins tend to accumulate in and preferentially affect particular kinds of neurons??
  • Subtle differences among subtypes of neurons

Robbins Basic Pathology

Clinical manifestations of degenerative diseases

• Cerebral cortical neurons
  • Loss of memory, language, insight, and planning, all components of dementia
• Basal ganglia
  • Movement disorders
• Cerebellum
  • Ataxia
• Motor neurons
  • Weakness

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• Degenerative diseases have primary targets
• Other brain regions are often affected later in the course
• Huntington disease
  • Start with movement disorders
  • Later cortical involvement, cognitive changes

Dementia

• Development of memory impairment and other cognitive deficits
  • Severe enough to decrease the affected person’s capacity to function at the previous level
  • Despite a normal level of consciousness
• Arises during the course of many neurodegenerative diseases
• Accompany numerous other diseases that injure the cerebral cortex

Robbins Basic Pathology

ALZHEIMER DISEASE

Alzheimer Disease

Most common cause of dementia in the elderly population

Insidious onset of impaired higher intellectual function

Altered mood and behavior

Progresses to disorientation, memory loss, and aphasia

Disabled, mute, and immobile

Death usually from pneumonia or other infections

• Age is an important risk factor
  • 3% in 65-74 years old
  • 19% in 75-84 years old
  • 47% in >84 years
• Most cases are sporadic
• 5-10% are familial
  • early onset

Beta amyloid (Aβ) accumulates in the brain over time

APP (amyloid precursor protein)Transmembrane protein

Cleaved by α-secretase and γ-secretase

Liberates peptide that is nonpathogenic

Robbins Basic Pathology

Aβ is created APP is sequentially cleaved by the enzymes β-amyloid converting enzyme (BACE) and γ-secretase

Mutations in APP or in components of γ-secretase (presenilin-1 or presenilin-2) lead to familial AD by increasing the rate at which Aβ is generated

Robbins Basic Pathology

Aβ peptides form pathogenic aggregates and contribute to the characteristic plaques and tangles of Alzheimer disease

Robbins Basic Pathology

Alzheimer Disease

• APP gene
• Chromosome 21
• Risk of AD is higher with an extra copy of the APP gene
  • Trisomy 21 (Down syndrome)
  • Small interstitial duplications of APP
• Apolipoprotein ε4 (ApoE4)
• Each ApoE4 allele that is present increases the risk of AD by approximately 4 fold
• Lower the age of onset
• How ApoE4 influences Aβ accumulation is unknown
  • May increase Aβ aggregation or deposition, or decrease Aβ clearance
• Small aggregates of Aβ pathogenic
  • alter neurotransmission
  • toxic to neurons and synaptic endings
• Large deposits of Aβ are a feature of end-stage AD
  • form of plaques
  • lead to neuronal death
  • elicit a local inflammatory response
  • result in further cell injury
  • altered region-to-region communication through mechanical effects on axons and dendrites

Presence of Aβ leads to hyperphosphorylation of the neuronal microtubule binding protein tau

Redistribution of tau from axons into dendrites and cell bodies

Aggregates into tangles

Contribute to neuronal dysfunction and cell death

• Macroscopic examination
  • Variable degree of cortical atrophy
  • Widening of the cerebral sulci
    • most in frontal, temporal, and parietal lobes
  • Compensatory ventricular enlargement (hydrocephalus ex vacuo)
• Microscopic level
  • Diagnosed by
  • Presence of plaques, extracellular lesion
  • Neurofibrillary tangles, intracellular lesion
• May also be present to a lesser extent in the brains of elderly nondemented persons
  • Diagnosis of AD are based on a combination of clinical and pathologic features
• Plaques
• Tangles
• Neuronal loss
• Glial reaction
• Constant progressive involvement of different parts of the brain
  • First in the entorhinal cortex
  • Then in the hippocampal formation and isocortex
  • Finally in the neocortex

Plaques contain a central core of amyloid and a surrounding region of dystrophic neurites

Robbins Basic Pathology

• Neuritic plaques
• Focal, spherical collections of dilated, tortuous, silver-staining neuritic processes
  • dystrophic neurites
• Often around a central amyloid core
• 20-200 µm in diameter
• Microglial cells and reactive astrocytes are present at their periphery
• Plaques can be found
  • Hippocampus
  • Amygdala
  • Neocortex
  • Relative sparing of primary motor and sensory cortices until late in the disease course

Immunohistochemical stain for Aβ

Peptide is present in the core of the plaques as well as in the surrounding region

Robbins Basic Pathology

• The amyloid core contains Aβ
• Diffuse plaques
  • Aβ deposits can also be found that lack the surrounding neuritic reaction
  • Typically found in the superficial cerebral cortex, the basal ganglia, and the cerebellar cortex
  • May represent an early stage of plaque development

Neurons containing tangles stained with an antibody specific for tau

Robbins Basic Pathology

• Neurofibrillary tangles
• Bundles of paired helical filaments
• Visible as basophilic fibrillary structures in the cytoplasm of the neurons
• Displace or encircle the nucleus
• Tangles can persist after neurons die
  • Form extracellular pathology
• Commonly found in cortical neurons
  • entorhinal cortex
  • pyramidal cells of the hippocampus
  • Amygdala
  • basal forebrain
  • raphe nuclei

• Neurofibrillary tangles
• Major component of paired helical filaments is abnormally hyperphosphorylated tau
• Tangles are not specific to AD
  • Found in other degenerative diseases as well

FRONTOTEMPORAL LOBAR DEGENERATION

Frontotemporal Lobar Degeneration

Degeneration and atrophy of temporal and frontal lobes

Progressive deterioration of language and changes in personality

Frontotemporal dementias

• Macroscopy
  • Atrophy of the brain that predominantly affects the frontal and temporal lobes
• Microscopy
  • FTLD-tau
    • inclusions contain tau, configuration differs from Alzheimer
    • caused by mutations in the gene encoding tau

Frontotemporal Lobar Degeneration Subtypes

• Pick disease
  • Subtype of FTLD-tau
  • Smooth, round inclusions, Pick bodies
• FTLD-TDP43
  • Aggregates containing the DNA/RNA-binding protein TDP-43
  • Predominantly frontal lobe cognitive impairment
  • Mutations in the gene encoding TDP-43
    • also mutated in a subset of cases of amyotrophic lateral sclerosis

PARKINSON DISEASE

Parkinsonism

Clinical syndrome characterized by tremor, rigidity, bradykinesia and instability

A range of diseases that damage dopaminergic neurons from the substantia nigra to the striatum

Drugs (dopamine antagonists) or toxins selectively injure dopaminergic neurons

• α-synuclein is a protein involved in synaptic transmission
• Parkinson disease
  • Characteristic neuronal inclusions containing α-synuclein
• Multiple system atrophy (MSA)
  • α-synuclein aggregates in oligodendrocytes
• Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD)
  • Tau-containing inclusions in neurons and glial cells
• Postencephalitic parkinsonism
  • 1918 influenza pandemic

Parkinson disease

• Most cases sporadic
• Autosomal dominant and recessive forms exist
• Autosomal dominant PD
  • Point mutations and duplications of the gene encoding α-synuclein
• Lewy body
  • Diagnostic feature of Parkinson disease
  • Inclusion containing α-synuclein
  • The linkage between α-synuclein and disease pathogenesis is unclear
• Defects in protein degradation may have a pathogenic role
  • Parkin
    • E3 ubiquitin ligase
  • UCHL-1
    • enzyme involved in recycling of ubiquitin from proteins targeted to the proteasome
• Mutations in protein kinase LRRK2
  • show either Lewy bodies containing α-synuclein or tangles containing tau
• Some forms of familial PD are associated with mutations in the PARK7 or PINK1 genes
  • important for normal mitochondrial function

Robbins Basic Pathology

Typical gross finding at autopsy is pallor of the substantia nigra and locus ceruleus

Robbins Basic Pathology

Lewy bodies may be found in those neurons that remain

Single or multiple, intracytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo

Robbins Basic Pathology

• Loss of the pigmented, catecholaminergic neurons in these regions associated with gliosis
• **Remaining neurons contain Lewy bodies **
• Ultrastructural examination
  • consist of fine filaments, densely packed in the core but loose at the rim, composed of α-synuclein, neurofilaments and ubiquitin
• Other major histologic finding is Lewy neurites
  • dystrophic neurites that also contain abnormally aggregated α-synuclein

Immunohistochemical staining for α-synuclein highlights more subtle Lewy bodies and Lewy neurites in many brain regions

Appear first in the medulla and then in the pons, before involvement of the substantia nigra

Lewy bodies and Lewy neurites eventually appear in the cerebral cortex and subcortical areas, including the cholinergic cells of the basal nucleus of Meynert and the amygdala → Dementia

HUNTINGTON DISEASE

Huntington Disease

Autosomal dominant movement disorder

Degeneration of the striatum (caudate and putamen)

Choreiform (dancelike)

Increased and involuntary jerky movements of all parts of the body

• CAG trinucleotide repeat expansions in a gene located on 4p16.3 that encodes the protein huntingtin
  • Normal alleles contain 11 to 34 copies of the repeat
  • In disease repeats increased, sometimes into the hundreds
  • Larger numbers of repeats resulting in earlier-onset disease
  • Expansions of the pathologic CAG repeats can occur during spermatogenesis
    • Paternal transmission may be associated with earlier onset in the next generation
• Toxic gain-of-function mutation
• Mutant protein is subject to ubiquitination and proteolysis, yielding fragments that can form large intranuclear aggregates
• Functional problems in:
  • Transcription factors
  • Protein degradation pathways
  • Mitochondrial function
  • Brain-derived neurotrophic factor (BDNF) signaling
• Macroscopy
  • **Brain is small **
  • Striking atrophy of the caudate nucleus and, sometimes less dramatically, the putamen
  • Pathologic changes develop over the course of the illness in a medial to lateral direction in the caudate and from dorsal to ventral in the putamen
  • Globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated
  • Atrophy frequently is also seen in the frontal lobe, less often in the parietal lobe, and occasionally in the entire cortex

Normal hemisphere on the left

Huntington disease on the right: atrophy of the striatum and ventricular dilation

An intranuclear inclusion in a cortical neuron is strongly immunoreactive for ubiquitin

Robbins Basic Pathology

• Microscopic examination
  • Loss of neurons from affected regions of the striatum
  • Medium-sized, spiny neurons that release the neurotransmitters γ-aminobutyric acid (GABA), enkephalin, dynorphin, and substance P are especially sensitive, disappear early in the disease
  • Fibrillary gliosis
    • More extensive than in the usual reaction to neuronal loss
  • Intranuclear inclusions that contain aggregates of ubiquitinated huntingtin protein

SPINOCEREBELLAR ATAXIAS

Spinocerebellar Ataxias

• Clinically heterogeneous group of diseases
• Caused by trinucleotide repeat expansion mutations
• CAG repeat expansions encoding polyglutamine tracts in various genes
  • similar to Huntington disease
  • Neuronal intranuclear inclusions

Friedreich ataxia

• Autosomal recessive
• Manifests in the first decade of life
  • Gait ataxia, hand clumsiness and dysarthria
  • Pes cavus and kyphoscoliosis
  • High incidence of cardiac disease and diabetes
• GAA trinucleotide repeat expansion in the gene encoding frataxin
  • protein that regulates cellular iron levels, particularly in the mitochondria
  • Decreased frataxin leads to mitochondrial dysfunction as well as increased oxidative damage

AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis

• Death of
  • Lower motor neurons in the spinal cord and brain stem
    • Denervation of muscles, muscular atrophy (the “amyotrophy” of the condition), weakness, and fasciculations
  • Upper motor neurons (Betz cells) in the motor cortex
    • Paresis, hyperreflexia, and spasticity, along with a Babinski sign
    • Degeneration of the corticospinal tracts in the lateral portion of the spinal cord (“lateral sclerosis”)
  • Sensation usually is unaffected, but cognitive impairment does occur, sometimes as a frontotemporal dementia
• Men>Women
• Fifth decade or later
• Bulbar amyotrophic lateral sclerosis
  • Degeneration of the lower brain stem cranial motor nuclei occurs early and progresses rapidly
• Most cases are sporadic
• 5-10% familial
  • Autosomal dominant inheritance
  • Begins earlier in life
• Mutations in the superoxide dismutase gene, SOD-1 , on chromosome 21
  • Most frequent genetic cause (20% of cases)
  • Generate abnormal misfolded forms of the SOD-1 protein
  • Trigger the unfolded protein response and apoptotic death
• TDP-43 and FUS
  • DNA/RNA binding proteins
  • Pathogenesis is unknown
• Macroscopy
  • Anterior roots of the spinal cord
    • Thin and gray (rather than white)
  • In severe cases
    • Precentral gyrus (motor cortex) may be mildly atrophic
• Microscopic examination
  • Reduction in the number of anterior horn cell neurons throughout the length of the spinal cord
    • Associated with reactive gliosis and loss of anterior root myelinated fibers
  • Neurons contain cytoplasmic inclusions that contain TDP-43
  • Death of upper motor neurons results in degeneration of the descending corticospinal tracts
  • Skeletal muscles show neurogenic atrophy

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas

Autopsy Pathology: A Manual and Atlas