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NMSK Exam 2: Neuro > 28. Degenerative Diseases > Flashcards

28. Degenerative Diseases Flashcards

1
Q

How do neurofibrillary tangles appear in pyramidal neurons vs. in rounder cells?

A
  • Pyramidal = elongated “flame” shape

- Rounder cells = “globose;” basket weave of fibers around nucleus

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2
Q

How is Alzheimers Inherited?

A

AD, but most cases are sporadic

  1. Sporadic: age and ApoE4 gene
  2. Early onset: mutations in prescinilin 1 and Down Syndrome due to extra Chr 21
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3
Q

Clinical Symptoms of Alzheimers

A
  1. Dementia: slow onset dementia => cognitive dfcitits => NO LOC that starts around 50YO
  2. Progressive disorientation and aphasia
  3. Within 5-10 years => disabled, mute and immobile
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4
Q

Gross morphology of Alzheimers

A
  1. Diffuse cortical atrophy, narrowing of gyri and widening of sulci
  2. Hydrocephalus ex-vacuo
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5
Q

In Alzheimers, what parts of the brain undergo atrophy first

A

frontal/temporal lobes => parietal lobes> occipital lobes

  • Structures in medial temporal lobe (hippocampus, entorhinal CTX and amygdala are affected 1st and severely atrophied later in disease)
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6
Q

Generation of which peptide aggregates are the critical initiating event for the development of AD?

A

Aβ first and then tau

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7
Q

Histology in Alzheimers

A
  1. Extracellular neuritic/senile plaques or diffuse plaques
  2. CAA (Cerebral amyloid angiopathy)
  3. Intracytoplasmic neurofibrillary tangles
  4. Granulovacuolar degeneration
  5. Hirano bodies
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8
Q

What are neuritic/senile plaques?

A

Cores of amyloid (AB40 + 42) with entrapped neutitic processes (dystrophic neurons) surrounded by reactive astrocytes and microglia

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9
Q

In alzheimers, where are neuritic plaques MC seen?

A
  1. Hippocampus
  2. Amygdala
  3. Neocortex
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10
Q

A higher number of (plaques/tangles) correlates better with the degree of dementia seen in AD?

A

Number of neurofibrillary tangles correlates better with the degree of dementia

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11
Q

Diffuse plaques seen in AD have no _____ and are predominantly made up of Aβ____

A

Diffuse plaques seen in AD have no​ amyloid core and are predominantly made up of Aβ 42

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12
Q

In ALZ, Diffuse plaques are an indicator of what?

A

Early stage of plaque deelopment, most commonly seen in patients with down syndrome

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13
Q

Where are diffuse plaques most common at?

A
  • 1. Superficial CTX
  • 2. CTX of cerebellum
  • 3. BG
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14
Q

Cerebral amyloid angiopathy are deposits of AB___ in the walls of the vessels.

What can they cause?

A

AB40

↑ risk of hemorrhage

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15
Q

Intracytoplasmic NF tangles are aggregates of what?

A

hyperphosphaylrated tau, a microtubule binding protein, + ubiquitin + MAP2

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16
Q

What are hirano bodies?

A

elongated, glassy eosinophilic bodies made up of actin located in pyramidal cells in hippocampus seen in Alzheimers

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17
Q

Neurofibrillary tangles are seen best with which stain?

A

Bielschowsky stain (silver stain)

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18
Q

What are granulovacuolar degneration?

A

small vacuoles filled with argyrophillic granules located in cytoplasm of neurons, MC in hippocampus and olfactory bulb

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19
Q

What histology finding in ALZ in found NL in aging?

A

Granulovaculoar degeneration

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20
Q

Why is severe cognitive impairment not a usual feature of MS?

A

Gray matter is relatively spared

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21
Q

What is seen morphologically in an active plaque of a patient with MS?

A
  1. Ongoing myelin breakdown with preservation of axons;
  2. Many lipid-laden, PAS +, MO filled with myelin debris;
  3. Lymphocytes and mononuclear cells (inflammatory cells) surround edges of plaques & venules
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22
Q

What is seen morphologically in an inactive plaque / shadow plaques of a patient with MS?

A
  1. Inactive plaque: no inflammatory cell infiltrate
  2. Shadow plaque: border between NL & affected white matter not sharply circumscribed
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23
Q

Sx of MS

A
  1. Optic neuritis: Blurred/no vision in 1 eye
    * -10-50% of ppl with optic neuritis develop MS
  2. Internuclear opthalmoplegia due to damage of MLF (medial longitudinal fasciculus)
  3. Brainstem affected: Ataxia, nystagmus, scanning speech

4. SC affected: LE motor and sensory loss

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24
Q

Neuromyelitis optica is due to antibodies against?

Major channel of which cell?

A

Aquaporin-4; major water channel of astrocytes

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25
Q

What is commonly found in the CSF of patients with Neuromyelitis Optica?

A
  1. Turbid
  2. ↑ Neutrophils
  3. ↑ Opening pressure
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26
Q

Although similar to MS, how does Acute Disseminated Encephalomyelitis (ADEM) differ?

When does it occur and what are the clinical manifestations?

A
  • Occurs in younger patients w/ an abrupt onset and may be rapidly fatal
  • Is a DIFFUSE monophasic demyelinating disease occuring after a viral infection or vaccination
  • Signs and symptoms develop 1-2 weeks after the antecedent infection as HA, lethargy, and coma; 20% die; 80% completely recover
  • In contrast to MS, all of the lesions look similar – monophasic; perivenular demyelination

*MS has focal findings w/ considerable variance in the size of lesions

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27
Q

Acute necrotizing hemorrhagic encephalomyelitis (AKA acute hemorrhagic leukoencephalitis of Weston Hurst) is almost invariable preceded by a recent episode of?

Who is most at risk?

A

- Upper respiratory infection (URI)

- Young adults and children

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28
Q

Which neurodegenerative disorder is characterized by loss of myelin in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum, including myelin loss WITHOUT evidence of inflammation?

A

Central pontine myelinolysis (aka osmotic demyelination disorder)

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29
Q

Neurofibrillary tangles are insoluble and apparently resistant to clearance in vivo, thus remaining visible in tissue as _______ or _______ tangles neuron dies.

A

“Ghost” or “Tombstone” tangles

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30
Q

The vasuclar amyloid seen in CAA is predominantly of which type?

A

Aβ40

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31
Q

What is typically the terminal event in a patient with AD?

A

Intercurrent disease, often pneumonia

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32
Q

How are Frontaltemporal Lobar Degenerations (FTLDs) distinguished from AD in term of clinical manifestations?

A

early-onset dementias that involve degeneration of the frontal & temporal lobe => progressive changes in personality and behavior (Frontal) and language/aphasia, that occur BEFORE ↓ in memory, often,

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33
Q

Tau pathology is seen in which FTD?

A
  1. Picks disease
  2. Progressive Supranuclear Palsy
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34
Q

What is the characteristic pattern of atrophy seen in Pick disease (degenerative disease of the frontal/temporal CTX=> early changes in behavior/personality => dementia?

A
  1. Selective lobar atrophy : Asymmetric, atrophy of the frontal and temporal lobes w/ sparing of the posterior 2/3 of superior temporal gyrus
  2. thinning of gyri, widening of sulci => knife edge appearance
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35
Q

What are Pick Cells vs. Pick Bodies?

How do Pick bodies stain?

A

- Pick cells = swollen cells

- Pick bodies = round aggregates of TAU in cytoplasm,

  • weakly basophilic and stain strongly with silver
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36
Q

What is Progressive Supranuclear Palsy and when is it commonly seen?

What is the prognosis?

A

A Tauopathy (does not contain Aβ)

  • MC in 50-70s M
  • Often fatal within 5-7 years
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37
Q

What are the clinical features of Progressive Supranuclear Palsy (PSP)?

A
  • Trunchal rigidity,
  • Disequilibrium w/ frequent falls
  • Difficulty w/ voluntary vertical gaze
  • Nuchal dystonia
  • pseudobulbar palsy,
  • mild progressive dementia
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38
Q

What is Progressive Supranuclear Palsy?

A

Widespread neuron loss in the GB, subthalamic nuclei, substantia nigra, PA grey matter and dendate nucleus MC in M 50-70 YO that causes truncal rigidity and fatal in 5- 7 years

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39
Q

Histology in

Progressive Supranuclear Palsy

A
  • Globose neurofillbrillary tangles: 4R tau straight filaments
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40
Q

CSF in Neuromyelitis Optica?

Other findings?

A
  1. Turbid
  2. ⬆︎ neutrophils
  3. ⬆︎ opening pressure

Ig and compliment deposits in BBB.

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41
Q

Histology in ADEM

A
  1. 1. Early on: PMNs (neutrophils) => later on mononuclear cells.
  2. 2. Lipid-laden MO
  3. 3. Perivenular demyelination
42
Q

Pt with Alzheimers by 40YO, be weary of what?

A
  1. Downsyndrome
  2. Mutation in presincilin 1/2
43
Q

Degeneration of neurons/grey matter in:

  1. CTX => ______;
  2. Brainstem/ BG => _______
A

Degeneration of neurons/grey matter in:

  1. CTX => dementia;
  2. Brainstem/ BG => movement disorders
44
Q

What else damages the nigrostriatal dopaminergic pathway?

A
  1. Parkinsons
  2. MSA (Multiple Systems Atrophy)
  3. Postencephalitic Parkinsonism (after influenza epidemia
45
Q

Describe Lewy Bodies.

A

Single or multiple cytoplasmic, eosinophilic, round to elongated inclusions of a-synuclein surrounded by a pale halo

46
Q

In PD, where are LB located?

A
  1. BG
  2. Cholinergic neurons in:
    1. Locus ceruleus
    2. Basal nucleus of Meynert
    3. Dorsal motor nucleus of Vagus N
47
Q

In dementia with lewy bodies there, is depigmentation of the substantia nigra and locus ceruleus w/ relative preservation of which structures?

A
  1. Cortex,
  2. Hippocampus
  3. Amygdala
48
Q

What are the inclusions found in the brain of patients who die of CTE?

A

Tau

49
Q

What 2 brain inclusions are associated with Parkinsons Disease?

A
    • Tau
    • α-synuclein
50
Q

Which disease has a clinical pattern noted to be Parkinsonian w/ abnormal eye movements?

A

Progressive Supranuclear Palsy (PSP)

51
Q

Multiple System Atophy (MSA) is characterized by cytoplasmic inclusions of ________ in oligodendrocytes (glial cells)

A

α-synuclein

52
Q

MSA is a Sporadic Disorder characterized by intracytoplasmic inclusions of alpha-synuclein in oligodendrocytes, affect 3 systems:

A
  1. Striatonigral circuit => Parkinsonism
  2. Olivopontocerebellar circuit => Ataxia
  3. ANS => Autonomic dysfunction => orthostatic hypotension
53
Q

Histology of MSA

A

Aggregates of alpha-synuclein in cytoplasm of oligodendrocytes

54
Q

How are the diagnostic glial cell inclusions in MSA stained?

A

Silver stain; show glial inclusions mainly in oligodendrocytes w α-synuclein and ubiquitin

55
Q

What chromosome is the HTT gene encoding the protein huntingtin found on?

A

Chromosome 4p16.3

56
Q

Gross Morphology and Histo in Huntingtons

A

Small brain

  1. Atrophy of caudate nucleus and body of corpus callosum => putamen; GB is secondarily affected
  2. Atrophy of frontal CTX
  3. Enlargement of ventricles (lateral)
  4. Loss of medium spiny GABA neurons in the caudate nucleus
  5. Intranuclear inclusions of Huntington protein in neuron.
57
Q

PRogression of sx in Huntingtons

A
  1. Motor => cognitive: dementia and depression => death in 15 years
58
Q

2 AR spinocerebellar degeneration disorders

A

1. Friedreich ataxia

2. Ataxia Telangiectasia

59
Q

Friedreich ataxia is associated with what expansion?

A

GAA repeat of gene on Chr9q13 that encodes frataxin

60
Q

When is the onset of Friedreich Ataxia and how does it manifest?

How do the symptoms progress and what do most affected individuals develop?

A
  1. First decade of life beginning with: gait ataxia => hand clumsiness => dysarthria and depressed DTRs (extensor plantar reflex is typically present)
  2. Sensory loss
  3. Wheelchair bound in 5 years
  4. Live to be 40 - 50; die from pulmonary infection and cardiac disease
61
Q

Complications seen in Friedriches Ataxia

A
  1. Cardiac arrhythmias and CHF
  2. DM
62
Q

Loss of axons and gliosis are seen where in Friedreich Ataxia?

A
  1. - Posterior columns
  2. - Corticospinal tracts
  3. - Spinocerebellar tracts
63
Q

Mutation in Ataxia-Telangiectasia

A
  1. AR mutated ATM gene on Chr11q22-23 that encodes a kinase that repairs dsDNA breaks => thus, cannot reapir dsDNA breaks
    2.
64
Q

When is the onset of Ataxia-Telangiectasia?

What are the common symptoms/triad?

A

Early childhood with

  1. Cerebellar dysfunction: unsteady walking
  2. Telangiectatic rashes on conjunctiva, skin and CNS
  3. Immunodeficiency => recurrent sinus infections

Progressive death in 20s because many develop lymphoid neoplasms (often T-cell leukemias), gliomas and cancers

65
Q

What is the prognosis of Ataxia-Telangiectasia and how do most of these patients die?

A
  • Die in 20s bc many develop T-cell/lymphoid neoplasms (T-cell leukemias), gliomas and cancers
66
Q

What has ⬆︎ sensitivity to XR-induced chromosomal abnormalities.

A

Ataxia-Telangiectasias

67
Q

What proteins aggregates do we see in ALS?

A
  1. TDP-53
  2. SOD-1 in familial disease
  3. FUS
68
Q

What is ALS?

A

AD progressive disease marked by loss of UMN in cerebral cortex and LMNs in spinal cord and brainstem + toxic protein accumulation

69
Q

Mutation in ALS

A
  • AD (5-10%)
  • 25% = toxic GOF of SOD1 on Chr21 => aggregation of protein.
70
Q

Course of ALS

A
  • 1st complain: asymmetric weakness of hands => drop objects
  1. Arms and legs cramp
  2. Weak muscles and fascilations (involuntary muscle contractions)
  3. Eventually, respiratory muscles are involved => recurrent bouts of pneumonia=> death due to respiratory depression
71
Q

What are characteristic morphological findings on the spinal cord and brain in ALS?

A
  1. Thin anterior roots
  2. Atophy of precentral gyrus
72
Q

Histology of ALS

A
  1. Loss of UMN => degeneration of corticospinal tracts
  2. ↓ neurons in anterior horn
  3. Bunina Bodies (PAS+ cytoplasmic inclusions of remnants of autophagic vacuoles)
  4. Neurogenic atrophy of Skeletal muscles
73
Q

What do the remaining neurons in ALS contain?

A

PAS-positive cytoplasmic inclusions called Bunina bodies (remnants of autophagic vacuoles)

74
Q

In ALS, if UMN involvement predmoinates =>

A

Primary lateral sclerosis

75
Q

In ALS, if LMN predominates => _____

A

Progressive muscular atrophy

76
Q

What is progressive bulbar palsy (Bublar ALS) associated with some patients with ALS?

Prognosis?

A
  • Degeneration of motor nuclei in the lower brainstem => RAPIDLY progressive problems speaking and swallowing (Deglutination and phonation)=
  • => only 50% living at 2 years
77
Q

child is NL at birth, but begins to miss developmental milestones. DDx?

A

Genetic metabolic diseases

78
Q

AR defect in catabolism of spingolipids, mucopolysaccharides or mucolipids => accumulates in lysosomes => neuronal death

A

neuronal storage disease

79
Q

Cortical involvement in [neuronal storage disease]

A

Loss of cognitive function and possible seizures

80
Q

Inherited mutations in enzymes needed to make/maintain myelin => defects in myelin synthesis or turnover => hypomyelination => deterioration of motor skills, spasticity, hypotonia or ataxia

Diseases and genetics?

A

Leukodystrophies: AR, except adrenoleukodystrophy (X-linked)

81
Q

How are leukodystrophies different from demyelinating diseases?

A

Insidious and progressive loss of cerebral function at younger ages

82
Q

Oxidative phosphorylation disorders caused by mutations in mitochondrial gense, involving gray matter AND skeletal muscle

A

Mitochondrial encephalopathies

83
Q

What is a neuronal storage disese

A

1. Tay Sachs: AR mutation of HEXA gene on Chr 15: => ↓ in enzyme hexosamindiase A => build-up of GM2 gangliosides because we cannot break it down.

84
Q

sx at Tay-sachs disease

A

Kid is fine at birth and until 1 YO =>

  • Cherry red spots in maculae
  • Degenerating mentally and physically until death at 2-3YO
85
Q

Name Mitochondrial encephalopaties

A
  • 1. MELAS
  • 2. MERRF
  • 3. Kearne Sayre Syndrome
  • 4. Leigh Syndrome (Subacute Necrotizing Encephalopathy)
86
Q

MELAS

A
  1. MELAS: mutated tRNA
    1. Mitochondrial encephalopthy
    2. Lactic acidosis
    3. Stroke like episodes
87
Q

MERRF

A

MERRF: mutated tRNA

  1. Myoclonic epilepsy
  2. Ragged red fibers
88
Q

What is Kearne-Sayre Syndrome sx?

A
  1. Cerebellar ataxia
  2. Progressive inability to move eyes and eyebrows
  3. Pigmentary retinopathy
  4. Cardiac conduction defects
89
Q

Kearne Sayre Syndrome

Histo

A
  1. Spongiform changes in gray and white matter
  2. ↓ neurons, most commonly in cerebellum
  3. RRF (ragged red fibers)
90
Q

Leigh Syndrome (Subacute Necrotizing Encephalopathy)

A

Symptoms: lactic acidosis, seizures and hypotonia

Histo:

  1. Multifocal symmetric destruction of brain tissue; esp preiventricular deep brain tissue
  2. Spongiform appearance
  3. Vascular proliferation

-

91
Q

Sx of B12 deficiency

A
    1. Anemia
  • 2. Neuro problems: at first, numbess, tingling and ataxia in LE => rapidly progress to muscle weakness => complete paraplegia

Can tx with B12 replacement, UNLESS paraplegia has developed.

92
Q

Histology of B12 deficiency

A
  1. Subacute combined degeneration of SC: Vacuolar swelling of myelin in BOTH [ascending tracts in posterior columnss] AND [descending pyramidal tracts]
93
Q

Thiamine (__) deficiency is often seen in who?

A

B1

Chronic alcoholics

  1. Wernicke encephalopathy: sudden onset of psychotic symptoms or opthalmoplegia (reversible w thiamine)
  2. Korsakoffs: memory problems and confabulation (irreversible)
  3. Beriberi: cardiac failure
94
Q

Pt has foci of hemorrhage and necrosis in the mammillary bodies and walls of 3rd/4th ventricles

DDx?

A

Thiamine (B1) deficiency)

95
Q

Pseudolaminar necrosis of the pyramidal neurons in Sommer Sector of Hippocampus/CTX & purkinje cells in the cerebellum

A

Hypoglycemia

96
Q

Pt has ketoacidosis=> dehydration => confusion, stupor => hyperosmolar coma. Fluids are quickly replaced to avoid what?

DDx ?

A

Cerebral edema

Hyperglycemia

97
Q

Carbon monoxide poisoning first affects what?

A
  1. Cerebral CTX (layers 3 and 4)
  2. Sommer sector
  3. Purkinje cells

=> Bilateral necrosis of GP

98
Q

What preferentially attacks the retina => degeneration of retinal ganglion cells => blindness.

What structure is fucked up

A
  • Methanol
  • Bilateral necrosis of putamen
99
Q

Ethanol/alcohol damages what cells?

A

Atophy of granule cells in anterior portion of vermis of cerebellum =>

  • 1. Truncal ataxia
  • 2. Unsteady gait
  • 3. Nystagmus
100
Q

Advanced cases of crhonic ethnol use causes what?

A

Bergman Gliosis => proliferation of adjacent astrocytes between depleted granular cell layer and molecular layer

101
Q

Radiation can cause what?

A

TUMORS: sarcomas, gliomas, meningiomas

102
Q

Histology of radiation effects

A
  1. Radiation necrosis: type of coagulative necrosis that favors white matter
  2. Cerebral edema
  3. Hyalinized BV: thick walls with intramural fibrin-like material

NMSK Exam 2: Neuro (15 decks)

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