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
2
Q
How is Alzheimers Inherited?
A
AD, but most cases are sporadic
- Sporadic: age and ApoE4 gene
- Early onset: mutations in prescinilin 1 and Down Syndrome due to extra Chr 21
3
Q
Clinical Symptoms of Alzheimers
A
- Dementia: slow onset dementia => cognitive dfcitits => NO LOC that starts around 50YO
- Progressive disorientation and aphasia
- Within 5-10 years => disabled, mute and immobile
4
Q
Gross morphology of Alzheimers
A
- Diffuse cortical atrophy, narrowing of gyri and widening of sulci
- Hydrocephalus ex-vacuo
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)
6
Q
Generation of which peptide aggregates are the critical initiating event for the development of AD?
A
Aβ first and then tau
7
Q
Histology in Alzheimers
A
- Extracellular neuritic/senile plaques or diffuse plaques
- CAA (Cerebral amyloid angiopathy)
- Intracytoplasmic neurofibrillary tangles
- Granulovacuolar degeneration
- Hirano bodies
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
9
Q
In alzheimers, where are neuritic plaques MC seen?
A
- Hippocampus
- Amygdala
- Neocortex
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
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
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
13
Q
Where are diffuse plaques most common at?
A
- 1. Superficial CTX
- 2. CTX of cerebellum
- 3. BG
14
Q
Cerebral amyloid angiopathy are deposits of AB___ in the walls of the vessels.
What can they cause?
A
AB40
↑ risk of hemorrhage
15
Q
Intracytoplasmic NF tangles are aggregates of what?
A
hyperphosphaylrated tau, a microtubule binding protein, + ubiquitin + MAP2
16
Q
What are hirano bodies?
A
elongated, glassy eosinophilic bodies made up of actin located in pyramidal cells in hippocampus seen in Alzheimers
17
Q
Neurofibrillary tangles are seen best with which stain?
A
Bielschowsky stain (silver stain)
18
Q
What are granulovacuolar degneration?
A
small vacuoles filled with argyrophillic granules located in cytoplasm of neurons, MC in hippocampus and olfactory bulb
19
Q
What histology finding in ALZ in found NL in aging?
A
Granulovaculoar degeneration
20
Q
Why is severe cognitive impairment not a usual feature of MS?
A
Gray matter is relatively spared
21
Q
What is seen morphologically in an active plaque of a patient with MS?
A
- Ongoing myelin breakdown with preservation of axons;
- Many lipid-laden, PAS +, MO filled with myelin debris;
- Lymphocytes and mononuclear cells (inflammatory cells) surround edges of plaques & venules
22
Q
What is seen morphologically in an inactive plaque / shadow plaques of a patient with MS?
A
- Inactive plaque: no inflammatory cell infiltrate
- Shadow plaque: border between NL & affected white matter not sharply circumscribed
23
Q
Sx of MS
A
-
Optic neuritis: Blurred/no vision in 1 eye
* -10-50% of ppl with optic neuritis develop MS - Internuclear opthalmoplegia due to damage of MLF (medial longitudinal fasciculus)
- Brainstem affected: Ataxia, nystagmus, scanning speech
4. SC affected: LE motor and sensory loss
24
Q
Neuromyelitis optica is due to antibodies against?
Major channel of which cell?
A
Aquaporin-4; major water channel of astrocytes
25
What is commonly found in the **CSF** of patients with **Neuromyelitis Optica?**
1. **Turbid**
2. **↑ Neutrophils**
3. **↑ Opening pressure**
26
Although similar to **MS**, how does **Acute Disseminated Encephalomyelitis (ADEM)** differ?
When does it occur and what are the clinical manifestations?
- 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**
27
**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?
**- Upper respiratory infection (URI)**
**- Young adults and children**
28
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?**
**Central pontine myelinolysis** (aka **osmotic demyelination disorder)**
29
**Neurofibrillary tangles** are **insoluble** and apparently **resistant to clearance in vivo**, thus remaining visible in tissue as _______ or _______ tangles neuron dies.
"**Ghost**" or "**Tombstone**" tangles
30
The vasuclar amyloid seen in CAA is predominantly of which type?
**Aβ40**
31
What is typically the terminal event in a patient with **AD**?
**Intercurrent disease, often pneumonia**
32
How are **Frontaltemporal Lobar Degenerations (FTLDs) d**istinguished from **AD** in term of clinical manifestations?
**early-onset dementias** that involve degeneration of the frontal & temporal lobe =\> progressive changes in p**ersonality and behavior (Frontal)** and l**anguage/aphasia,** that occur **_BEFORE_** ↓ in memory, often,
33
**Tau pathology** is seen in which **FTD**?
1. **Picks disease**
2. **Progressive Supranuclear Palsy**
34
What is the characteristic pattern of atrophy seen in **Pick disease (degenerative disease of the frontal/temporal CTX=\> early changes in behavior/personality =\> dementia?**
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**
35
What are **Pick Cells** vs. **Pick Bodies?**
How do **Pick bodies stain?**
**- Pick cells** = swollen cells
**- Pick bodies** = round aggregates of _TAU_ in _cytoplasm_,
* **weakly basophilic** and **stain strongly with silver**
36
What is **Progressive Supranuclear Palsy** and when is it commonly seen?
What is the prognosis?
A **Tauopathy** (does not contain Aβ)
- MC in **50-70s M**
- Often **fatal within 5-7 years**
37
What are the clinical features of **Progressive Supranuclear Palsy (PSP)?**
* **Trunchal rigidity**,
* Disequilibrium w/ frequent falls
* Difficulty w/ voluntary vertical gaze
* **Nuchal dystonia**
* pseudobulbar palsy,
* mild progressive dementia
38
What is **Progressive Supranuclear Palsy?**
**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**
39
Histology in
## Footnote
**Progressive Supranuclear Palsy**
* **_Globose_ neurofillbrillary tangles: 4R tau straight filaments**
40
CSF in Neuromyelitis Optica?
Other findings?
1. Turbid
2. ⬆︎ neutrophils
3. ⬆︎ opening pressure
Ig and compliment deposits in BBB.
41
Histology in **ADEM**
1. _1. Early on:_ **PMNs (neutrophils)** =\> later on **mononuclear cells.**
2. **2. Lipid-laden MO**
3. **3. Perivenular demyelination**
42
Pt with Alzheimers by 40YO, be weary of what?
1. Downsyndrome
2. Mutation in presincilin 1/2
43
Degeneration of **neurons/grey matter** in:
1. CTX =\> \_\_\_\_\_\_;
2. Brainstem/ BG =\> \_\_\_\_\_\_\_
Degeneration of **neurons/grey matter** in:
1. CTX =\> dementia;
2. Brainstem/ BG =\> movement disorders
44
What else damages the **nigrostriatal** dopaminergic pathway?
1. **Parkinsons**
2. **MSA (Multiple Systems Atrophy)**
3. **Postencephalitic Parkinsonism (after influenza epidemia**
45
Describe Lewy Bodies.
Single or multiple **cytoplasmic**, **eosinophilic**, **round** to elongated inclusions of **a-synuclein** surrounded by a **pale halo**
46
In **PD**, where are LB located?
1. **BG**
2. Cholinergic neurons in:
1. **Locus ceruleus**
2. **Basal nucleus of Meynert**
3. **Dorsal motor nucleus of Vagus N**
47
In _dementia with lewy bodies_ there, is **depigmentation** of the **substantia nigra** and **locus ceruleus** w/ relative preservation of which structures?
1. **Cortex,**
2. **Hippocampus**
3. **Amygdala**
48
What are the inclusions found in the brain of patients who die of **CTE**?
**Tau**
49
What 2 brain inclusions are associated with **Parkinsons Disease?**
1. - Tau
2. - α-synuclein
50
Which disease has a clinical pattern noted to be Parkinsonian w/ abnormal eye movements?
**Progressive Supranuclear Palsy (PSP)**
51
Multiple System Atophy (MSA) is characterized by **cytoplasmic** inclusions of ________ in **oligodendrocytes (glial cells)**
**α-synuclein**
52
MSA is a **Sporadic Disorder** characterized by intracytoplasmic inclusions of alpha-synuclein in oligodendrocytes, affect 3 systems:
1. **Striatonigral circuit =**\> Parkinsonism
2. **Olivopontocerebellar circuit** =\> Ataxia
3. **ANS** =\> Autonomic dysfunction =\> orthostatic hypotension
53
Histology of MSA
Aggregates of **alpha-synuclein** in **cytoplasm** of **oligodendrocytes**
54
How are the diagnostic glial cell inclusions in **MSA** stained?
**Silver stain**; show glial inclusions mainly in oligodendrocytes w α-synuclein and ubiquitin
55
What chromosome is the HTT gene encoding the protein huntingtin found on?
**Chromosome 4p16.3**
56
Gross Morphology and Histo in **Huntingtons**
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
PRogression of sx in Huntingtons
1. Motor =\> cognitive: dementia and depression =\> death in 15 years
58
2 AR spinocerebellar degeneration disorders
**1. Friedreich ataxia**
**2. Ataxia Telangiectasia**
59
**Friedreich ataxia** is associated with what expansion?
**GAA repeat** of gene on **Chr9q13** that encodes **frataxin**
60
When is the onset of **Friedreich Ataxia** and how does it manifest?
How do the symptoms progress and what do most affected individuals develop?
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
Complications seen in **Friedriches Ataxia**
1. **Cardiac arrhythmias** and **CHF**
2. **DM**
62
Loss of axons and gliosis are seen where in **Friedreich Ataxia?**
1. **- Posterior columns**
2. **- Corticospinal tracts**
3. **- Spinocerebellar tracts**
63
**Mutation** in Ataxia-Telangiectasia
1. AR mutated ATM gene on Chr11q22-23 that encodes a kinase that repairs dsDNA breaks =\> thus, cannot reapir dsDNA breaks
2.
64
When is the onset of **Ataxia-Telangiectasia?**
What are the common symptoms/_triad_?
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
What is the prognosis of Ataxia-Telangiectasia and how do most of these patients die?
* Die in 20s bc many develop **T-cell/lymphoid neoplasms (T-cell leukemias), gliomas and cancers**
66
What has ⬆︎ sensitivity to **XR-**induced chromosomal abnormalities.
**Ataxia-Telangiectasias**
67
What proteins aggregates do we see in **ALS**?
1. **TDP-53**
2. **SOD-1 in familial disease**
3. **FUS**
68
What is **ALS**?
AD progressive disease marked by **loss of UMN in cerebral cortex** and **LMNs** in spinal cord and brainstem + **toxic protein accumulation**
69
Mutation in **ALS**
* AD (5-10%)
* 25% = toxic **GOF** of **SOD1** on **Chr21** =\> aggregation of protein.
70
Course of ALS
* **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
What are characteristic **morphological** findings on the spinal cord and brain in ALS?
1. Thin anterior roots
2. Atophy of precentral gyrus
72
Histology of **ALS**
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
What do the remaining neurons in ALS contain?
PAS-positive cytoplasmic inclusions called **Bunina bodies (**remnants of autophagic vacuoles)
74
In **ALS**, if **UMN** involvement predmoinates =\>
**Primary lateral sclerosis**
75
In **ALS**, if **LMN** predominates =\> \_\_\_\_\_
**Progressive muscular atrophy**
76
What is **progressive bulbar palsy (Bublar ALS)** associated with some patients with ALS?
Prognosis?
* Degeneration of motor nuclei in the lower brainstem =\> RAPIDLY progressive problems speaking and swallowing (Deglutination and phonation)=
* =\> only 50% living at 2 years
77
child is NL at birth, but begins to miss developmental milestones. DDx?
**Genetic metabolic diseases**
78
**AR** defect in catabolism of spingolipids, mucopolysaccharides or mucolipids =\> accumulates in lysosomes =\> neuronal death
**neuronal storage disease**
79
Cortical involvement in [**neuronal storage disease]**
**Loss of cognitive function** and possible **seizures**
80
**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?**
**Leukodystrophies**: _AR_, except _adrenoleukodystrophy (X-linked)_
81
How are **leukodystrophies** different from **demyelinating diseases?**
**Insidious** and **progressive** loss of cerebral function at **younger ages**
82
**Oxidative phosphorylation** disorders caused by mutations in mitochondrial gense, involving **gray matter** AND **skeletal muscle**
**Mitochondrial encephalopathies**
83
What is a neuronal storage disese
**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
sx at **Tay-sachs disease**
Kid is **fine** **at birth** and **until 1 YO** =\>
* **Cherry red spots in maculae**
* Degenerating mentally and physically until **death at 2-3YO**
85
Name Mitochondrial encephalopaties
* **1. MELAS**
* **2. MERRF**
* **3. Kearne Sayre Syndrome**
* **4. Leigh Syndrome** (Subacute Necrotizing Encephalopathy)
86
**MELAS**
1. **MELAS**: mutated tRNA
1. **Mitochondrial encephalopthy**
2. **Lactic acidosis**
3. **Stroke like episodes**
87
MERRF
**MERRF**: mutated tRNA
1. Myoclonic epilepsy
2. Ragged red fibers
88
What is **Kearne-Sayre Syndrome sx?**
1. Cerebellar ataxia
2. Progressive inability to move eyes and eyebrows
3. Pigmentary retinopathy
4. Cardiac conduction defects
89
**Kearne Sayre Syndrome**
Histo
1. **Spongiform** changes in _gray_ and _white_ matter
2. **↓ neurons,** most commonly in **cerebellum**
3. **RRF** (ragged red fibers)
90
**Leigh Syndrome (Subacute Necrotizing Encephalopathy)**
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
Sx of B12 deficiency
* 1. **Anemia**
* **2. Neuro problem**s: 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
Histology of **B12 deficiency**
1. **Subacute combined degeneration of SC:** Vacuolar swelling of myelin in BOTH **[ascending tracts in posterior columnss]** AND **[descending pyramidal tracts]**
93
**Thiamine** (\_\_) deficiency is often seen in who?
**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
Pt has foci of **hemorrhage** and **necrosis** in the **mammillary bodies** and **walls of 3rd/4th ventricles**
**DDx?**
Thiamine (B1) deficiency)
95
**Pseudolaminar necrosis** of the _pyramidal neurons in Sommer Sector of Hippocampus/CTX_ & _purkinje cells in the cerebellum_
**Hypoglycemia**
96
Pt has ketoacidosis=\> dehydration =\> confusion, stupor =\> hyperosmolar coma. Fluids are quickly replaced to avoid what?
DDx ?
Cerebral edema
Hyperglycemia
97
**Carbon monoxide** poisoning first affects what?
1. **Cerebral CTX (layers 3 and 4)**
2. **Sommer sector**
3. **Purkinje cells**
=\> **_Bilateral necrosis of GP_**
98
What preferentially attacks the **retina** =\> degeneration of **retinal ganglion cells** =\> **blindness.**
**What structure is fucked up**
* _Methanol_
* _Bilateral necrosis of putamen_
99
**Ethanol/alcoho**l damages what cells?
Atophy of **granule cells** in **anterior portion of vermis of cerebellum** =\>
* **1. Truncal ataxia**
* **2. Unsteady gait**
* **3. Nystagmus**
100
Advanced cases of crhonic ethnol use causes what?
**Bergman Gliosis** =\> proliferation of adjacent astrocytes between depleted granular cell layer and molecular layer
101
**Radiation** can cause what?
**TUMORS:** _sarcomas_, _gliomas_, _meningiomas_
102
**Histolog**y of radiation effects
1. **Radiation necrosis**: type of **coagulative necrosis** that favors white matter
2. **Cerebral edema**
3. **Hyalinized BV:** thick walls with intramural fibrin-like material
