Neuropathology Flashcards
1
Q
Gross changes in Alzheimers?
A
Diffuse atrophy
Flattened cortical sulci
Enlarged cerebral ventricles
2
Q
Histological changes in Alzheimers?
A
Neuronal loss in cortex and hippocampus Synaptic loss Granulovascular degeneration Senile plaques Neurofibrillary tangles Hirano bodies
3
Q
What is granulovascular degernation?
A
Small vacuoles with central granules in cytoplasm of neurons - particularly in temporal lobes
4
Q
Structure of senile plaques
A
Insoluble amyloid peptide deposits
Peptide called Beta A4 peptide
5
Q
Structure of amyloids
A
Fibrils of multimeric chains of peptides deposited extracellulaly, with beta pleated sheet confirmation
6
Q
What cleaves beta A4?
A
Cleaved from amyloid-beta precursor protein by beta and gamma-secretases
7
Q
What prevents cleavage of amyloid beta precursor protein?
A
Alpha secretase
8
Q
Subtypes of plaques?
A
Neuritic plaque
Diffuse
9
Q
Structure of neuritic plaque
A
Beta A in form of amyloid fibrils, among which are irregularly swollen dystrophic neuritis (defenerated neuronal processes)
10
Q
How are neuritic plaques visualised?
A
Neurites visualised with silver stains.
May be seen as an eosinophilic mass on haematoxylin and eosin stains.
11
Q
Core of neuritic plaques?
A
May contain dense central core of amyloid
12
Q
Periphery of neuritic plaques?
A
Microglia and astrocyte processes
13
Q
Diseases in which neuritic plaques are seen?
A
Normal ageing
Downs
14
Q
What is the ‘apple green’ birefringence of stained stissue with neuritic plaques?
A
Amyloid sensitive stain Congo red under polaroid light leads to ‘apple green’ stain of neuritic plaques due to presence of beta-pleated sheets.
15
Q
Structure of diffuse plaques?
A
Consist of non-fibrillar extracellular A beta.
16
Q
Which plaques are not related to cognitive decline?
A
Diffuse
17
Q
Peptides in diffuse plaques?
A
Same peptides as those responsible for amyloid formation in neuritic plaques but not polymerized to form fibrils and lack of beta-sheet configuration.
18
Q
What are neurofibrillary tangles composed of?
A
Cytoskeletal elements - primarily abnormally phosphorylated tau protein.
19
Q
What type of tauopathy is Alzheimers?
A
One of several degenerative tauopathies
20
Q
What is tau?
A
Peptide required for microtubule assembly.
21
Q
Function of microtubules?
A
Transport of materials down axons.
22
Q
What stimulates formation of abnormal tau?
A
Beta A4 peptide interacts with cholinergic receptors, stimulating abnormal hyperphosphorylation of tau.
23
Q
Where is hyperphosphorylated tau present?
A
Abnormal tau
Degenerated neurites
24
Q
How can hyperphosphorylated tau be visualised?
A
Staining with antibody to abnormal tau
25
Which conditions do neurofibrillary tangles occur in?
```
Alzheimers
Downs
Dementia pugilistica (punch-drunk syndrome)
Parinkson-dementia complex of Guam
Hallervorden-Spatz disease
Normal elderly
```
26
Location of tangles?
Mainly intraneuronal
| Upon neuronal degeneration may appear extracellularly, thus losing their basophilia
27
How can tangles be visualised?
Faintly basophilic
| Tau immunostaining and silver impregnation can be used to improve chances of light microscopic detection.
28
Location of tangles on early Alzheimers?
Tangles and neuropil threads are restricted to parts of the entorhinal cortex and CA1 field of hippocampus.
29
Location of tangles as Alzheimers develops?
Tangles and neutrophil threads accumulate in increasing density in other parts of the hippocampus and medical temporal neocortex, then in other cortical regions and in subcortical grey matter structures such as hypothalamus and thalamus.
30
What staging scheme is used to describe extent of tangle related abnormalities in Alzheimers?
Braak and Braak (1995)
31
Which stages of Braak and Braak's staging scheme operationally define Alzheimers?
Stages V-VI
32
Structure of C Hirano bodies?
Rod-shaped eosinophilic bodies n cytoplasm of neurons
| Intracellular aggregates of actin and actin-associated proteins
33
Location of Hirano bodies when neuron dies?
Extracellular space
34
Location of HIrano bodies normally?
Hippocampal pyramidal cells
35
Pathology of cerebral amyloid angiopathy?
Accumulation of A beta in walls of blood vessels, particularly arteries and arterioles in cerebral cortex overlying leptomeninges
36
What % of the elderly have Cerebral amyloid angiopathy?
30%
37
What % of patients with Alzheimers have Cerebral Amyloid Angiopathy?
90%
38
What important disease can Cerebral Amyloid Angiopathy?
Haemorrhagic strokes confined to superficial blood vessels.
39
How does Cerebral Amyloid Angiopathy lead to haemorrhagic stroke?
Rupture of amyloid laden blood vessels causes superficial lobar haemorrhages that may extend into subarachnoid space
40
Relation between tangles and cognitive decline
Increase in number and distribution
41
Link between tangles, neuritic plaque and cognitive decline?
If both are present, presence of even a few tangles in a single field in neocortex can suggest significant cognitive decline.
42
Best neuropathological correlate of decline?
Number of synapces
43
Marker for synapses?
Antibody to synaptophysin, a protein fund in presynaptic endings
44
Where is synaptophysin found?
Presynaptic endings
45
Cellular pattern of neuronal loss in hippocampal pathology?
Subiculum of hippocampal formation and layers II and IV of entorhinal cortex.
46
Affected cells involved in hippocampal pathology?
Connect hippocampal formation with association cortices, basal forebrain, thalamus and hypothalamus, structures crucial to memory.
47
Significance of neuronal loss in hippocampal pathology?
Isolates hippocampal formation from its input and output, contributing to memory disorder in Alzheimers
48
What is Binswanger's Disease?
Subcortical vascular dementia/subcortical arteriosclerotic encephalopathy
Many small infarctions of what matter that spares cortical regions.
Co-exists with Alzheimers-type changes
49
Which type of dementia co-exists with Alzheimers?
Subcortical
50
Histology of Lewy bodies?
Weakly eosinphilic
Spherical
Cytoplasmic inclusions
51
Where are Lewy bodies in Parkinsons?
Confined to substantia nigra
52
Where are Lewy bodies in Lewy body Dementia?
Substantia nigra
Areas of cerebrum including temporal and frontal lobe and cingulate gyrus
Dorsal motor nucleus of vagus
53
Difference between lewy bodies in substantia nigra and cortex?
In cortex they are less conspicuous, eosinophilic and lack clear halo
Take up homeneous eosinophilic staining in cytoplasm along with peripheral displacement of nucleus
54
Correlation between number of Lewy bodies and cognitive decline?
None
55
What can we use to identify Lewy body?
Antibody to protease ubiquitin
| Staining with alpha-synuclein antibodies
56
What do lewy bodies contain?
Accumulations of alpha-synuclein
57
What type of disease is Lewy body dementia?
Degenerative synucleopathies
58
What does alpha-synuclein do?
Accelerates reuptake of dopamine in neurons; this dopamine overload may be toxic
59
What are Lewy neuritis?
Nerve cell processes that contain aggregates of alpha-synuclein
60
Where are Lewy neuritis most numerous?
CA2/3 region of hippocampus
| Substania nigra
61
Which diseases do Lewy neurites occur?
Lewy body Dementia
| Idiopathic Parkinsons
62
Where does microvacuolation occur in Lewy Body Dementia?
Microvacuoalation of cerebral cortex, mainly in medial temporal region.
63
What are Tauopathies?
Diseases with tau deposits
64
What are synucleopathies?
Disease with alpha synuclein deposits
65
Name some tauopathies?
```
Alzheimers
Picks
Progressive supranuclear palsy
Corticobasal degenerations
Frontotemporal dementia with Parkinsonism (FTDP-17)
```
66
Name some synucleopathies?
Parkinsons
Lewy Body Dementia
Multisystem atrophy
67
Which types of pathology is frontotemporal dementia associated with?
Frontal lobe degeneration type
Picks type
Motor neurone disease type
68
Most common type of frontotemporal dementia?
Frontal lobe degeneration
69
Underlying pathology of Frontal lobe degeneration?
Spongiform degeneration or microvacuolation of superficial neuropil seen chiefly in layers III and V of cortex
Loss of large cortical nerve cells with minimal gliosis
70
Which cells are mainly lost in Frontal lobe degeneration?
Large cortical nerve cells
71
Characteristics of Picks disease?
Prepronderance of atrophy in frontotemporal regions
72
What are Pick cells?
Abnormal swollen oval-shaped neuronal cells with loss of Nissl's substance and peripherally displaced nucleus
73
What are Picks bodies seen in post-mortem?
Argentophilic, tau and ubiquitin reactive filamentous inclusions
74
Are Hirano bodies seen in Picks disease?
Yes but less than in Alzheimers
75
Characteristics of motor neurone disease type frontotemporal disease?
Cerebral atrophy is less marked
Limbic areas are largely preserved
Ubiquitinated inclusions in frontal cortex and hippocampus
76
Cell loss in motor neurone disease type frontotemporal disease?
Large cortical nerve cells
Microvacuolation
Mild gliosis
77
MND pathology in motor neurone disease type frontotemporal disease?
MND pathology in anterior horn cells
78
Pathology in Huntington's dementia?
Severe loss of small neurons in caudate and putamen with subsequent astrocytosis
Head of caudate shrinks and there is 'ex vacuo' dilatation of anterior horns of lateral ventricles
79
Characteristics of Huntington's dementia?
Protein deposits form nuclear inclusions in neurons
80
Forms of CJD?
Sporadic
Familial
Variant
81
Most common form of CJD?
Sporadic
82
What is variant CJD related to?
Bovine spongiform encephalopathy
83
Characteristic pathological features of CJD?
None due to short course of disease
84
Pathological features of CJD >6 months?
Degree of generalized cerebral atrophy
85
Microscopic changes in CJD?
Spongiform encephalopathy secondary to neutrophil variation
Round to oval vacuoles in neuropil of cortical gray matter - vacuoles are single or multiloculated.
Vacuoles may coalesce to microcysts.
86
Cell loss in CJD?
Neuronal loss
| Gliosis
87
What is Prion protein?
Normal neuronal cell surface protein
88
Which gene encodes prion protein?
On chromosome 20
89
What happens to prion protein in CJD?
Chromosome 20 is converted via conformational change to abnormal form - PrPSc.
90
What does PrPSc do?
Protease-resistant
Accumulates in CNS
Triggers conversion of normal PrPc to PrPSc.
91
What causes degenerative changes in cerebral cortex in CJD?
PrPSc.
92
How can PrPSc be identified?
Immunoperoxidase staining
93
How can PrPSc be transmitted between people?
If person has spongiform encephalopathy, via:
pituitary extracts
cornal transplants
dural grafts
contaminated electrodes from neurosurgical procedures
94
Pathology in vCJD?
Marked accumulation of prion protein
| Plaques are florid
95
What protein is found in CSF in CJD?
14-3-3
96
What is protein 14-3-3 associated with?
CJD
Viral encephalitis
Stroke
97
Which type of CJD is protein 14-3-3 least frequent in?
Variant CJD
98
In which type of CJD are the EEG changes lacking?
Familial
99
In which type of CJD are 14-3-3 proteins absent?
Familial - <50%
100
What may have an influence on susceptibility of disease?
Presence of polymorphisms at codon 129 of PrP
101
Which aa may be present at codon 129 of PrP?
Methionine
| Valine
102
Which phenotype of codon 129 at PrP is present in CJD?
M/M phenotype
103
What % of people with sporadic CJD have M/M phenotype?
73%
104
What % of people with variant CJD have M/M phenotype?
100%
105
Most supportive diagnostic test for CJD?
MRI
106
Abnormality seen in MRI in CJD?
Posterior thalamic region (pulvinar sign)
107
Which type of MRI most shows pulvinar sign?
FLAIR sequences of MRI
108
Age of onset of classic CJD?
7th or 8th decade of life
109
Age of onset of vCJD?
3rd/4th decade of life
110
Course of classic CJD?
5 months
111
Course of vCJD?
1 year
112
Symptoms of classic CJD?
Early neurological signs
| Dementia
113
Symptoms of vCJD?
Early psychiatric/behavioural signs with delayed neurological features
114
EEG signs in classic CJD?
Triphasic, sharp waves
115
EEG signs in vCJD?
Triphasic waves rare
| Changes often non-specific
116
In which type of CJD are trophasic waves seen?
Classic CJD
117
In which type of CJD is pulvinar sign not seen?
CLassic
118
In which type of CJD are large number of plaques noted in biopsy?
Variant
119
Tonsils in classic CJD?
Prion protein cannot be isolated from lymphoid tissue
120
Tonsils in vCJD?
Tonsillar tissue carries prion agent
121
Major HIV receptors?
CD4
| CD8
122
Chemokine receptors associated with HIV?
CXCR4 and CCR5 considered HIV-1 co-receptors
123
Main method of replication in HIV?
CD4+ helper T lymphocytes main route of multiplication and entry apart from monocytes
124
Source of CNS infection in HIV?
Infected CD4+ T cells and monocytes
125
Characteristic of stains of HIV in brain?
Infecting macrophages rather than lymphocytes
126
What is Macrophage-tropism?
Related to mutation in region of gp120 which is the external glycoprotein of HIV
127
Which mutation is related to the external glycoprotein of HIV?
Macrophage-tropism of a specific region of gp120
128
How does HIV-1 cross blood brain barrier?
Trojan Horse hypothesis:
| Enters CNS as passenger in cells to the brain via CD4 T cells or monocytes.
129
What confirms the Trojan Horse hypothesis in HIV?
Virus accumulation in perivascular region
130
What is the alternative hypothesis of how HIV enters CNS?
Entry of free HIV-1 by migration between or transcytosis of endothelial cells.
131
Most commonly infected neurocells of HIV-1?
Perivascular macrophage and microglia
132
Which CNS cells contain receptors/co-receptors for HIV-1 entry?
Astrocytes
Oligodendrocytes
Neurons
Perivascular macrophages and microglia
133
Components of mechanism of HIV
Direct effect of HIV-1 infection
| Indirect consequences of infection comprising secretion of cytokines and neurotoxins
134
How do infected macrophages and microglia lead to neurodegeneration in HIV?
1. Shedding viral proteins
2. Releasing significant amount of cytokines and neurotoxins into CNS
3. Tat and TNF-alpha contribute to disruption of blood brain barrier which becomes more permeable to infected monocytes and cytokines in periphery
135
What do pro-inflammatory cytokines secreted by infected macrophages and microglia in HIV do?
Activate microglia and astrocytes which in turn secrete neurotoxins
136
What secretes neurotoxins in HIV?
Microglia and astrocytes activated by pro-inflammatory cytokines stimulated by infected macrophages and microglia
137
What type of neuronal injury occurs in HIV?
Apoptosis
138
How does apoptosis occur in HIV to neuronal cells?
By toxic products released by HIV-infected macrophages and microglia or by activated astrocytes
139
Which factors cause demyelination of oligodendrocytes?
Tumour necrosis factor
140
Which factors are neurotoxic and cause apoptosis of neuronal cells?
Platelet activating factor
Quinolinic acid
Nitric oxide
Some metabolites of arachidonic acid
141
Findings in biopsy of HIV in CNS
Infiltration of macrophages in CNS
Formation of microglial nodules
Astrocyte activation and damage
Myelin damage
142
Cells in white and grey matter in biopsy of HIV?
Multinucleated giant cells from virus-induced fusion of microglia and/or macrophages
143
Where is neuronal loss found in biopsies in HIV?
Hippocampus
Basal ganglia
Caudate nucleus
144
Findings in biopsy of severe cases of HIV?
Lipid macrophages
145
Most common psychiatric presentation in AIDs?
HIV-related dementia
| Depression
146
What % of HIV-infected patients present with psychosis?
10%
147
What is viral load used for in clinical practice?
To predict stage of disease
Monitor disease progression
Formulate treatment strategies
148
Definition of viral load?
Actual number of viral particles in cubic millimetre of blood
149
Can CSF viral load be used in HIV?
No - not accurate indicator of CNS disease
150
Weight, length and volume changes in schizophrenia re brain?
Decreased weight
Decreased length and volume of cerebral hemispheres
Enlargement of lateral ventricles - particularly temporal horns
151
Which tissue volume is reduced in schizophrenia?
Thalamus
| Temporolimbic structures including hippocampus, amygdala and parahyppocampal gyrus
152
White matter reductions in schizophrenia?
Parahippocampal gyrus or hippocampus
153
What happens to septum pellucidi in schizophrenia?
Increased incidence of cavum septi pellucidi
154
What happens to basal ganglia in schizophrenia?
Reduced volume, particularly in preneuroleptic area in catatonic patients.
Enlargement due to classic neuroleptics - reversed by atypicals
155
In which type of epilepsy is schizophrenia-like psychosis more common in?
Temporal lobe epilepsy when focus is on left hemisphere
156
Where is the planum temporale?
Posterior superior surface of superior temporal gyrus
157
What is planum temporale?
Lateralized brain structure involved with language
158
What happens to planum temporale in schizophrenia?
Consistent reversal of normal left-larger-than-right asymmetry of planum temporale surface area
159
What is Heschl's gyrus?
Primary auditory cortex
160
Is astrogliosis evident in schizophrenia?
No
161
Any cell number or size change in schizophrenia?
Reduced numbers and size in affecting neurons in hippocampus and DLPFC
162
Neuronal density in schizophrenia?
Increased, may relate o observed decrease in neuronal size, with decreased dendritic arborisation and decreased neuropil compartment.
163
Changes in brain archeticture in schizophrenia?
Subtle cytoarchitectural anomalies in hippocampal function, frontal cortex - significant cellular disarray in CA3-CA4 interace
164
What do synaptic studies in schizophrenia show?
Decrements in presynaptic markers in hippocampus and DLPFC.
| Reflect reduction in synaptic contacts formed
165
What does decrements in presynaptic markers in hippocampus and DLPFC in schizophrenia support?
Hypothesis of excessive synaptic pruning in schizophrenia.
166
Which synapses are vulnerable in schizophrenia?
Glutamatergic synapses in hippocampus and DLPFC, with predominantly GABAergic involvement in cingulate gyrus.
167
Affect of antipsychotics in histology of schizophrenia?
Alter synaptic and neuronal morphology, particularly caudate-putamen and may increase glial density in prefrontal cortex
168
Pathological changes of Wernickes?
Degenerative changes including gliosis, small haemorrhages in third ventricle and aqueduct and cerebellar atrophy
169
Where is small haemorrhage seen in Wernickes?
```
Third ventricle
Mamillary bodies
Hypothalamus
Mediodorsal thalamic nucleus
Colliculi
Midbrain tegmentum
```
170
Brain damage in uncomplicated alcoholism?
Brain shrinkage likely due to white matter loss - reversible
171
Where is alcohol-related neuronal loss found?
Superior frontal association cortex
Hypothalamus - supraoptic and paraventricular nuclei
Cerebellum
172
Cell count changes in autism?
Lower Purkinje cell count
173
Neocortex changes in Autism?
Inconsistent changes - increased cortical volume possibly related to reduced pruning
174
Pathological changes in Autism?
Hypoplasia of cerebellar vemis and cerebellar hemispheres
