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Neuro BSc > Module 2 - Dementia (AD, PD, PD+, FTD, HD, Prion) > Flashcards

Module 2 - Dementia (AD, PD, PD+, FTD, HD, Prion) Flashcards

1
Q

Gross Pathology of Alzheimer’s Disease:

A

Frontal and temporal atrophy, sparing of other loves and primary motor and sensory cortices
Hippocampal atrophy with ventricular enlargement + widening of sulci + thinning of gyri + thinning of corpus callosum

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2
Q

Histology of Alzheimer’s Disease:

A

Extracellular plaques (Aβ) + neurofibrillary tangles (hyperphosphorylated tau) + cerebral amyloid angiopathy + neuronal loss

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3
Q

Which secretases are amyloidogenic and which are non-amyloidogenic?

A

α-secretase + Ɣ-secretase -> non-amyloidogenic but Ɣ-secretase + β-secretase -> amyloidogenic

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4
Q

What does Aβ do intraceullarly (pathologically)?

A

Oligomers of Aβ promote dysfunction of proteasome, synapse, mitochondria and Ca2+

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5
Q

Risk factors for Alzheimer’s Disease:

A

Age, FH, head trauma, PD, depression, other

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6
Q

Which chromosome has many mutations which lead to amyloidogenic cleavage and early onset of AD?

A

21

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7
Q

Which chromosome leads to presenilin, part of the gamma-secretase pathway?

A

14

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8
Q

Which chromosome contains the apoliproteinE gene?

A

19

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9
Q

Describe the effects of ApoE:

A

Release ApoE -> S100β -> microglial activation -> IL-1 -> astrocyte activation -> ApoE -> amyloid cascade

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10
Q

Describe the gross pathology of frontotemporal dementias:

A

Knife-like gyri atrophy of frontal and temporal lobes, sometimes unilateral

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11
Q

Describe the histology of frontotemporal dementias:

A

Pick bodies (3R tau), neuronal loss, gliosis, balloon neurons

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12
Q

What stain do you use if FTD is tau negative?

A

Ubiquitin

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13
Q

Describe the gross pathology of MSA:

A

Cotrical and cerebellar atrophy - shrinkage of middle cerebellar peduncle, pons (widening of transverse fibres) and inferior olivary nucleus. Pallor of locus coeruleus and substantia nigra.

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14
Q

Describe the gross pathology of CBD:

A

Fronto-parietal atrophy, deep cerebellar nuclei and substantia nigra.

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15
Q

Describe the gross pathology of PSP:

A

Atrophy of basal ganglia, subthalamus and brainstem.

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16
Q

Describe the histology of MSA:

A

α-synuclein immunoreactive glial cytoplasmic inclusions (GCI) – Papp Lantos bodies.
Neuronal cytoplasmic inclusions, neuronal nuclear inclusions, glial nuclear inclusions and neuropil threads

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17
Q

Describe the histology of CBD:

A

Balloon neurons and astrocytic plaques. Glial and neuronal inclusions of 4R tau.

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18
Q

Describe the histology of PSP:

A

Tufted astrocytes, coiled bodies in the oligodendrocytes, neuronal and glial 4R tau inclusions. Neuronal loss and gliosis.

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19
Q

What three conditions come under multiple system atrophy and how is it categorised clinically?

A

Olivopontocerebellar atrophy, Shy-Drager syndrome and Striatonigral degeneration. MSA-P and MSA-C (Parkinsonism or cerebellar features dominant)

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20
Q

Which chromosome has the tau gene?

A

17

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21
Q

How many isoforms of tau are there?

A

6

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22
Q

Describe the gross pathology of prion disease:

A

General atrophy - widened sulci, thinner gyri, dilated ventricles

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23
Q

Describe the histology of prion disease:

A

Multiple vacuoles within the neuropil an sometimes the perikaryon of neurons - spongiform changes of cerebral cortex and deep grey matter structures. Accumulation of prion protein, astrogliosis, neuronal and synaptic loss.

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24
Q

Name three prion diseases:

A

Creutzfeldt-Jakob disease, Gerstmann-Straussler-Sheinker syndrome, fatal familial insomnia.

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25
Q

Which chromosome contains the gene for prion protein?

A

20

26
Q

PrP^p is resistant to what enzyme?

A

Proteinase K

27
Q

How does PrP^p spread?

A

The protein unfolds and refolds into beta sheets which act as seeds and propagate.

28
Q

How many types of CJD are there?

A

4 - Types 1 and 2 are sporadic, type 3 is iatrogenic and type 4 is variant. OR 1 and 2A are sporadic and 2B is iatrogenic

29
Q

What are the three hypotheses for mechanism of action?

A

Follicular dendritic cell in gut, retrograde up vagus or through synapses or uptake by cells after cell dies and releases prion protein.

30
Q

Describe the gross pathology of Parkinson’s Disease:

A

Pallor of substantia nigra

31
Q

Describe the histology of PD:

A

Lewy bodies and lewy neurites. Eosinophilic inclusion bodies made of alpha-synuclein.

32
Q

How do the bodies progress through the brain?

A

Begins in dorsal motor nucleus of glossopharyngeal and vagus nerves, anterior olfactory nucleus, and enteric nerve cell plexus
Proceeds in rostral direction toward neocortex

33
Q

What is the neuritic dystrophy hypothesis of Lewy neurodegeneration?

A

α-synuclein blocks up axon and stops transport and then α-synuclein everywhere.

34
Q

Describe the gross pathology of Huntington’s disease:

A

Temporal-parietal atrophy + ventricular enlargement (more lengthways than width ways because of caudate atrophy).

35
Q

Describe the histology of Huntington’s disease:

A

Abnormal mHtt protein strands form protein aggregates rather than folding into functional protein- they coalesce and form inclusion body within the cells + gliosis. Degeneration and death of medium spiny GABAergic neurons in the caudate and putamen.

36
Q

Which chromosome is the Huntingtin gene on?

A

4

37
Q

How many CAG repeats to get HD?

A

CAG repeat of >=29 risk in next generation, >=35 and might get HD, next gen at risk, >=40 will get HD

38
Q

Which chromosome has mutations that lead to frontotemporal dementias?

A

17

39
Q

Which FTDs are tau negative?

A

FTLD-TDP (A-D), FTLD-FUS, FTLD-UPS

40
Q

What are the dopaminergic neuron pathways?

A

Nigro-striatal pathway: Substantia nigra to striatum.

Meso-cortical and meso-limbic: VTA to cortex and limbic system (nucleus accumbens and olfactory tubercle).

41
Q

What are the motor and non-motor symptoms of PD?

A

Motor: Resting tremor, rigidity, brady/akinesia, loss postural reflexes
Neuropsychiatric: hallucinations, anxiety, paranoia, confusion, agitation, depression, dementia, psychosis, visuospatial dysfunction, hypersexuality, spending/gambling mania
Autonomic and vegetative: bladder, bowel, hypotension, impotence, dysarthria, dysphagia, drooling, rash, anosmia
Sleep: restless leg syndrome, R.E.M. Sleep behaviour disorder, periodic limb movement disorder (PLMD), nightmares, nocturia, insomnia
Iatrogenic: dyskinesia, painful dystopia (when off or peak dose), pain in face/limbs/abdomen, sweating/flushing, akathisia, breathlessness, internal tremor

42
Q

What is the dual hit hypothesis?

A

In PD, an unknown neurotropic pathogen enters brain via nasal route with anterograde progression into the temporal lobe and via gastric route with subsequent retrograde atonal and transneuronal transport.

43
Q

Which areas are affected by multi system degeneration in PD? (Land and Obeso 2004)

A
  • Motor: substantia nigra, PPN
  • Sleep: hypothalamus (hypocretin, Hist.), PPN, thalamus (GABA), raphe (H5T), RAF (ACh, NMDA), Pineal (Melatonin), Locus Coeruleus, (Noradrenalin)
  • Autonomic: hypothalamus, medullary nuclei, spinal cord, peripheral ganglia, cardiac sympathetic plexus, skin
  • Cognitive: substantia nigra, VTA, locus coeruleus, raphe, basal forebrain, limbic, hippocampus, cerebral cortex, thalamus
  • Sensory: olfactory pathway, visual pathway & association cortex, retina
44
Q

What are some risk factors of PD?

A

Age, family history, rural living, farming, gardening, pesticide use, well water, industrial/chemical exposure, diet, trauma, emotional stress, premorbid personality
FHx O.R.= 3.4; rural living O.R.= 1.8

45
Q

Gibbs and Lees 1988 showed what with regards to Lewy Bodies?

A

Incidental Lewy Body disease, up to 33% in 11th decade.

46
Q

Which drugs for PD affect dopamine?

A

Indirect Agonists: Precursor (L-DOPA, Duodopa) Release (Amantadine)
Direct Agonists: Apomorphine, Pramipexole, Ropinirole, Rotigotine
Enzyme Blockers: Dopamine DeCarboxylae (DDC) (Sinemet, Madopar) MAO (Selegiline/ Rasagiline (may also be neuroprotective, promotes anti-apoptotic genes, trials still ongoing)) COMT (Entacapone (periphery only), Tolcapone, Opicapone)
Other: Stalevo (L-DOPA + DDC + Entacapone)

47
Q

What are some advantages and disadvantages of L-DOPA?

A

Advantages: Gold standard because best at controlling motor symptoms (esp. rigidity, bradykinesia)
Comes in CR for better symptom control during sleep, increased on time
Also comes in dispersable formulations for faster absorption (also often easier to take pill if dysphagia)
Can be taken with other PD drugs
Disadvantages: <5% to brain
CR has slow on
Role of dietary protein
Honeymood period
On/off
Permanent induction of dyskinesia

48
Q

Advantages and disadvantages of DA agonists?

A

Advantages: delay introduction of L-DOPA/reduce dose of L-DOPA and therefore lower risk of dyskinesia induction
Neuroprotection?
Disadvantages: Less well tolerated/ effective than L-DOPA
Effect wanes (then add L-DOPA?)
Psychological: hallucinations, delusions, paranoia, punding, impulsivity
Side-effects: N & V, Hypotension, oedema, fibrosis, somnolence & ‘sleep attacks’

49
Q

What other medications are used for autonomic and sleep symptoms?

A

Resting tremor: AntiACh (worsen memory so not in people ith dementia)
Low BP (orthostatic hypotension; dizziness, falls): fluids, salt, NSAIDs, Fludrocortisone, Midodrine, DHE, Flurbiprofen, Indomethacin, L-DOPS
Bladder (frequency, urgency, incontinence, nocturia): Oxybutinin, Tolteradine, Desmopressin
Bowel (constipation): diet & fluids, oral meds, enemas, suppositories
Drooling: ophth. gtt., Atropine, Glycopyrrolate, patches, BTX
Seborrhoea: tar shampoo, topical steroids
Impotence: drugs, surgery
Sleep: Avoid Rasagiline, Amantadine (caffeine!) late in day
sustained release L-DOPA; agonists
short-acting hypnotic: Zolpidem, Temazepam
Nocturia: anticholinergic, Desmopressin
Dreams/Hallucinations/RBD: reduce DA drugs: Clonazepam, Quetiapine
Treat depression, joint/muscular problems

50
Q

What drug regime is required in PDD?

A

Do not treat ‘benign hallucinations’
Remove/reduce inciting medication (anticholinergics, dopamine agonists, Amantadine), identify triggers (infection, trauma, surgery)
Avoid conventional dopamine-blocking drugs:
Clozapine, Quetiapine, Olanzapine, Risperidone, Sulpiride, Aripiprazole
(NB- benefit of Donepezil, Rivastigmine, Memantine in Lewy Body Type Dementias = PDD & DLB)
80% with dementia after 20 years
PDD associated with higher Abeta.

51
Q

What drugs treat depression in PD?

A

Optimise Dopaminergic therapy
Tricyclics (now second line): constipation, delay L-DOPA absorption, worse dyskinesia, sedation & confusion, cardiac dysrythmia
SSRI/ SNRI/ NSSA/ MAO-A(B)
Counselling / Carer Input / Group Activities
Exercise (every 15-20 mins!)
Electroconvulsive therapy

52
Q

What drugs induce Parkinsonism?

A

Dopamine-Blocking Drugs: Used in psychosis, depression, dyskinesia (Haloperidol, Thioridazine, Promethazine, Fluphenazine, Chlorpromazine, Perphenazine, Trifluoperazine, Tetrabenazine) Used in dizziness, nausea (Metoclopramide, Prochlorperazine)
Calcium Blockers: Flunarizine, Cinnarizine, Diltiazem, Verapamil
Other:Amlodipine, Olanzapine, Risperidone, Sulpiride, Amiodarone, Cimetidine, Valproate, SSRIs, Cyclosporine

53
Q

What clinical examinations can be used for dementia?

A

MMSE (Mini Mental State Examination), MoCA (Montreal

Cognitive Assessment, ACE (Addenbrookes Cognitive Assessment)

54
Q

What are the symptoms of AD and which areas of the brain are they associated with?

A

Episodic, especially recent but eventually old memories too. Dependent on medial temporal lobes, including the hippocampus and entorhinal cortex (other memories are semantic, working, procedural).
As disease progresses, patients develop impairment in executive function, attention, language, visuospatial function, personality and behaviour and eventually motor control. This is mirrored by increasing dysfunction/atrophy in parietal and frontal regions.
There is also increasing neuropsychiatric involvement, including apathy, depression, delusions, hallucinations and agitation.

55
Q

What is the DSM-5 criteria for dementia?

A

Evidence of significant cognitive decline in from a previous level of performance in one or more cognitive domains (learning and memory, language, executive function, complex attention, perceptual-motor, social cognition) and these deficits interfere with independence in everyday activities. At a minimum, assistance should be required with complex instrumental activities of daily living, such as paying bills or managing medications. The deficits do not occur exclusively in the context of delirium and cannot be better explained by another mental disorder.

56
Q

How does atypical AD present?

A

– Speech disturbance/Progressive aphasia (impaired word finding, more left sided temporal atrophy)
– Behavioural Symptoms
– Progressive Visuospatial Symptoms/Posterior Cortical Atrophy

57
Q

What is posterior cortical atrophy and how does it present?

A

Also called Benson’s syndrome, it is a type of atypical AD.
Insidious onset with gradual progression, there are visual complaints with a normal eye examination, and these vision problems are found through the disorder. There is relatively preserved anterograde memory and insight early in the disorder. Absence of stroke, tumour, early Parkinsonism and hallucinations. Elements of Gerstmann’s syndrome, alexia, presenile onset, dressing apraxia.
Affects parieto-occipital regions in focal/asymmetrial lesions. Beh et al 2014

58
Q

What are some possible diagnostic tools for AD?

A

Neuropsychology
CT/MRI
FDG PET/amyloid PET/Tau PET
Abeta1-42, tau (Abeta:tau ratio), pTau

59
Q

What is the evidence for ACh in AD?

A

In 1970s was discovered that there evidence of severe loss of cholinergic transmission in the cerebral cortex, most severe in temporal lobes, limbic and paralimbic
Also that cholinergic antagonists lead to memory impairments
Acetylcholine has a key role in learning and memory, as well as arousal and attention
Severity of dementia found to correlate with cholinergic loss (cf PD)
Positive effect of Tacrine demonstrated in 1980s
Mesulam 2004

60
Q

What treatments are used to manage AD?

A

Donepezil, Galantamine and Rivastagmine are NICE approved for mild to moderate AD and lead to modest improvement in cognition, behaviour and ADLs (>30 placebo RCTs, increase up to 2 MMSE points over 6-12 months
But can cause GI side effects and lower HR, no effect on survival and effect wanes after 2-4 years.
Memantine (low-mod affinity NMDA R. open channel blocker), NICE approved for mod. and severe, improves cognition and function
But can cause confusion and headaches
Combination therapy?
Antipsychotics associated with more falls, worsening cognition, Parkinsonian symptoms and death so only specialists prescribe as last resort
Check for infections, thyroid problems, vitamin deficiencies, dehydration
Withdraw other meds if possible and sleeping pills

61
Q

What medications are in trial for AD?

A

2nd gen in trials at the moment but:
some patients developed meningoencephalitis
Post mortem showed reduction in plaques but not tangles
Vaccine did show improvement in cognition and reduction CSF tau but also reduction in brain volume
Monoclonal antibodies to Abeta: solanezumab, aducanumab, etc. - possibly slow cognitive decline…
BACE inhibitors, eg. verubecestat, reduces production of Abeta.
Gamma-secretase inhibitors found to be toxic Sevigny 2016
Tau aggregation inhibitors: well tolerated but effective? Guathier et al 2016
5-HT-Idalopirdine, 5-HT6 antagonist, may potentiate effects of AChEIs.
Atomoxetine (NA reuptake inhibitor), Guanfacine (alpha 2 agonist), NA affected as early as ACh but earlier trials showed no effect of NA drugs.
GLP1 analogue, prevent tau phosphorylation and restores intracellular transport of tau -> aberrant insulin signalling in AD. Liraglutide also reduces amyloid formation and inflammation.
Giving drugs too late? Were previous trials on patients with AD?

Neuro BSc (16 decks)

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