neurodegenerative brain pathologies

Question 1

what is the most common prion disease

Answer 1

CJD

Question 2

describe prion diseases

Answer 2

transmissible
doesn’t involve transfer of DNA or RNA only protein

Question 3

what are symptoms of sporadic CJD and how to investigate it

Answer 3

progressive dementia, motor disturbances and death within a year

investigate
-imaging- change in the signal in the back of the thalamus

-biopsy-frontal lobe, distribution of pathology is not predictable, not a definitive test in a patient

-EEG

-studies underway to find a biomarker

Question 4

what changes can be seen in CJD

Answer 4

Basic structural staining - spongiform change—holes in the tissue. Seen in cerebellum

prion protein deposits- proteinopathy and you can use antibodies to see this as well, clumps are seen in cerebellum

Question 5

describe structural changes of the prion protein and how this can give rise to prion disease

Answer 5

Prion protein is a normal cellular protein- function is not clearly known.
Normally in alpha helical structure loosely folded. Every now and then it an unfold there is an equilibrium.
That is normal.
In some cases, it can fold in much tighter beta pleated structure – amyloid structure.
Equilibrium is maintained.
But every now and then some beta pleated sheet protein can initiate a seed protein in the brain, and there can be irreversible propagation and can form the plaque.
In transgenic mice if you knock out prion protein, you cannot transmit a prion disease to that mouse, you need host protein to be converted to the pathological form.

Question 6

what is the biggest risk factor of AD

Answer 6

age

Question 7

what is neuropathology of AD

Answer 7

-amyloid plaques AB
-extracellular plaques
-neurofibrillary tangles
-cerebral amyloid angiopathy
-neuronal loss (cerebral atrophy-Cerebral amyloid angiopathy (CAA) is a condition in which proteins called amyloid build up on the walls of the arteries in the brain)

Question 8

what is the macroscopic pathology of AD

Answer 8

-cortical atrophy and hippocampal atrophy
-gyri have shrunk and the sulci have gone wider
-widened ventricles

Question 9

what is the microscopic pathology of AD and describe the neurofibrillary tangles seen in AD

Answer 9

paired helical filaments, tau a microtubule associated protein, stabilization of microtubules dependent on phosphorylation state
hyperphosphorylation of tau destabilizing microtubules

extracellualar plaques - AB protein

amyloid beta protein

Question 10

describe the ABC assessment in AD

Answer 10

ABC score at the end of the report, and it determines how likely the pathology we see caused the dementia.
-where are the plaques (cortex  cerebellum)
-where are the tangles and how many are there.
-how many target plaques are seen in one microscopic field.

Question 11

what is the immunisation of AD

Answer 11

Get rid of AB protein – this is what they are trying to do now.
In animals you can clear it effectively.
Clinical trials were done- 2002 trial was halted they got too many side effects.
After immunisation – ab protein was cleared but made no difference to the patients decline, given too late.
If you get it early enough it may work?

don’t stop the progression of disease
but they found that after post-mortem 20% didnt even have AD

Question 12

what is the drug given to help slow the progression of AD, describe how it works and what benefit was seen

Answer 12

Lecanemab-is a medicine given to slow the progression of mild Alzheimer’s disease (AD). This medicine reduces clumps of proteins called amyloid-beta proteins that play a key role in AD.
its a monoclonal antibody designed to target and reduce amyloid-beta plaques in the brain, which are a hallmark of Alzheimer’s Disease (AD). The presence of these plaques is associated with the progression of Alzheimer’s, leading to neurodegeneration and symptoms such as memory loss, confusion, and cognitive decline.

benefit:
-reduces cognitive decline by 27% in a 18 month study (van Dyck et al., 2022)

Question 13

what does the locus classicus refer to in terms of PD dopaminergic neurones

Answer 13

Black line
– substantial nigra
- where you find the dopaminergic neurones
– they have neuromelanin
– they have a pigment.
Involved in initiation of movement by connections to basal ganglia

Question 14

whats the projection of dopaminergic neurones

Answer 14

the substantia nigra projects from the midbrain (substantia nigra) to the striatum (basal ganglia) and this area is involved in movement

Question 15

whats is the main pathology/hallmark seen in PD

Answer 15

The pathology of Parkinson’s Disease (PD) is characterized by the accumulation of alpha-synuclein, a protein that forms abnormal deposits known as Lewy bodies within neurons. This process is associated with the loss of dopaminergic neurons, particularly in a region of the brain called the substantia nigra, which plays a crucial role in controlling movement.

These are inclusions (Not normally in the cell, but its found in the cell)—aggregates of a-synuclein due to mutation in the alpha-synuclein gene leading to the aggregation.

This is a neuron, it has a nucleus, nucleolus, cytoplasm, and there is the pigment(neuromelanin).
The pigment is the big blob that you can stain and that is the lewy body

Question 16

what is the Braak staging

Answer 16

Starts in the medulla and progresses up to the basal forebrain and basal ganglia and out to the cortex, and that reflects the emergency of the different symptoms.

Early Stages (1-2): Pathology is thought to begin in the lower brainstem, which might explain early non-motor symptoms like sleep disturbances. At this point, symptoms are often non-motor and can precede the classic motor symptoms by years.

Intermediate Stages (3-4): The pathology progresses to involve the substantia nigra in the midbrain, where the loss of dopaminergic neurons leads to the classic motor symptoms of PD, such as bradykinesia (slowness of movement), resting tremor, rigidity, and postural instability. The symptoms become more apparent and debilitating.

Advanced Stages (5-6): The pathology eventually spreads to higher brain regions, including the cerebral cortex. This progression correlates with the development of cognitive symptoms, dementia, and other non-motor symptoms that can affect behaviour and mood.

Question 17

what is PD plus disorders

Answer 17

characterised by the primary features but with addition features

Question 18

what is parkinsonism and what are the three examples of PD plus syndrome

Answer 18

Parkinsonism is an umbrella term used to cover a range of conditions that share similar symptoms to Parkinson’s including PD plus symptoms

-multiple system atrophy
-progressive supranuclear palsy
-corticobasal degeneration

Question 19

what is multiple system atrophy and the two categories it can be and what is its microscopic pathology

Answer 19

Multiple System Atrophy (MSA) is a rare neurological disorder that affects your body’s movements and some of its automatic functions, like blood pressure and bladder control. It’s like Parkinson’s disease in some ways because it can make movements slow and difficult. However, MSA is different because it involves more parts of the body and usually gets worse faster.

-MSA-P - predominant parkinsonism

-MSA-C - cerebellar features

mixed neuronal and glial pathology but largely affects glial cells. presence of cytoplasmic inclusions filled with the neuronal protein alpha-synuclein within oligodendrocytes, the glial brain cells that create the myelin sheath surrounding the neuronal axons

Question 20

what is corticobasal degeneration

Answer 20

Corticobasal Degeneration (CBD) is a rare brain disorder that gets worse over time. It affects various parts of the brain, especially the cortex (the brain’s outer layer, involved in thinking and movement) and the basal ganglia (deep brain structures that help start and control movement).

Imagine the brain as a control center that sends out commands for movements and thoughts. In CBD, parts of this control center start to break down or deteriorate, which leads to trouble with moving one side of the body, making it stiff or shaky. People with CBD might also find it hard to use their hands for precise tasks, like buttoning a shirt, and they could experience unusual feelings or difficulties in understanding how to move their body properly.

As CBD progresses, it can also affect thinking and memory, making it hard for someone to plan, organize, or remember things. It’s a bit like having a phone or computer that starts glitching and can’t run its programs or apps properly.

Question 21

what is CBD microscopic pathology

Answer 21

its a tauopathy
Protein Misfolding: In CBD, there’s an abnormal accumulation and misfolding of a protein called tau. Normally, tau helps stabilize the internal structure of nerve cells. But in CBD, tau proteins clump together abnormally inside brain cells, forming deposits called tauopathies. This disrupts the normal functioning of cells.

Cell Damage and Death: The accumulation of abnormal tau leads to damage and eventually death of nerve cells in affected areas of the brain, such as the cortex and basal ganglia. These regions are crucial for movement, coordination, and cognitive functions.

balloon neurons and astrocytic plaques
-Balloon neurons are abnormal, swollen neurons (brain cells) that appear larger than normal neurons due to their swollen state. These neurons have a distinctive, rounded shape and an enlarged cell body, which is why they are referred to as “balloon” neurons.The swelling is believed to be caused by the accumulation of abnormal proteins inside the neuron, disrupting its normal structure and function. In the context of CBD and similar disorders, this often involves the abnormal accumulation of tau protein.

-Astrocytic plaques are abnormal accumulations of protein found in the brain, specifically within astrocytes, which are a type of glial cell. Glial cells support and maintain neurons in the brain. In the context of tauopathies, these plaques are primarily composed of misfolded tau protein.
Unlike the amyloid plaques seen in Alzheimer’s disease, astrocytic plaques are characterized by the accumulation of abnormal protein in astrocytes, leading to distinctive star-shaped formations. These are different from the plaques found in the spaces between neurons.

Question 22

what is progressive supranuclear palsy

Answer 22

Progressive Supranuclear Palsy (PSP) is a rare brain disorder that affects movement, control of walking (gait) and balance, vision, speech, and swallowing. The disease results from the deterioration of cells in areas of the brain above the nuclei (supranuclear), particularly in the brainstem, basal ganglia, and cerebral cortex.

Movement Problems: People with PSP often experience stiffness and difficulty moving, similar to Parkinson’s disease. However, PSP includes unique symptoms like difficulty moving the eyes, which can make it hard to look up or down.

Balance and Gait Issues: One of the early signs of PSP is a loss of balance while walking. This can lead to falls, often backward, which is a common symptom that differentiates it from other movement disorders.

Vision Problems: The “supranuclear” aspect of the disease name refers to the brain areas controlling eye movements that are affected. Patients may have trouble with eye movement, leading to blurred or double vision (diplopia), and difficulty in looking up or down without tilting the head.
part of the motor cortex may be affected - which is involved in the control of the ocular motor nerve It is the motor cortex that instructs the ocular motor nerve. The problem is somewhere between motor cortex and the ocular motor nerve.

Speech and Swallowing Difficulties: Speech may become slow and slurred, and swallowing problems can develop, leading to a risk of choking or aspiration pneumonia.

Cognitive Changes: Some individuals may experience changes in personality, memory, and thinking skills, although these symptoms can vary widely among patients.

The cause of PSP is not fully understood, but it involves the accumulation of a protein called tau in the brain, leading to cell damage and death in the affected areas

Question 23

What is microscopic pathology of PSP

Answer 23

tauopathy

-tufted astrocytes are a type of astrocytic inclusion characterized by abnormal accumulations of tau protein within astrocytes. Astrocytes are a type of glial cell in the brain that support and nourish neurons.Appearance: These inclusions have a unique “tufted” appearance under a microscope, with dense, filamentous projections extending from the cell body.

-coiled bodies in oligodendrocytes are another type of pathological inclusion found within oligodendrocytes, which are glial cells responsible for producing the myelin sheath that insulates nerve fibers. Like tufted astrocytes, coiled bodies are composed of abnormal accumulations of tau protein. Appearance: These inclusions appear as round or oval structures with a coiled or filamentous internal structure when viewed under a microscope.

Question 24

what is Pick’s disease

Answer 24

Pick’s disease, also known as frontotemporal dementia (FTD), is a type of brain disorder that affects certain areas of the brain, leading to changes in personality, behavior, and language. This condition is one form of frontotemporal lobar degeneration/atrophy (FTLD), which targets the frontal and temporal lobes of the brain, areas responsible for controlling reasoning, personality, movement, speech, and language.

Simple Explanation of Pathology:
Affected Brain Areas: In Pick’s disease, the frontal and temporal lobes of the brain shrink (atrophy). This damage leads to changes in how a person thinks, acts, and communicates.

Protein Buildup: The hallmark of Pick’s disease pathology is the presence of abnormal protein deposits in the brain. Unlike Alzheimer’s disease, which involves amyloid and tau proteins, Pick’s disease often involves abnormal tau proteins These proteins form aggregates inside brain cells, interfering with their function and eventually leading to cell death.

Symptoms: The damage and shrinking of brain tissue lead to symptoms like emotional changes, difficulty in making decisions or planning, changes in social behavior, and problems with speech and language. Unlike Alzheimer’s, memory may be relatively preserved in the early stages of Pick’s disease.

Question 25

what is the molecular diagnosis of these tuaopathies

Answer 25

This is a western blot, that uses antibodies to pick up certain proteins, on those proteins that have been separated on an electrical gradient.

There are 6 isoforms of tau, different lengths, depending on how many different binding sites there are for microtubules.- these are microtubule binding repeats (isotope)
Shortest – 3R/0N
Longest – 4R/2N

Normally it is soluble, in pathology it is aggregated and insoluble.
You will see 3 larger bands, the tau are hyperphosphorylated.
If you dephosphorylate the aggregated proteins, you can resolve all 6 bands.

CBD and PSP – 4R tauopathy.
You only resolve 2 bands on the insoluble aggregates and when you dephosphorylate – only those isoforms with 4 microtubule binding sites are the ones you can see.

Picks
Only 3 isoform- 3R tauopathy.

AD – are a mix

Question 26

how can antibodies be used for picks disease

Answer 26

picks disease - antibodies can be used to identify the different isoforms of the tau protein

Question 27

what are the 2 main types of frontotemporal lobe dementia

Answer 27

-behavioural variant FTD (BvFTD) - frontal lobes are affected first and causes changes in personality and behvaiour

-primary progressive aphasia (PPA) - temporal lobes are affected first and this causes loss/problems with language