Categorising Dementia

Question 1

Which protein aggregate is found in each of the Dementia / parkinson’s? (amyloidopathies vs synucleinopathies vs tauopathies)

Answer 1

Alzheimer’s disease there is deposition of amyloid and tau

Parkinoson’s disease is a synucleinopathy as is dementia with lewy body and multiple system atrophy

Cretzfeldt- Jacob is a prion disease

Tauopathies are Alzheimer’s disease, down’s syndrome, PSP, CBD, FTD, Parkinson’s disease linked to chromosome 17 and Pick’s disease

Question 2

List reversible causes of Cognitive decline and screening tests?

Answer 2

Screening: B12/Folate, TFT, ESR/CRP, EUC, FBC, CT

Reversible

 Vitamin B12

 Subdural hematoma

 Thyroid disease

 Normal pressure hydrocephalus

 Neurosyphilis

 Neoplasms

 Some vascular

Question 3

What is cortical vs subcortical cognitive impariment?

Answer 3

Cortical vs. Subcortical Dementias

 Cortical dementias -

o Loss of cognitive function

o 4As: amnesia, aphasia, agnosia, apraxia

o Examples: Alzheimer’s, multi-infarct dementia

 Subcortical dementias

o Loss of coordination of cognitive function

o 4Ds: dysmnesia, delay, depletion, dysexecutive

o Also: emotional incontinence, personality change, attentional dysfunction, gait & urinary disturbance

o Symptoms overlap with frontal- temporal dementia o Examples: Binswanger’s, Parkinson’s, Huntington’s

Question 4

Treatments for dementia - What are the mechanisms of action for Donepezil, rivastigmine, galantamine, memantine, caprylic triglyceride?

Answer 4

Cognitive Enhancers

 Cholinesterase inhibitors

o Donepezil (Aricept)

o Rivastigmine (Exelon)

o Galantamine (Razadyne)

 Glutamatergic NMDA antagonist

o Memantine for moderate/severe DAT

 Ketone diet

o Caprylic triglyceride (Axona): a “medical food” for mild/moderate DAT

Question 5

What does the black box warning on antipsychotics in the elderly relate to (dementia related psychosis)? R 2017

Answer 5

Black Box Warning on Antipsychotics  Elderly pts with dementia-related psychosis treated with typical and atypical antipsychotics (AP) are at increased risk of death compared to placebo (PLC) o Meta-analysis of 17 placebo-controlled trials o Risk of death: 1.6-1.7 times higher in antipsychotic group  Death rates (typical 10 week treatment) o AP group: 4.5% o PLC group: 2.6%  Causes o Cardiovascular: MI, sudden death o Infectious: pneumonia and neuroleptic malignant syndrome

Question 6

What are the risk factors for Alzheimer’s type dementia?

Answer 6

Risk Factors  Age  Mild cognitive impairment (MCI), amnestic type  Family history ( risk by 2-3 times)  Head trauma  Lower level of education  Female sex  Exposure to toxic chemicals  APO-E, epsilon 4 allele

Question 7

What is MCI - R 2017

Answer 7

Amnestic MCI  Mild cognitive impairment, amnestic type o Subjective memory complaints plus o Impaired memory performance on testing compared to controls  Hippocampal atrophy,  tau plasma levels  10%-15% convert to Alzheimer’s per year o Compared to 1%-2% in normal controls o 25% of amnestic MCI do not progress to Alzheimer’s  Best discriminator: delayed recall Not affecting function

Question 8

What are the pathological findings in Alzheimer’s disease?

Answer 8

Senile plaques (extracellular) 1. Abnormal neuronal processes plus 2. Glial cells plus 3. Amyloid beta (Aβ) insoluble form: Aβ-42 Neurofibrillary tangles (intracellular) 1. Single and paired helical cytoskeletal filaments 2. Microtubular proteins–tau and ubiquitin Early neuronal loss o Hippocampal CA1 subfield has lost 60% of neurons in stage of very mild dementia

Question 9

Early onset dementia (Alzheimer’s): Genetics:

Answer 9

Early onset dementia: (<65 yrs): 5%-10% of cases o Half are familial and due to autosomal dominant missense mutations o Half are non-familial due to ‘sporadic’ Alzheimer disease, like the late-onset form Mutations of Early-Onset Disease  Autosomal dominant missense mutations 1. Presenilin 1 (on chr 14) 2. Presenilin 2 (on chr 1) 3. Amyloidprecursorprotein(APP) (on chr 21)  All 3 mutations cause aberrant cleavage of APP o Produce amyloid beta 42, main neurotoxic peptide that forms senile plaques – lets Ca++ into neurons! o Presenilin 1 & 2 are proteases. When abnormal, they cleave APP in the wrong place  Trisomy 21: 3 APP genes present in genome

Question 10

Late onset Dementia (Alzheimer’s): genetics

Answer 10

 Late onset (≥65 yrs): 90%-95% of cases o Sporadic: multiple genes contribute to dementia

Question 11

Explain Apolipoprotein E in Alzheimer’s dementia

Answer 11

Apolipoprotein E  Lipoprotein stores, metabolizes, & transports cholesterol & triglycerides to liver  Three alleles of ApoE (ε2, ε3, ε4) o Epsilon 4 allele: risk increased by 2.5 o Epsilon 3 allele: neutral o Epsilon 2 allele: protective  Epsilon 4 present in 25% of people and in ~60% of DAT pts  Testing not recommended

Question 12

What are lewy bodies?

Answer 12

What are Lewy bodies? o Abnormal aggregation of proteins: Alpha-synuclein, neurofilament, and ubiquitin o Usually single Lewy body found per neuron  Where are Lewy bodies? o Substantia nigra o Locus ceruleus, dorsal raphe, substantia innominata, & dorsal motor nucleus of the vagus o Neocortex: in many patients with Parkinson’s disease & in all patients with DLB

Question 13

How would you assess for cognitive impairment (order of investigations) R 2017

Answer 13

1. history and examination , screen for depression 2. collateral history and cognitive assessments 3. Labs and CT (plain) or MRI - B12 / TFT,

Question 14

What are the side effects of Cholinesterase inhibitors? R 2017

Answer 14

Symptomatic bradycardia - avoid in atrioventricular block, sick sinus syndrome, bradycardia Relative contraindications, bleeding gastric ulcers, seizures, bronchial muscle spasm secondary to asthma or COPD. Other SE - GI upset (diarrhoea)

Question 15

Clinical syndrome matching: R 2017 Under 65 Memory disturbance Personality change, fluctuating Mixture of UMN and LMN deficits Normal sensation. What protein accumulation is found in FTD? Which one is found in FTD with MND?

Answer 15

FTD with MND Frontotemporal dementias are heterogeneous with the two most common protein accumulations in these cases consisting of tau or TDP-43. Nearly all of the cases of FTD with motor neuron disease have TAR DNA-binding protein 43 (TDP-43) protein accumulations.

Question 16

What are features of PSP - R 2017

Answer 16

Atypical parkinsonism, eyelid opening apraxia, retrocollis, subcortical dementia including slowness of mental processing and memory retrieval deficit, depression, supranuclear vertical gaze palsy Global aphasia is not a characteristic clinical feature of progressive supranuclear palsy.

Question 17

What clinical score is useful in evalutating driving safety in dementia in America - R 2017

Answer 17

The clinical dementia rating (CDR) score has the strongest evidence as being useful in the identification of driving safety, with patients with scores above 1 being at substantially higher risk for unsafe driving.

Question 18

Which medications are most useful to lessen neuropsychiatric sx (including Delusions) in AD, PD, LBD? R 2107

Answer 18

Acetylcholinesterase inhibitors can reduce neuropsychiatric symptoms (including psychosis) in patients with Alzheimer’s disease, Parkinson’s disease dementia and diffuse Lewy body disease.

Question 19

What is procedural memory? Where is the lesion if someone is having difficulty with procedural memory? What diseases are issues with procedural memory commonly reported in? R 2017

Answer 19

Procedural memory is the ability to acquire (with practice) cognitive and behavioral skills that subsequently operate automatically. Procedural memory is associated with lesions of the basal ganglia-cerebellumsupplementary motor area system. Procedural memory problems are commonly reported in patients with Parkinson disease (PD) and affect tasks such as playing a musical instrument or golfing.

Question 20

What is episodic, semantic and working memory? Where is the lesion if someone is having difficulty with each of these memory? What diseases are issues with each of these memory commonly reported in?

Answer 20

Episodic memory localizes to the medial temporal lobe-Papez circuit system, semantic memory to the anterior and inferior temporal lobes, and working memory to the prefrontal cortexsubcortex- parietal-association cortex system. Episodic memory deficits are typical of Alzheimer disease (AD). Semantic memory deficits are typical of Alzheimer disease and frontotemporal lobar degeneration (FTD). Working memory deficits can result from multiple cerebrovascular events, AD, FTD, PD, dementia with Lewy Bodies, and traumatic brain injury.

Question 21

What is Balint syndrome and where is the lesion?

Answer 21

Balint syndrome localizes to the posterior parietal regions and consists classically of the triad of optic ataxia, ocular dysmetria and asimultagnosia.

Question 22

What is the clinical triad of NPH What predicts outcomes of shunting in NPH? What symptoms are most likely to improve post shuntin? - R 2017

Answer 22

Normal pressure hydrocephalus is characterized by cognitive difficulties, gait apraxia and urinary incontinence. Imaging typically demonstrates a communicating hydrocephalus. Although the diagnosis of normal pressure hydrocephalus can be problematic, some studies have stratified both positive and negative predictors of outcome from shunting. Patients whose initial presentation is gait disorder have a better chance of successful outcome (if other confounding diagnoses, such as parkinsonism, are excluded), while those with dementia of greater than 2 years’ duration, dementia preceding the gait disorder, or other factors which are more consistent with Alzheimer dementia (aphasia and loss of hippocampal volume) predict a poorer outcome from shunting. Presence of urinary incontinence is not predictive of improvement from shunting. Gait abnormalities are the most likely to improve after ventriculoperitoneal shunting.

Question 23

R 2017 - Imaging of CJD

Answer 23

The correct answer is prion disease. There is restricted diffusion involving the left occipital and left lateral temporal cortices. This patient had sporadic Creutzfeldt-Jakob disease, a progressive neurodegenerative disorder resulting from misfolded prion proteins. The imaging abnormality does not respect vascular territories, making ischemic infarction unlikely. Hypoxic brain injury typically causes symmetric abnormalities. The limbic, or medial temporal, structures appear normal. Hashimoto’s encephalopathy more commonly results in lesions in the white matter and/or brain stem.

Question 24

R 2017 - images of FTD

Answer 24

FTD s

Question 25

Binswanger Disease - What is it What are the typical imaging findings?

Answer 25

Binswanger disease is characterized by subcortical foci of patchy T2 hyperintensities in white matter

Question 26

Which medication should you try for cognitive impariment in LBD?

Answer 26

drugs that inhibit acteyl cholinesterase the mainstay of treatment for cognitive impairment. Donepezil was significantly superior to placebo on both the MMSE in behavioral measures A randomized double-blinded study of citalopram and risperidone in 31 patients with DLBD showed that most patients with behavioral disturbances or psychosis associated with DLB tolerate citalopram or risperidone poorly and do not seem to benefit from either medication. Quetiapine fumarate would help this patient’s behavioral symptoms but would not improve the cognitive dysfunction.

Question 27

What is the MOA of Riluzole? What is the benefit of Riluzole in MND? R 2017

Answer 27

The discovery of elevated CSF glutamate levels in patients with ALS led to the study of glutamate release inhibitors, such as riluzole, in the treatment of ALS. Studies have shown that riluzole has an 8% benefit on survival at 12 months and a 9% benefit on survival at 18 months.

Question 28

What is florbetapir?

Answer 28

Florbetapir (Amyvid) is a marker for the imaging of beta-amyloid protein aggregates in the brain. These aggregates form the core of neuritic plaques, one of the two pathological hallmarks of Alzheimier’s disease. The other pathological hallmark of Alzheimer’s disease is neurofibrillary tangles composed of phosphorylated tau proteins. Pittsburgh compound B is also approved for the imaging of beta-amyloid protein aggregates in the brain but is less available for routine clinical use due to its short half-life

Question 29

What are the two pathological hallmarks of Alzheimer’s disease?

Answer 29

Senile neuritic plaques and neurofibrillary tangles. Neurofibrillary tangles composed of phosphorylated tau protein and senile neuritic plaques with beta amyloid protein aggregate core.

Question 30

R 2017

Answer 30

This is a senile plaque of AD

Question 31

Answer 31

This is an intracytoplasmic neurofibrillary tangle of AD

Question 32

Rite 2017

Answer 32

Lewy body - eosinophilic cytoplasmic inclusion (alpha synuclein) in a neuron with melanin granules.

More common within the cells of the substantia nigra.

Parkinson’s disease

Lewy body disease (large number)

Multiple systems atrophy (within glia)

Question 33

Answer 33

Gray matter vacuoles of classic CJD

Question 34

Answer 34

Intracyoplasmic intraneuronal argyrophilic (i.e., silver staining) round bodies seen in the swollen neuron bodies

Pick’s disease, which represents ~ 10% of patients with FTD