Pathology CNS (demyelinating.degenerating disease)
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How is natural history of demyelinating disease determined?
- by the limited capacity of the CNS to regenerate normal myelin and
- by the degree of secondary damage to axons that occurs as the disease runs its course
What is the characteristic feature of MS?
Multiple sclerosis (MS) is an autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space.
What is the mc demyelinating disorder?
What is the usual course of MS?
- In most individuals with MS, the clinical course takes the form of relapsing and remitting episodes of variable duration (weeks to months to years) marked by neurologic defects, followed by gradual, partial recovery of neurologic function.
- The frequency of relapses tends to decrease during the course of time, but there is a steady neurologic deterioration in most affected individuals
What is the major underlying mechanism in MS?
immune response that is directed against the components of the myelin sheath
What is the genetic of MS?
- single-nucleotide polymorphisms in IL-2 and IL-7 receptor genes
What is the pathophysiology of MS?
- Disease is initiated by CD4+ TH1 and TH17 T cells that react against self myelin antigens and secrete cytokines.
- TH1 cells secrete IFNγ, which activates macrophages, and TH17 cells promote the recruitment of leukocytes.
- The demyelination is caused by these activated leukocytes and their injurious products.
- The infiltrate in plaques and surrounding regions of the brain consists of T cells (mainly CD4+, some CD8+) and macrophages
What is the gross morphology of plaques in MS?
- Lesions appear as multiple, well-circumscribed, somewhat depressed, glassy, graytan, irregularly shaped plaques.
- In the fresh state these are firmer than the surrounding white matter (sclerosis).
- Plaques can be found throughout the white matter and also extend into gray matter, since these have myelinated fibers running through them.
- The lesions often have sharply defined borders.
- Plaques commonly occur adjacent to the lateral ventricles. They are also frequent in the optic nerves and chiasm, brainstem, ascending and descending fiber tracts, cerebellum, and spinal cord
What are the features of active plaques in MS?
- Ongoing myelin breakdown with abundant macrophages containing lipid-rich, PAS-positive debris.
- Perivascular cuffing of lymphocytes and monocytes especially at the outer edge of the lesion.
- Centered on small veins.
- Relative preservation of axons and depletion of oligodendrocytes.
- In time, astrocytes undergo reactive changes. As lesions become quiescent, the inflammatory cells slowly disappear.
What are the features of inactive plaque?
- Within inactive plaques, little to no myelin is found, and there is a reduction in the number of oligodendrocyte nuclei;
- Astrocytic proliferation and gliosis are prominent.
- Axons in old gliotic plaques show severe depletion of myelin and are also greatly diminished in number
What are the types of plaques in MS?
those that are sharply demarcated and centered on blood vessels, either with (pattern I) or without (pattern II) deposition of immunoglobulin and complement, and those that are less well demarcated and are not centered on vessels (patterns III and IV). These latter two are distinguished by the distribution of oligodendrocyte apoptosis (III, widespread; IV, central only). It has been observed that only one pair of patterns (I/II or III/IV) may be present in a given individual, suggesting that these may reflect distinct mechanisms rather than different stages of lesion.
What are shadow plaques?
- the border between normal and affected white matter is not sharply circumscribed. In this type of lesion some abnormally thinned-out myelin sheaths can be demonstrated, especially at the outer edges.
- This phenomenon is most commonly interpreted as evidence of partial and incomplete remyelination by surviving oligodendrocytes.
What are clinical manifestations of MS?
- Unilateral visual impairment, due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis), is a frequent initial manifestation of MS. However, only some affected individuals (10% to 50%, depending on the population studied) with optic neuritis go on to develop MS. Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus.
- Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the voluntary control of bladder function
What are the examination of CSF in MS?
mildly elevated protein level, and in one third of cases, there is moderate pleocytosis. IgG levels in the CSF are increased and oligoclonal IgG bands are usually observed on immunoelectrophoresis; these are indicative of the presence of a small number of activated B cell clones, postulated to be self-reactive, in the CNS.
What are the neuroimaging finding in MS?
- gadolinium-enhancing lesions
- B,C--> FlAIR
- D,E--> T1
What are the features of neuromyelitis optica?
- The development of synchronous (or near synchronous) bilateral optic neuritis and spinal cord demyelination.
- White cells are common in the CSF, often including neutrophils.
- Within the damaged areas of white matter, there is typically necrosis, an inflammatory infiltrate including neutrophils, and vascular deposition of immunoglobulin and complement.
- These lesions have been suggested to be mediated by humoral immune mechanisms.
- Many affected individuals show antibodies to aquaporins, which are in part responsible for maintenance of astrocytic foot process and thus the integrity of the blood-brain barrier
What are the features of ADEM?
- Diffuse, monophasic demyelinating disease that follows either a viral infection or, rarely, a viral immunization.
- Symptoms typically develop a week or two after the antecedent infection and include headache, lethargy, and coma rather than focal findings, as seen in MS.
- The clinical course is rapid, and as many as 20% of those affected die; the remaining patients recover completely
- Only grayish discoloration around white-matter vessels.
- On microscopic examination, myelin loss with relative preservation of axons can be found throughout the white matter.
- In the early stages, polymorphonuclear leukocytes can be found within the lesions; later, mononuclear infiltrates predominate. The breakdown of myelin is associated with the accumulation of lipid-laden macrophages.
- In contrast with MS, all lesions appear similar, consistent with the clinically monophasic nature of the disorder
What are the features of acute necrotizing hemorrhagic encephalomyelitis?
- A fulminant syndrome of CNS demyelination, typically affecting young adults and children. The illness is almost invariably preceded by a recent episode of upper respiratory infection
- High fatality
- A perivenular distribution of demyelination and widespread dissemination throughout the CNS (sometimes with extensive confluence of lesions).
- However, the lesions are much more severe than those of ADEM and include destruction of small blood vessels, disseminated necrosis of white and gray matter with acute hemorrhage, fibrin deposition, and abundant neutrophils. Scattered lymphocytes are seen in foci of demyelination.
What are the features of CPM?
- Loss of myelin (with relative preservation of axons and neuronal cell bodies) in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum but sparing the periventricular and subpial regions.
- Lesions may be found more rostrally (supratentorial); it is extremely rare for the process to extend below the pontomedullary junction.
- The condition is most commonly associated with rapid correction of hyponatremia, although it can be associated with other severe electrolyte or osmolar imbalance, as well as orthotopic liver transplantation.
- The clinical presentation of central pontine myelinolysis is that of a rapidly evolving quadriplegia.
- Myelin loss without evidence of inflammation; neurons and axons are well preserved.
- Due to monophasic nature of the disease all lesions appear to be at the same stage of myelin loss and reaction.
What are the general features of degenerative disease?
- Diseases of gray matter characterized by the progressive loss of neurons with associated secondary changes in white matter tracts.
- The pattern of neuronal loss is selective, affecting one or more groups of neurons while leaving others, sometimes immediately adjacent, intact
- Presence of protein aggregates that are resistant to degradation through the ubiquitin-proteasome system. These aggregates are recognized histologically as inclusions. The basis for aggregation may be directly related to an intrinsic feature of a mutated protein (e.g., expanded polyglutamine repeats in Huntington disease), a feature of a peptide derived from a larger precursor protein (e.g., Aβ in Alzheimer disease), or an unexplained alteration of a normal cellular protein (e.g., α-synuclein in sporadic Parkinson disease).
....................... is the most common cause of dementia in the elderly
Alzheimer disease (AD)
What is the course of AD?
- The disease usually becomes clinically apparent as insidious impairment of higher intellectual function, with alterations in mood and behavior.
- Later, progressive disorientation, memory loss, and aphasia become manifest, indicating severe cortical dysfunction.
- Eventually, in 5 to 10 years, the affected individual becomes profoundly disabled, mute, and immobile.
- Social cognition is preserved until late in the disease
- Death is usually due to aspiration
Mutation in which genes can be used as diagnostic marker for AD?
Which genetic testing is considered a RF but not a diagnostic marker for AD?
epsilon4 allele of APOE
What are the diagnostic use of amyloid beta for AD?
- Amyloid PET
- Reduced amyloid beta-42 in CSF
What are the MRI finding in AD?
temporo-parietal and hippocampal atrophy
FDG-PET in AD shows...........
decreased metabolism in the temporo-parietal cortex at resting state
.............increases in CSF of patients with AD
What is the best diagnostic test for AD?
What are the general pathologic features of AD?
- Cortical atrophy marked by widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal lobes
- hydrocephalus ex vacuo
- Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and amygdala, are involved early in the course and are usually severely atrophied in the later stages
- Meuritic (senile) plaques and neurofibrillary tangles.
- Progressive and eventually severe neuronal loss and reactive gliosis in the same regions that bear the burden of plaques and tangles
............................., are involved early in the course and are usually severely atrophied in the later stages of AD
Structures of the medial temporal lobe, including hippocampus, entorhinal cortex and amygdala
What are the neuritic plaques?
- Focal, spherical collections of dilated, tortuous, neuritic processes (dystrophic neurites) often around a central amyloid core, which may be surrounded by clear halo
- microglial cells and reactive astrocytes at the periphery
- found in the hippocampus, amygdala, and neocortex, although there is usually relative sparing of primary motor and sensory cortices
- The dominant component of the amyloid plaque core is Aβ
- Visible by Congo-red
What are diffuse plaques?
- There is deposition of Aβ peptides with staining characteristics of amyloid in the absence of the surrounding neuritic reaction.
- Superficial portions of cerebral cortex as well as in basal ganglia and cerebellar cortex.
- Diffuse plaques appear to represent an early stage of plaque development.
- In some brain regions (cerebellar cortex and striatum) these diffuse plaques represent a major manifestation of the disease, with other clear-cut findings of Alzheimer disease, or in isolation.
- While neuritic plaques contain both Aβ40 and Aβ42, diffuse plaques are predominantly made up of Aβ42
A, Plaques with dystrophic neurites surrounding amyloid cores are visible (arrows). B, Plaque core and surrounding neuropil are immunoreactive for Aβ. C, Neurofibrillary tangle is present within one neuron, and several extracellular tangles are also present (arrows). D, Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm. E, Tangle (upper left) and neurites around a plaque (lower right) contain tau, demonstrated by immunohistochemistry
First pathological involvement in AD is seen in............
What are NFT?
- Bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. In pyramidal neurons, they often have an elongated “flame” shape; in rounder cells, the basket weave of fibers around the nucleus takes on a rounded contour (“globose” tangles).
- Neurofibrillary tangles are visible as basophilic fibrillary structures with H&E staining but are dramatically demonstrated by silver (Bielschowsky) staining
- Cortical neurons, especially in the entorhinal cortex, as well as in other sites such as pyramidal cells of the hippocampus, the amygdala, the basal forebrain, and the raphe nuclei
- Neurofibrillary tangles are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue sections as “ghost” or “tombstone” tangles long after the death of the parent neuron. Ultrastructurally, neurofibrillary tangles are composed predominantly of paired helical filaments
- Major component of paired helical filaments is abnormally hyperphosphorylated forms of the protein tau, an axonal microtubule-associated protein that enhances microtubule assembly
- Other components include MAP2 (another microtubule-associated protein) and ubiquitin.
- Paired helical filaments are also found in the dystrophic neurites that form the outer portions of neuritic plaques and in axons coursing through the affected gray matter as neuropil threads
What is cerebral amyloid angiopathy/
- Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of Alzheimer disease; however, it can also be found in brains of individuals without AD.
- Vascular amyloid is predominantly Aβ40, as is also the case when CAA occurs without AD
Granulovacuolar degeneration is ..................
- the formation of small (∼5 μm in diameter), clear intraneuronal cytoplasmic vacuoles, each of which contains an argyrophilic granule.
- While it occurs with normal aging, it is most commonly found in great abundance in hippocampus and olfactory bulb in AD
What are Hirano bodies?
- 1) Hirano bodies, found especially in AD, are elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded filaments, with actin as their major component.
- 2) They are found most commonly within hippocampal pyramidal cells
What is the pathological course of AD?
Pathologic changes (specifically plaques, tangles, and the associated neuronal loss and glial reaction) are evident earliest in the entorhinal cortex, then spread through the hippocampal formation and isocortex, and then extend into the neocortex
The fundamental abnormality in AD is .................................
the deposition of Aβ peptides
What plays major pathogenic role in AD?
What is the structure of APP?
APP is a cell surface protein with a single transmembrane domain that may function as a receptor, although ligands have remained elusive. The Aβ portion of the protein extends from the extracellular region into the transmembrane domain.
How is APP processed?
- Processing of APP begins with cleavage in the extracellular domain, followed by an intramembranous cleavage.
- There are two potential pathways, determined by the type of initial proteolytic event.
- If the first cut occurs at the α-secretase site within the Aβ sequence, then Aβ is not generated (the nonamyloidogenic pathway). This mostly occurs at the cell surface, since the various enzymes with α-secretase activity are involved in the shedding of surface proteins.
- Surface APP can also be endocytosed and may undergo cleavage by β-secretase, which cuts at the N-terminal region of the Aβ sequence (the amyloidogenic pathway).
- Following cleavage of APP at either of these sites, the γ-secretase complex performs an intramembranous cleavage
- When paired with a first cut by α-secretase, it will produce a soluble fragment, but when paired with β-secretase cleavage, it generates Aβ.
- The variation in peptide length (Aβ40 vs Aβ42) arises from alterations in the exact location of the γ-secretase cleavage.
- The γ-secretase complex—containing presenilin, nicastrin, pen-2, and aph-1—is also responsible for processing of Notch, a cell fate-determining molecule Once generated, Aβ is highly prone to aggregation—first into small oligomers (which may be the toxic form responsible for neuronal dysfunction), and eventually into large aggregates and fibrils
What is the genetic of AD?
- The gene encoding APP, on chromosome 21, lies in the Down syndrome region (trisomy, duplication, and point mutation)
- Majority of early-onset familial AD encode the two presenilins (PS1 on chromosome 14 and PS2 on chromosome 1). These mutations lead to a gain of function, such that the γ-secretase complex generates increased amounts of Aβ, particularly Aβ42
The chromosomes responsible for genetic AD are
How does amyloid beta cause neurotoxicity?
- Small aggregates of Aβ can result in synaptic dysfunction, such as blocking of long-term potentiation and changes in other membrane properties.
- While aggregates are difficult to degrade, monomeric Aβ can be degraded by a variety of proteases. Both small aggregates and larger deposits elicit an inflammatory response from microglia and astrocytes.
- This response probably assists in the clearance of the aggregated peptide, but may also stimulate the secretion of mediators that cause damage.
- Additional consequences of the activation of these inflammatory cascades may include alterations in tau phophosrylation, along with oxidative injury to the neurons
What is the importance of apolipoprotein E in AD?
- The genetic locus on chromosome 19 that encodes apolipoprotein E (ApoE) has a strong influence on the risk of developing AD.
- Three alleles exist (ε2, ε3, and ε4) based on two amino acid polymorphisms. The dosage of the ε4 allele increases the risk of AD and lowers the age of onset of the disease.
- This ApoE isoform promotes Aβ generation and deposition.
- Overall, this locus has been estimated to convey about a quarter of the risk for development of sporadic AD.
What is the role of Tau in AD?
- Tau is a microtubule-associated protein present in axons in association with the microtubular network.
- With the development of tangles in AD, it shifts to a somatic-dendritic distribution, becomes hyperphosphorylated, and loses the ability to bind to microtubules.
- It is, however, thought that the primary abnormality in AD is in Aβ and not in tau, because mutations affecting Aβ lead to the formation of tangles and AD but mutations in the gene encoding tau, MAPT, cause one of the frontotemporal dementia but neither Aβ deposition nor AD.
What are the biomarkers for AD that correlate with severity?
- Presence of a large burden of plaques and tangles is highly associated with severe cognitive dysfunction.
- The number of neurofibrillary tangles correlates better with the degree of dementia than does the number of neuritic plaques.
- Biochemical markers that have been correlated with the degree of dementia include loss of choline acetyltransferase, synaptophysin immunoreactivity, and amyloid burden
What are the general features of FTD?
- progressive deterioration of language and changes in personality corresponding to degeneration and atrophy of temporal and frontal lobes.
- Tauopathy in most of them
- Include FTD with or without taupathy, Pick, PSP, CBD
What are the features of Frontotemporal Dementia with Parkinsonism Linked to Tau Mutations?
- MAPT gene encoding tau
- FT atrophy
- NFT with either 4R tau or a mixture of 3R and 4R tau
- Nigral degeneration
- neuronal loss, gliosis
What are the clinical features of Pick disease?
Early onset of behavioral changes together with alterations in personality (frontal lobe signs) and language disturbances (temporal lobe signs).
What are the morphological features of brain in Pick disease?
- Pronounced, frequently asymmetric, atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe.
- The atrophy can be severe, reducing the gyri to a wafer-thin (“knife-edge”) appearance
- Bilateral atrophy of the caudate nucleus and putamen
- neuronal loss is most severe in the outer three layers of the cortex
- Some of the surviving neurons show a characteristic swelling (Pick cells), while others contain Pick bodies, which are cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods. Ultrastructurally, these are composed of straight filaments, vesiculated endoplasmic reticulum, and paired helical filaments that are immunocytochemically similar to those found in AD, and contain 3R tau.
- Unlike the neurofibrillary tangles of AD, Pick bodies do not survive the death of their host neuron and do not remain as markers of the disease
What are the clinical features of PSP?
- Progressive supranuclear palsy is an illness characterized clinically by truncal rigidity with dysequilibrium and nuchal dystonia; pseudobulbar palsy and abnormal speech; ocular disturbances, including vertical gaze palsy progressing to difficulty with all eye movements; and mild progressive dementia in most affected individuals.
- The onset of the disease is usually between the fifth and seventh decades
What are the pathological features of PSP?
- Widespread neuronal loss in the globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal gray matter, and dentate nucleus of the cerebellum.
- Globose neurofibrillary tangles are found in these affected regions, in neurons as well as in glia.
- Ultrastructural analysis reveals 15-nm straight filaments that are composed of 4R tau
True or false : MAPT is mutated in PSP
- Associated with polymorphism
What are the clinical features of CBD?
- Extrapyramidal rigidity, asymmetric motor disturbances (jerking movements of limbs), and sensory cortical dysfunction (apraxias, disorders of language); cognitive decline occurs, and may be prominent in some cases.
- The same MAPT haplotype linked to progressive supranuclear palsy is also highly associated with corticobasal degeneration
What is the histologic feature of CBD?
- Cortical atrophy, mainly of the motor, premotor, and anterior parietal lobes. These regions of cortex show severe loss of neurons, gliosis, and “ballooned” neurons (neuronal achromasia) that can be highlighted with immunocytochemical methods for phosphorylated neurofilaments.
- Tau immunoreactivity has been found in astrocytes (“tufted astrocytes”), oligodendrocytes (“coiled bodies”), basal ganglionic neurons, and, variably, cortical neurons.
- Clusters of tau-positive processes around an astrocyte (“astrocytic plaques”) and the presence of tau-positive threads in gray and white matter may be the most specific pathologic findings of corticobasal degeneration.
- The substantia nigra and locus ceruleus show loss of pigmented neurons, neuronal achromasia, and tangles. Similar to progressive supranuclear palsy, the tau deposits in corticobasal degeneration contain predominantly 4R tau
The most specific finding in CBD is ..................
Clusters of tau-positive processes around an astrocyte (“astrocytic plaques”) and the presence of tau-positive threads in gray and white matter
What are the features of FTD without tau pathology?
- Also seen in ALS
- usually tau-negative, ubiquitin-containing inclusions are found in superficial cortical layers in temporal and frontal lobes and in the dentate gyrus (giving rise to the term FTD-U for ubiquitin).
- Some of these cases are familial and show linkage to chromosome 17 but are caused by mutations in the gene for progranulin (an inflammatory modulator protein), which is close to the MAPT locus
dementia has been associated with so-called strategic infarcts, which are usually embolic and involve brain regions such as the
hippocampus, dorsomedial thalamus, or the cingulate gyrus of the frontal cortex
What are the features of parkinsonism?
- Diminished facial expression, stooped posture, slowness of voluntary movement, festinating gait (progressively shortened, accelerated steps), rigidity, and a “pill-rolling” tremor.
- This type of motor disturbance is seen in a number of conditions that have in common damage to the nigrostriatal dopaminergic system.
What are the causes of parkinsonism?
- Parkinson disease (PD)
- Multiple system atrophy
- Postencephalitic parkinsonism (influenza)
- Progressive supranuclear palsy and corticobasal degeneration
What are the features of PD?
This diagnosis is made in individuals with progressive L-DOPA-responsive signs of parkinsonism (tremor, rigidity, and bradykinesia) in the absence of a toxic or other known underlying etiology
What is the macroscopic finding in PD?
pallor of the substantia nigra and locus ceruleus
What is the morphology in PD?
- Pallor of the substantia nigra and locus ceruleus.
- Loss of the pigmented, catecholaminergic neurons in these regions, associated with gliosis.
- Lewy bodies may be found in some of the remaining neurons. These are single or multiple, cytoplasmic, eosinophilic, round to elongated inclusions that often have a dense core surrounded by a pale halo. Ultrastructurally, Lewy bodies are composed of fine filaments, densely packed in the core but loose at the rim; these filaments are composed of α-synuclein.
- Lewy bodies may also be found in the cholinergic cells of the basal nucleus of Meynert, which is depleted of neurons (particularly in patients with abnormal mental function), as well as in other brainstem nuclei including the locus ceruleus and the dorsal motor nucleus of the vagus
What are the genes associated with PD?
- 1. α-synuclein, an abundant lipid-binding protein normally associated with synapses that is also a major component of the Lewy body AD
- 2. LRRK2 (leucine-rich repeat kinase 2) are a more common cause of autosomal dominant PD
- 3. A juvenile AR form of PD is caused by loss of function mutations in the gene encoding parkin, an E3 ubiquitin ligase with a wide range of substrates. NO LB
- 4. DJ-1, a protein involved in regulating redox responses to stress; or the gene encoding the kinase PINK1, which appears to regulate normal mitochondrial function, AR
What is the pathogenesis of PD?
- a misfolded protein/stress response triggered by α-synuclein aggregation; defective proteosomal function due to the loss of the E3 ubiquitin ligase parkin; and altered mitochondrial function caused by the loss of DJ-1 and PINK1
- Reduced complex I
- Pesticide also are RF
What are additional clinical features of PD?
What are the features of LBD?
- Fluctuating course (pronounced variation in attention and alertness), visual hallucinations, and prominent frontal signs, parkinsonism, severe neuroleptic senstivity, REM disorder,
- Early changes in complex attention and executive function rather than learning and memory
- presence of Lewy bodies in a wide range of cortical locations (less distinct than BS), contain alpha-synuclein
- Lewy neurites
- depigmentation of the substantia nigra and locus ceruleus, paired with relative preservation of the cortex, hippocampus, and amygdala.
- there is evidence that Lewy bodies and Lewy neurites are found first in the medulla, progress over time to reach the midbrain (when it becomes manifest as PD), and can eventually progress across the nervous system to reach the cortex (and manifest as dementia with Lewy bodies).
What are the features of FTD?
- 1. Behavioral variant; a. Three or more of the following behavioral symptoms:i. Behavioral disinhibition. ii. Apathy or inertia. iii. Loss of sympathy or empathy. iv. Perseverative, stereotyped or compulsive/ritualistic behavior. v. Hyperorality and dietary changes.
- b. Prominent decline in social cognition and/or executive abilities.
- 2. Language variant: a. Prominent decline in language ability, in the form of speech production, word finding, object naming, grammar, or word comprehension
- Relative sparing of learning and memory and perceptual-motor function.
What are the features of dementia in AD, FTD, and LBD?
- FTD--> Language and behavior and social cognition/Little Learning and memory
- LBD--> early change in complex attention and executive function rather than learning and memory
- AD--> Learning and memory / No social cognition
What is the pathological hallmark of MSA?
Presence of glial cytoplasmic inclusions, typically within the cytoplasm of oligodendrocytes
What are the types of MSA?
The dominant symptoms can be parkinsonism (MSA-P), or cerebellar dysfunction (MSA-C), or autonomic dysfunction (MSA-A).
What is the morphology of MSA?
- In cerebellar forms there is typically atrophy of the cerebellum, including the cerebellar peduncles, pons (especially the basis pontis), and medulla (especially the inferior olive)
- In parkinsonian forms the atrophy involves both the substantia nigra and striatum (especially putamen).
- Since autonomic symptoms are related to cell loss from the catecholaminergic nuclei of the medulla and the intermediolateral cell column of the spinal cord, there are usually no specific gross findings. Atrophic brain regions show evidence of neuronal loss as well as variable numbers of neuronal cytoplasmic and nuclear inclusions.
- cytoplasmic inclusions were originally demonstrated in oligodendrocytes with silver impregnation methods and contain α-synuclein as well as ubiquitin and αB-crystallin. The inclusions are ultrastructurally distinct from those found in other neurodegenerative diseases and are composed primarily of 20- to 40-nm tubules (also seen in other cells)
What is the primary pathologic event in MSA?
Glial cytoplasmic inclusions
What are the general characteristics of HD?
- Autosomal dominant disease characterized clinically by progressive movement disorders and dementia, and histologically by degeneration of striatal neurons.
- Jerky, hyperkinetic, sometimes dystonic movements involving all parts of the body (chorea) are characteristic; affected individuals may later develop parkinsonism with bradykinesia and rigidity. The disease is relentlessly progressive, with an average course of about 15 years to death.
What is the genetic of HD?
- The HD gene, located on chromosome 4p, encodes huntingtin.
- In the first exon of the gene there is a stretch of CAG repeats, which encodes a polyglutamine region near the N terminus of the protein. Normal HD genes contain 6 to 35 copies of the repeat; when the number of repeats is increased beyond this level it is associated with disease.
- There is an inverse relationship between repeat number and age of onset, such that longer repeats are associated with earlier onset
Why HD in father is associated with anticipation?
Repeat expansions occur during spermatogenesis, so that paternal transmission is associated with early onset in the next generation, the phenomenon of anticipation
True or False: new mutations are uncommon in HD
What is the pathological hallmark of HD?
atrophy of the caudate nucleus
What are the gross features of HD?
- The brain is small and shows striking atrophy of the caudate nucleus and, less markedly at early stages, the putamen. The globus pallidus may be atrophied secondarily, and the lateral and third ventricles are dilated.
- Atrophy is frequently also seen in the frontal lobe, less often in the parietal lobe, and occasional in the entire cortex
Which cells are most and earliest affected in HD?
- caudate nucleus, especially in the tail and portions nearer the ventricle
- medial-to-lateral direction in the caudate
- Loss of small neurons generally occurs first
- The medium-sized, spiny neurons that use γ-aminobutyric acid as theirneurotransmitter, along with enkephalin, dynorphin, and substance P, are especially affected.
Which striatal structure is not affected in HD?
Which neurons are spared in HD?
Two populations of neurons are relatively spared, the diaphorase positive neurons that contain nitric oxide synthase and the large cholinesterase-positive neurons; both appear to serve as local interneurons
What are the histological features of HD?
- Atrophy of Caudate> Putamen>GB
- Atrophy of frontal cortex
- The medium-sized, spiny neurons that use γ-aminobutyric acid as theirneurotransmitter, along with enkephalin, dynorphin, and substance P, are especially affected
- fibrillary gliosis that is more extensive than in the usual reaction to neuronal loss. There is a direct relationship between the degree of degeneration in the striatum and the severity of clinical symptoms. Protein aggregates containing huntingtin can be found in neurons in the striatum and cerebral cortex
What is the pathogenesis of HD?
The loss of medium spiny striatal neurons leads to dysregulation of the basal ganglia circuitry that modulates motor output. These neurons normally function to dampen motor activity; thus, their degeneration in HD results in increased motor output, often manifested as choreoathetosis. The cognitive changes associated with the disease are probably related to the neuronal loss from cerebral cortex
What are the clinical features of HD?
- The age at onset is most commonly in the fourth and fifth decades and is related to the length of the CAG repeat in the HD gene.
- Motor symptoms often precede the cognitive impairment.
- The movement disorder of HD is choreiform, with increased and involuntary jerky movements of all parts of the body; writhing movements of the extremities are typical.
- Early symptoms of higher cortical dysfunction include forgetfulness and thought and affective disorders, but there is progression to a severe dementia.
- Although individuals with HD have an increased risk of suicide, intercurrent infection is the most common natural cause of death.
What are the three types of SCA?
polyglutamine diseases linked to expansion of a CAG repeat, similar to HD; expansion of non–coding region repeats, similar to myotonic dystrophy; and other types of mutations
What are the features of CAG repeat SCA?
- Intranuclear inclusions
- Sequestration and depletion of chaperone proteins by the formation of abnormal aggregates driven by the polyglutamine tracts as well as transcriptional dysregulation
What are the clinical features of Fredriech Ataxia?
- Begin in First decade of life with Gait ataxia
- Followed by hand clumsiness and dysarthria. Deep tendon reflexes are depressed or absent, but an extensor plantar reflex is typically present.
- Joint position and vibratory sense are impaired, and there is sometimes loss of pain and temperature sensation and light touch.
- Most affected individuals develop pes cavus and kyphoscoliosis.
- There is a high incidence of cardiac arrhythmias and congestive heart failure. Concomitant diabetes is found in about 10% of patients.
- Most patients become wheelchair-bound within about 5 years of onset; the cause of death is intercurrent pulmonary infections and cardiac diseas
What is the pathophysiology of Fredriech ataxia?
- Expansion of a GAA trinucleotide-repeat in the first intron of a gene on chromosome 9q that encodes a protein called frataxin.
- Affected individuals have extremely low levels of the protein, which normally localizes to the inner mitochondrial membrane, where it may have a role in regulation of iron levels.
- Because iron is an essential component of many of the complexes of the oxidative phosphorylation chain, mutations in frataxin have been suggested to result in generalized mitochondrial dysfunction.
What are the morphological features of Fredriech ataxia?
- 1) Spinal cord shows loss of axons and gliosis in the posterior columns, the distal portions of corticospinal tracts, and the spinocerebellar tracts.
- 2) There is degeneration of neurons in the spinal cord (Clarke column), the brainstem (cranial nerve nuclei VIII, X, and XII), the cerebellum (dentate nucleus and the Purkinje cells of the superior vermis), and the Betz cells of the motor cortex3) Large dorsal root ganglion neurons are also decreased in number; their large myelinated axons, traveling both in the dorsal roots and in dorsal columns, undergo secondary degeneration.
- 4) The heart is enlarged and may have pericardial adhesions. Multifocal destruction of myocardial fibers with inflammation and fibrosis is detectable in about half the affected individuals who come to autopsy.
What are the clinical features of AT?
- Ataxic-dyskinetic syndrome beginning in early childhood, with the subsequent development of telangiectasias in the conjunctiva and skin; and immunodeficiency.
- The disease is relentlessly progressive, with death early in the second decade.
- Affected individuals first come to medical attention because of recurrent sinopulmonary infections and unsteadiness in walking.
- Later on, speech is noted to become dysarthric, and eye movement abnormalities develop.
- Many affected individuals develop lymphoid neoplasms, often T-cell leukemias.
What is the genetic basis for AT?
- The ataxia-telangiectasia mutated (ATM) gene on chromosome 11q encodes a kinase with a critical role in orchestrating the cellular response to double-stranded DNA breaks.
- Cells from individuals with the disease show increased sensitivity to x-ray-induced chromosome abnormalities; these cells continue to replicate damaged DNA rather than stopping to allow repair or undergoing apoptosis.
- The carrier frequency of ataxia-telangiectasia has been estimated at 1%; in these individuals the mutated ATM allele may underlie an increased risk of cancer, specifically breast cancer.
- It has been suggested that mutations in ATM result in failure to remove cells with DNA damage from the developing nervous system, predisposing it to degeneration
What are the characteristic morphological finding in AT?
- The abnormalities are predominantly in the cerebellum, with loss of Purkinje and granule cells; there is also degeneration of the dorsal columns, spinocerebellar tracts, and anterior horn cells, and a peripheral neuropathy.
- Telangiectatic lesions have been reported in the CNS as well as in the conjunctiva and skin of the face, neck, and arms.
- Cells in many organs (e.g., Schwann cells in dorsal root ganglia and peripheral nerves, endothelial cells, pituicytes) show a bizarre enlargement of the nucleus to two to five times normal size and are referred to as amphicytes.
- The lymph nodes, thymus, and gonads are hypoplastic.
ALS is caused by .....
loss of lower motor neurons in spinal cord and brainstem and upper motor neurons that project in corticospinal tracts
What is the molecular genetic of ALS?
- 10% genetic
- 25% due to SOD on chromosome 21, missense, adverse gain-of-function
What is the pathogenesis of ALS?
- mutated SOD1 protein is misfolded and triggers an injurious unfolded protein response
- Alterations in axonal transport, neurofilament abnormalities, toxicity mediated by increased levels of the neurotransmitter glutamate, and aggregation of other proteins (such as one called TDP-43 that is sometimes found in cytoplasmic inclusions in neurons in ALS)
What is the morphology of ALS?
- anterior roots of the spinal cord are thin
- The precentral gyrus may be atrophic
- reduction in the number of anterior-horn neurons throughout the length of the spinal cord with associated reactive gliosis and loss of anterior-root myelinated fibers. Similar findings are seen in the hypoglossal, ambiguus, and motor trigeminal cranial nerve nuclei
- PAS-positive cytoplasmic inclusions, called Bunina bodies, that appear to be remnants of autophagic vacuoles
- Atrophy of muscles due to LMN
- Loss of the upper motor neurons leads to degeneration of the corticospinal tracts, resulting in volume loss and absence of myelinated fibers, which may be particularly evident at the lower segmental levels
What are the symptoms of ALS?
- Early symptoms include asymmetric weakness of the hands, manifested as dropping objects and difficulty in performing fine motor tasks, and cramping and spasticity of the arms and legs.
- As the disease progresses, muscle strength and bulk diminish, and involuntary contractions of individual motor units, termed fasciculations, occur.
- The disease eventually involves the respiratory muscles, leading to recurrent bouts of pulmonary infection.
...............are involved late in ALS
Progressive muscular atrophy and bulbar ALS involve ......and......
What are the features of Bulbospinal Atrophy (Kennedy Syndrome)?
- XL adult onset
- distal limb amyotrophy and bulbar signs such as atrophy and fasciculations of the tongue and dysphagia. Affected individuals manifest androgen insensitivity, gynecomastia, testicular atrophy, and oligospermia.
- expansion of a CAG/polyglutamine repeat in the androgen receptor
- degeneration of lower motor neurons in the spinal cord and brainstem
- nuclear inclusions containing aggregated androgen receptor
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