Dementia Flashcards
Alzheimer’s Disease - Genetics
Alzheimer’s disease is a progressive degenerative disease of the brain accounting for the majority of dementia seen in the UK
Genetics:
- most cases are sporadic
- 5% of cases are inherited as an autosomal dominant trait
- mutations in the amyloid precursor protein (chromosome 21), presenilin 1 (chromosome 14) and presenilin 2 (chromosome 1) genes are thought to cause the inherited form
- apoprotein E allele E4 - encodes a cholesterol transport protein
Alzheimer’s Disease - Pathological Changes
Pathological changes:
Macroscopic: widespread cerebral atrophy, particularly involving the cortex and hippocampus
Microscopic: cortical plaques due to deposition of type A-Beta-amyloid protein and intraneuronal neurofibrillary tangles caused by abnormal aggregation of the tau protein
Biochemical: there is a deficit of acetylecholine from damage to an ascending forebrain projection
Alzheimer’s Disease - Neurofibrillary tangles
Neurofibrillary tangles
Paired helical filaments are partly made from a protein called tau and in AD, tau proteins are excessively phosphorylated
Alzheimer’s Disease - Mx:
Management
- NICE now recommend the three acetylcholinesterase inhibitors (donepezil, galantamine and rivastigmine) as options for managing mild to moderate Alzheimer’s disease
- Memantine (a NMDA receptor antagonist) is reserved for patients with moderate - severe Alzheimer’s
Alzheimer’s Disease - Drug Mx - Acetylcholinesterase Inhibitors
Cholinesterase inhibitors such as donepezil, galantamine and rivastigimine are licensed for use in patients with mild to moderate Alzheimers disease. The National Institute for Health and Care Excellence (NICE) currently recommends treatment for all patients with moderate Alzheimers disease with a Mini Mental State Examination (MMSE) score of 10 20.
The British National Formulary lists sick sinus syndrome and supraventricular conduction problems (such as atrial flutter and atrial fibrillation) as relative contraindications in the prescribing of cholinesterase inhibitors. Although it is not specifically stated in NICE guidance there is a large evidence base to support the practice of performing a routine ECG prior to initiating treatment. There is insufficient evidence to support the use of routine echocardiograms prior to the initiation of cholinesterase inhibitor
The diagnosis of an atrioventricular nodal block is a contraindication for cholinesterase inhibitors, which could precipitate complete heart block.
Alzheimer’s and Memantine: Example Question
A 74-year-old female has been diagnosed with moderate to severe Alzheimer’s disease, on a background of a two-year progressive gradual cognitive decline. Her family had tried to cope on their own without seeking medical help, putting it down to old age but now, most likely requires nursing home care. MMSE 7/30. She has a past medical history of previous myocardial infarctions. She has not complained of chest pain recently and her ECG demonstrates no ischaemic changes, a PR interval of 290ms. What is the most appropriate treatment strategy?
Donepezil > Memantine Galantamine Rivastigmine Aspirin
There are two key facts to this patient: firstly, the patients MMSE is suggestive of severe dementia. Secondly, the diagnosis of 1st degree heart block and hence atrioventricular nodal block is a contraindication for cholinesterase inhibitors, which could precipitate complete heart block. In accordance with the latest set of NICE guidelines, donepezil, galantamine and rivastigmine are all appropriate for mild to moderate dementia, defined as MMSE between 10 and 26/30. However, only memantine, an NMDA antagonist, has demonstrated efficacy and is licensed for severe Alzheimer’s disease.
Lewy Body Dementia
Lewy body dementia is an increasingly recognised cause of dementia, accounting for up to 20% of cases. The characteristic pathological feature is alpha-synuclein cytoplasmic inclusions (Lewy bodies) in the substantia nigra, paralimbic and neocortical areas
The relationship between Parkinson’s disease and Lewy body dementia is complicated, particularly as dementia is often seen in Parkinson’s disease. Also, up to 40% of patients with Alzheimer’s have Lewy bodies
Neuroleptics should be avoided in Lewy body dementia as patients are extremely sensitive and may develop irreversible parkinsonism. Questions may give a history of a patient who has deteriorated following the introduction of an antipsychotic agent
Lewy Body Dementia - Features and Mx
Features
progressive/fluctuating cognitive impairment
parkinsonism
visual hallucinations (other features such as delusions and non-visual hallucinations may also be seen)
Mx:
Currently, evidence best supports cholinesterase inhibitors in the treating of Lewy Body Dementia.
Lewy Body Dementia - Diagnosis
Diagnosis
usually clinical
single-photon emission computed tomography (SPECT) is increasingly used. It is currently commercially known as a DaTscan. Dopaminergic iodine-123-radiolabelled 2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123-I FP-CIT) is used as the radioisotope. The sensitivity of SPECT in diagnosing Lewy body dementia is around 90% with a specificity of 100%
Lewy body dementias core clinical features are fluctuating cognition, visual hallucinations (present in 2/3rds of cases) and parkinsonism. Two out of three are needed for diagnosis. The visual hallucinations are often very vivid.
NB a syndrome of executive and visuospatial dysfunction on a background of PD diagnosis more than 12 months before diagnosis of cognitive impairment = Parkinson’s dementia rather than Lewy Body Dementia
Lewy Body Dementia Diagnosis and Mx - Example Question
A 64 year old man presents with a 6 month history of abnormal behaviours which have been noticed by his wife. He has described seeing vivid visual hallucinations of clowns in his living room which sometimes talk to him and appear very real. He believes that he is the head of a circus and is about to go on a world tour although this is not true.
At times he is lucid and is fully independent but at other times he is disorientated in time and place and is unable to perform simple tasks such as preparing food and going to the shops. His wife thinks that his mood is also lower since the onset of symptoms. He presented in A+E today because of having a second fall in two weeks.
There is no history of infective symptoms. He went to see his GP two days ago who thought that he may have a UTI and prescribed trimethoprim.
He has a history of stroke 10 years ago and hypertension and takes warfarin, amlodipine and enalapril.
Physical examination is unremarkable except for slightly increased tone on the left side compared to the right.
Bloods:
Hb 14.9 g/dl
Platelets 387 * 109/l
WBC 12.8 * 109/l
Na+ 142 mmol/l
K+ 4.6 mmol/l
Urea 6.4 mmol/l
Creatinine 84 µmol/l
Bilirubin 6 µmol/l ALP 64 u/l ALT 15 u/l Calcium 2.35 mmol/l Albumin 41 g/l
MSU (from GP from 2 days ago): Heavy growth of E.coli Sensitive to trimethoprim, nitrofurantoin, amoxicillin and co-amoxiclav
CT Brain: some generalised atrophy and periventricular white matter changes normal for age. Changes in keeping with an old left sided lacunar infarct
Mini Mental State Examination 17/30
Which medications would most appropriately treat the underlying diagnosis?
Olanzapine > Rivastigmine Co-amoxiclav Sinemet Aspirin 300mg
The answer is Rivastigmine. The diagnosis here is Lewy Body dementia. Lewy body dementias core clinical features are fluctuating g cognition, visual hallucinations (present in 2/3rds of cases) and parkinsonism. Two out of three are needed for diagnosis. The visual hallucinations are often very vivid. This patient definitely has two out of the three. He also may have parkinsonism as he has bilaterally increased tone that is not in keeping with his old lacunar infarct.
He also has a few supportive features of Lewy Body Dementia hallucinations in other modalities, delusions, depression and repeated falls.
Currently, evidence best supports cholinesterase inhibitors in the treating of Lewy Body Dementia. It must be remembered that these patients have high sensitivity to neuroleptics so Olanzapine should not be used here. Schizophrenia is a less likely diagnosis as visual hallucinations are rare in late onset schizophrenia and late onset schizophrenia itself is rare. Also, fluctuating mental state is not usually seen in schizophrenia.
Whilst this patient has a UTI, it is sensitive to trimethoprim and therefore is already being appropriately treated and therefore further antibiotics are not required. As the symptoms have been present for 6 months, UTI is unlikely to be the underlying diagnosis.
Whilst the patient does have risk factors for stroke and focal neurology and a TIA is possible, it does not explain his other symptoms and therefore aspirin would not therefore represent treatment for the underlying diagnosis.
The patient does show features of parkinsonism but a diagnosis of Lewy Body is more suggested by the cognitive and psychiatric symptoms and therefore Sinemet would be not be considered before a cholinesterase inhibitor.
Lewy Body Dementia - Mx
Currently, evidence best supports cholinesterase inhibitors in the treating of Lewy Body Dementia. It must be remembered that these patients have high sensitivity to neuroleptics so Olanzapine should not be used.
Reversible Causes of Dementia - Example Question
An 88-year-old woman is brought in by her daughter as her memory has been deteriorating over the past year. Upon clarification with her daughter, it is confirmed that the patient has deteriorated over many months and has not had an acute illness. She has no significant past medical history apart from an appendicectomy when she was a teenager. On examination, the patient is comfortable at rest, has a temperature of 36.8 degrees Celcius, heart rate of 70 beats per minute and blood pressure of 115/90mmHg. What should be included in her initial screen apart from haematology and biochemistry?
> Thyroid function tests, and serum B12 and folate Thyroid function tests, serum B12 and folate, syphilis, and HIV Thyroid function tests, serum B12 and folate, lumbar puncture, midstream urine Thyroid function tests, serum B12 and folate, syphilis, and midstream urine Thyroid function tests, serum B12 and folate, syphilis, and lumbar puncture
In making a diagnosis of dementia, potentially reversible causes should be sought for and treated. Although syphilis and HIV need to be considered as a source of her symptoms, they are not tests that should be routinely done. These tests should be conducted if there is a suggestive history or clinical presentation.
The history is not suggestive of an acute deterioration which would make delirium a concern. Therefore a mid stream urine is not necessary at this stage. Cerebrospinal fluid assessment should not be performed as a routine investigation for dementia.
Dementia - Common Causes
Common causes
Alzheimer’s disease
cerebrovascular disease: multi-infarct dementia (c. 10-20%)
Lewy body dementia (c. 10-20%)
Dementia - Rarer Causes
Rarer causes (c. 5% of cases) Huntington's CJD Pick's disease (atrophy of frontal and temporal lobes) HIV (50% of AIDS patients)
Dementia - Important Differentials which are possible treatable
Important differentials, potentially treatable hypothyroidism, Addison's B12/folate/thiamine deficiency syphilis brain tumour normal pressure hydrocephalus subdural haematoma depression chronic drug use e.g. Alcohol, barbiturates
