Pathophysiology and Pharmacology of Dementia

These flashcards cover key terms and concepts related to the pathophysiology and pharmacology of dementia as discussed in Dr. Paul Hubbard's lecture.

Dementia

An overarching term for changes in cognitive function, mostly associated with age.

Alzheimer’s Disease (AD)

A neurodegenerative disease characterized by amyloid plaques and neurofibrillary tangles, often described as age-related.

Lewy Body Dementia (LBD)

A type of dementia associated with alpha-synuclein protein deposits, often related to Parkinson's disease.

Vascular Dementia

Dementia caused by ischemic events or cerebrovascular disease, contributing to about 25% of dementia cases.

Frontotemporal Dementia (Pick’s Disease)

A group of dementias that usually appears in people aged 50-60, associated with tau and TDP43 protein aggregates.

Beta-Amyloid

A protein that, when overly accumulated in the brain, is linked to Alzheimer's disease pathology.

Tau Neurofibrillary Tangles

Tangled threads of tau protein that disrupt neuronal function and are significant in various types of dementia.

Acetylcholinesterase Inhibitors

Drugs such as Donepezil and Rivastigmine used to increase acetylcholine levels and moderate dementia symptoms.

Cholinergic System

A system in the brain affected by neuronal loss in dementia, particularly Alzheimer's disease, impacting cognitive function.

Hyperphosphorylated Tau (HPτ)

Abnormally phosphorylated tau protein associated with neurofibrillary tangles in Alzheimer’s disease.

Proteinopathies

Diseases characterized by abnormal protein deposition, such as those seen in various types of dementia.

Huntington’s Disease

A hereditary neurodegenerative disorder caused by mutations in the Huntingtin gene, leading to choreiform movements.

Excitotoxicity

Pathological process where neurons are damaged by excessive stimulation by neurotransmitters such as glutamate.

AI in Neuropathology

The use of artificial intelligence technologies to enhance diagnostic accuracy and treatment strategies in neuropathology.

Neurotransmitter

Chemical messengers, such as acetylcholine, that transmit signals across synapses in the nervous system.

Cerebral Amyloid Angiopathy

A condition characterized by the deposition of amyloid proteins in the walls of cerebral blood vessels, leading to hemorrhage.

What is dementia in broad terms?

An umbrella term for progressive decline in cognitive functions severe enough to interfere with daily life.

Is Alzheimer’s disease separate from dementia?

No it is a type of dementia and the most common cause.

Name three diseases under the dementia umbrella.

Alzheimer’s disease Lewy body dementia Parkinson’s disease dementia Huntington’s disease vascular dementia frontotemporal dementia.

Why is distinguishing dementia types clinically important?

Treatments differ and management needs depend on the specific pathology.

How were dementia types traditionally confirmed?

At postmortem via examination of neuropathology.

Name two modern approaches for early dementia diagnosis.

Cerebrospinal fluid biomarker analysis and smell testing.

What is the shared pathological theme across many dementias?

Abnormal protein aggregation in the brain.

What does hyperphosphorylation of a protein mean?

Excessive phosphorylation that alters function and promotes aggregation.

How does protein aggregation cause symptoms?

Disrupts cellular processes leading to neuronal death and network dysfunction.

What are the two hallmark lesions of Alzheimer’s disease?

Beta amyloid plaques and tau neurofibrillary tangles.

Where are beta amyloid plaques found?

Extracellularly around neurons.

Where are tau tangles located?

Inside neurons in cell bodies axons and dendrites.

What gross brain change occurs in advanced Alzheimer’s?

Cortical atrophy with enlarged ventricles.

What precursor protein forms beta amyloid?

Amyloid precursor protein APP.

Which enzyme starts the non amyloidogenic pathway?

Alpha secretase.

Which enzymes produce A beta in the amyloidogenic pathway?

Beta secretase and gamma secretase.

What is the consequence of a shift toward beta and gamma secretase activity?

Increased production of aggregation prone A beta peptides.

What is tau’s normal role?

Stabilising microtubules in neurons.

What happens to tau in Alzheimer’s disease?

It becomes hyperphosphorylated detaches from microtubules and aggregates.

Which pathology correlates better with symptoms in Alzheimer’s disease?

Tau tangles.

Where does tau deposition begin in Braak staging?

The entorhinal region of the medial temporal lobe.

How does tau pathology spread?

From medial temporal lobe to hippocampus then to widespread cortex.

What is the role of beta amyloid in tau spread?

It enhances cell to cell propagation of tau.

What are two alpha synuclein based structures in Lewy body dementia?

Lewy bodies and Lewy neurites.

Which brain region is affected early in Lewy body diseases?

The olfactory bulb.

Where does Lewy pathology begin in early PD and DLB staging?

The olfactory bulb and dorsal motor nucleus of the vagus.

What pigment is lost from substantia nigra neurons in PD?

Neuromelanin.

Which basal ganglia pathway becomes overactive in PD?

The indirect movement inhibiting pathway.

How does DLB differ from Parkinson’s disease dementia?

DLB presents with dementia before or at the same time as parkinsonism whereas PDD appears after established PD.

Which basal forebrain nucleus provides major cortical acetylcholine?

The nucleus basalis of Meynert.

Which brainstem region also provides cholinergic projections?

The dorsolateral pontine tegmental region.

Where are nicotinic receptors typically located in the CNS?

Presynaptically to modulate neurotransmitter release.

Which muscarinic receptor subtypes are postsynaptic?

M1 and M3.

What is the main limitation of AChE inhibitors?

They are symptomatic only and not disease modifying.

Why do AChE inhibitors cause peripheral side effects?

They increase acetylcholine in peripheral tissues unaffected by dementia.

Which receptor does memantine antagonise?

The NMDA type glutamate receptor.

What A beta species do monoclonal antibodies target?

A beta oligomers protofibrils and fibrils.

What serious imaging abnormality is associated with anti amyloid antibodies?

Amyloid related imaging abnormalities ARIA.

Name one emerging therapeutic target not involving amyloid.

Rapamycin pathways tau reduction or immune modulation.

Which neurons are most vulnerable early in Huntington’s disease?

GABAergic medium spiny neurons of the indirect pathway.

What is a macroscopic sign of Huntington’s disease?

Flattened caudate nucleus with enlarged ventricles.

Which marker indicates astrocyte activation in Huntington’s disease?

GFAP increased staining.

Name two cerebrovascular pathologies linked to vascular dementia.

Atherosclerosis with ischaemia haemorrhage and cerebral amyloid angiopathy.

What protein aggregates occur in frontotemporal dementia?

Pick bodies tau TDP43 and FET family proteins.

What is dementia?

An overarching term for cognitive decline mostly associated with age and difficult to diagnose specifically in life.

What three proteins are commonly involved in neurodegenerative proteinopathies?

Hyperphosphorylated tau amyloid beta and alpha synuclein.

What is APP?

Amyloid precursor protein the source of A beta peptides.

What is the damaging form of amyloid?

The beta amyloid version is most toxic when overproduced.

What does the macroscopic Alzheimer slide contrast show?

A healthy brain has thicker cortex while severe dementia shows marked cortical loss.

What stage shows early amyloid deposition?

Preclinical stages before symptoms.

What is the first region affected by tau in Braak staging?

The entorhinal area.

What is the synergistic effect between A beta and tau?

A beta enhances spreading of tau pathology.

What two pathological inclusions define Lewy body disease?

Lewy bodies and Lewy neurites.

What is the key pathological sign in PD?

The Lewy body in substantia nigra neurons.

What structure loses neuromelanin in PD?

The substantia nigra.

What is the direct pathway’s function?

To initiate movement.

What is the indirect pathway’s function?

To inhibit movement.

Which pathway dominates when dopamine is lost?

The indirect pathway.

Where does cholinergic degeneration first appear in Alzheimer’s disease?

Basal forebrain nuclei including nucleus basalis of Meynert.

What brainstem cholinergic nucleus may show tangles?

The pedunculopontine nucleus.

What effect do AChE inhibitors have on acetylcholine?

They increase acetylcholine by blocking its breakdown.

What are common AChE inhibitor side effects?

Nausea vomiting diarrhoea anorexia weight loss bradycardia sleep disturbance.

What does memantine inhibit?

NMDA receptor mediated excitotoxic glutamate signalling.

What process do monoclonal antibodies aim to reduce?

Amyloid plaque formation.

What adverse effects can anti amyloid antibodies cause?

Oedema and haemorrhage seen as ARIA.

Name one future drug target pathway.

Tau reduction immune modulation or cell cycle modification.

What is Huntington’s disease caused by?

Misfolding and deposition of mutant Huntingtin protein.

What brain area shows major neuron loss in Huntington’s disease?

The striatum caudate and putamen.

What pathological grading system is used in HD?

Vonsattel grading which examines macro and microscopic striatal changes.

What cells show glial reactivity in HD?

Astrocytes shown by increased GFAP.

What causes vascular dementia?

Ischaemic injury from vascular events or multiple small infarcts.

What pathology contributes to haemorrhage risk in vascular dementia?

Cerebral amyloid angiopathy.

What proteins characterize frontotemporal dementia?

Tau Pick bodies TDP43 and FET proteins.

What are the main protein aggregates seen in frontotemporal dementia and Pick's disease?

Tau Pick bodies TDP43 aggregates and FET family protein aggregates.

What are Pick bodies composed of?

Abnormally aggregated tau protein.

What is TDP43?

A TAR DNA binding protein that misfolds and forms pathological aggregates in FTD.

Why is TDP43 important in FTD pathology?

Its aggregation disrupts nuclear protein function and contributes to neuronal degeneration.

What are FET proteins?

A family of RNA binding proteins including FUS EWS and TAF15 that can abnormally aggregate in FTD.

Which protein aggregate gives Pick's disease its name?

Tau Pick bodies.

Which protein aggregate is associated with RNA processing dysfunction in FTD?

FET family proteins such as FUS EWS and TAF15.

Which aggregate is most commonly associated with neuronal loss in many FTD cases?

TDP43 aggregates.