Dementia for the FRACP Part 1Rohan Gunathilake MD

What is Dementia?

1. Acquired neurocognitive decline 2. Across one or more domains3. Interferes with independence4. Not due to delirium or other

psychiatric disorder

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), 2013

What is new in DSM-5?

• Major Neurocognitive Disorder (dementia is gone - not really!)

• Domains: Learning and memory, complex attention, language, perceptual-motor, executive function, and social cognition

• Memory loss is not an essential criteria• Psychometric definition for major vs. minor

NCD

Major vs. Minor Neurocognitive Disorder

Note: Should not be rigid – Major and minor exist in a continuum

Risk factors for dementia

Non-modifiable• Advancing age• Female gender• Educational achievement• Ethnicity: African American• Family history (x2.5)• Specific genetic mutations• MCI• Head injury

ModifiableIncreased Risk• Hypertension• Diabetes• Smoking• Hypercholesterolemia• Hyperhomocysteinemia

Decreased Risk• Physical exercise• Diet

Prevalence of dementia nearly doubles every 5 years after the age of 60

Ferri et al, Lancet 2005

Risk factors for dementia

Non-modifiable• Advancing age• Female gender• Educational achievement• Ethnicity: African American• Family history (x2.5)• Specific genetic mutations• MCI• Head injury

ModifiableIncreased Risk• Hypertension• Diabetes• Smoking• Hypercholesterolemia• Hyperhomocysteinemia

Decreased Risk• Physical exercise• Diet

Genetic factors in Alzheimer Dementia

Loy et al, Lancet 2014

Mendelian forms of AD

• Fortunately rare – only 500 families with AD• Autosomal dominant with high penetrance• Life time risk of developing dementia >95%• Multigenerational • Younger onset• May have myoclonus at early stages• 3 causative genes: APP (chromosome 21),

PSEN 1 (Chro 14) and PSEN 2 (Chro 1)

Loy et al, Lancet 2014

Mendelian forms of AD

• PSEN 1 – accounts for 60% Mendelian AD families

• APP– Sequence mutation 15%– Duplication 8%

• PSEN 2 – rare**86% families with younger onset (<60 years) AD and >3 generations affected are +ve consider genetic testing

Loy et al, Lancet 2014

Genetically complex AD

• Polygenic (genetically complex) variations – each increase risk by small amount only (+ environment)

• Late onset• Unlikely to pass all genetic variations to the

offspring• Can skip generations• Genetic testing have poor predictive power

Loy et al, Lancet 2014

Genetically complex AD

• Among known genetic variations, apo E and TREM 2 are best characterized

• Normal genotype = E3/E3 (61%)• OR for AD: E2/E2 = 1.5

E3/E4 (24%) = 3E4/E4 (2%) = 8

Genetically complex AD

Nature Reviews Neuroscience 10, 333-344 (2009)

Genetically complex AD

• 75% with once copy of E4 do not develop AD• 50% with AD do not have E4 variation• Genetic testing has poor predictive value and

is not recommended

Neuropathology of AD

Varon et al, Dement Geriatr Cogn Disord 2011

Pathogenesis AD

1. Amyloid (Senile) plaques – extracellular- protein fragments snipped from APP

2. Neurofibrillary tangles – intracellular-chemically altered tau tangled with other threads

Aβ42

Aβ40

Oligomers&Intermediateforms

Amyloid plaques

inflammation

NEJM 2010; 362:329-44

NEJM 2010; 362:329-44

Synaptic loss

Giacobini, Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.223

Amyloid hypothesis in AD- summary

Apo E4

Clinical features of AD

NEUROLOGY 2005;65(Suppl 3):S10–S17

Clinical features of AD

Nature Reviews Drug Discovery 2007; 6, 295-303

Lancet Neurol. 2013;12(2)-207-16

Amyloid imaging with 11C-PIB PET

Transaxial and sagittal planes of 11C-PIB PET scans in a normal control (NC), a 11C-PIB-positive NC (NC+), 11C-PIB-negative MCI subject (MCI−), a 11C-PIB-positive MCI subject (MCI+), a highly 11C-PIB-positive MCI subject (MCI++), and a 11C-PIB-positive AD patient (AD) J. Med. Chem. 2007; 46, 2740–2754

Mean CSF Aβ42 and total tau levels in autopsied proven cases

CSF Aβ42 CSF total tau

Schoonenboom et al, Neurology 62, 1580–1584

Treatment of Alzheimer Disease

Non-pharmacological• Carer support• Education• Socialisation• Cognitive engagement• Nutrition• Exercise• Smoking and ETOH• Diving and home safety• Advanced Care planning

Pharmacological• Cholinesterase Inhibitors• Memantine

Cholinesterase inhibitors mechanism of action

Eur Heart J. 2013;34(33):2580-2581

Memantine mechanism of action

CNS Drugs 2003: 17 (9)

Aricept product monograph, Pfizer

Rivastigmine patch in mild to moderate AD

Int J Geriatr Psychiatry. 2007 May;22(5):456-67

Memantine in Moderate-to-Severe Alzheimer's Disease

Reisberg B et al. N Engl J Med 2003;348:1333-1341.

Therapeutic targets in AD

BASE 1 inhibitors

BapineuzumabSolanezumab

Behavioural and psychological symptoms of dementia (BPSD)

Management of BPSD

Non-pharmacological• Behavioural intervention• Music therapy• Pet therapy• Aromatherapy• Bright light therapy

Pharmacological• Choline esterase Inhibitors• Memantine• Atypical antipsychotics• Antidepressants:

citalopram, SSRI• Antiepileptics

Past FRACP1 Questions

An 87-year-old woman with dementia was found wandering late at night. When she was returned to her home, it was found to be infested, unlocked and the gas stove was on. Her MMSE was 13/30. After hospitalisation, it is apparent that she requires residential care. However, she demands to return home. Her nearest relative is a second cousin living in another city but has not been in contact with her for several years. Her neighbour has been informally acting as a caregiver and providing limited supervision. Who should make the decision regarding institutionalisation in residential care?A. PatientB. Relative (second cousin)C. Carer (neighbour)D. Statutory guardianE. Medical practitioner

An 80 year-old lady has end-stage dementia and lives in a HLC nursing home. She is doubly incontinent, bed bound and doesn’t recognize family members. She has developed a new neurological dysphagia. She coughs lots when given thin fluids and aspirates. She spits out thickened fluids. She has been admitted to hospital twice with aspiration pneumonia. She has been made nil by mouth while awaiting assessment but appears to be distressed by not being allowed to eat and drink. What is the appropriate treatment?A. PEG feedingB. Nasogastric feedingC. Keep her nil by mouth and give subcutaneous fluidsD. Allow her to have any food or drink that she wantsE. Thickened fluids only

A 75-year-old woman presents with a twelve-month history of deteriorating behaviour and memory and increasing social withdrawal. She has been tearful and emotional with poor quality sleep. A diagnosis of depression has been made by her general practitioner, and she has been commenced on Sertraline 50mg / day with a limited response over the last eight weeks. Neurological examination reveals normal tone and no pyramidal findings. She scores 21/30 on a MMSE. TSH, full blood count, urea and electrolytes, calcium and liver function tests are normal. Cranial CT Scan shows age related involutional change. Her EEG demonstrates diffuse symmetrical slowing over both frontotemporal head regions with an excess of delta activity.The most likely diagnosis is:A. undertreated Major depressionB. diffuse Lewy body disease with associated depressionC. Alzheimers type dementia with associated depressionD. Creutzfeldt Jakob disease with associated depressionE. depression with hysterical conversion disorder

• The most common reason for reduced oral intake in people with end stage dementia is:A. impaired swallowingB. deliberate self harmC. physical inactivityD. increased metabolic rateE. dental disease

For a patient aged above 75 years old, what is the most likely risk factor for late onset dementia?A. Homozygous ApoE defectB. HypertensionC. Atrophy on CT brainD. Advancing ageE. Mild cognitive impairment

The clinical diagnosis of Alzheimer's type dementia requires:A. apraxiaB. agnosiaC. impaired consciousnessD. impaired functionE. inattention

A 79 year old man is brought in by his daughter after she notes he has mild confusion. His MMSE is 25/30. He is unable to draw intersecting pentagons. When asked to draw a clock face, the numbers are crowded to the right side. He is unable to dress himself, but has no weakness.What is the most likely diagnosis?A. Progression of dementiaB. Delirium with sedative useC. Right lacunar strokeD. Right posterior cerebral artery branch strokeE. Right middle cerebral artery branch stroke

An 80 year old lady is found wandering on the street. There is no useful history from the patient. On examination, she is drowsy and is disoriented to time and place. Her temperature is 37.9 degrees Celsius, BP is 125/80 mmHg and pulse rate is 100/minute. She appears to be having auditory and visual hallucinations. Which of the following features will indicate likely delirium rather than dementia?A. Disorientation to time and placeB. DrowsinessC. Fever of 37.9 degrees CelsiusD. HallucinationsE. Tachycardia

70 year old gentlemen presented to OPD for falls investigation. Physical examination reveals intention tremor and mild ataxic gait. Mild cognitive impairment also noted. The patient’s daughter’s son had recently been diagnosed with intellectual impairment. What is the most likely underlying genetic defect?A. Freidrich’s AtaxiaB. Fragile X syndromeC. Huntington’s diseaseD. Spinocerebellar ataxia type 1

An 80 year old man with dementia is still living at home with his wife as his principal carer. He was recently commenced on risperidone for behavioural and aggression issues. He has been refusing to take the risperidone and his wife has been crushing it and putting it in his food. What principle ofmedical ethics does this most contravene?A. AutonomyB. BeneficenceC. Distributive justiceD. Non maleficence‐E. Competency

Cholinesterase inhibitors are widely used to improve cognitive function in Alzheimer's disease. Which of the following urinary symptoms would be the most likely type A (dose-dependent) adverse drug reaction?A. Increased urinary frequencyB. Reduced urine outputC. Increased urine outputD. Urinary retentionE. Stress incontinence

An elderly patient complains of subjective memory loss and poor performance. In which aspect of the MMSE will a deficit suggest future development of dementia?A. RegistrationB. Recall and memoryC. Figure copying eg. Intersecting pentagonsD. Attention and calculationE. Language

An 82-year-old male has had Parkinson's disease for ten years. His current medications include levodopa/carbidopa and pergolide. For the last 18 months he has been in high level care (nursing home) because of his immobility but can still walk five-ten metres with a forearm support frame. His MMSE is 26/30. For the last three-six months he has had increasing problems with hallucinations of people coming into his room and has repeatedly accused his family members of stealing money from his bank account. The most appropriate first step in the management of his hallucinations and paranoia is:A. commence risperidoneB. commence clozapineC. cease pergolideD. reduce dose of levodopa/carbidopaE. commence trimethoprim

In a patient with extrapyramidal symptoms, which of the following is more suggestive of Lewy bodydisease than Parkinson’s disease?A. Rest tremorB. RigidityC. Visual hallucinationsD. Response to dopaminergic agonistsE. Bradykinesia

PDD and LBD

• PD and DLB not 2 separate entities but represent a spectrum of same pathological process; difference because of parts of the brain affected• Neo cortical and Limbic deposition of:

1. Lewy Bodies: Eosinophilic inclusions found in the nerve cells made up of Ubiquitin and aggregations of Alpha Synculein

2. Lewy Neurites : Thread like inclusions within neurites

• LBD - Early involvement of Amygdala – cognitive changes, and temporal lobe - hallucinations

Parkinson Disease Dementia

• 1 year rule: PDD = onset of dementia > 1 year after diagnosis of PD

• By 15 years >80% with PD have dementia• Prominent impairment of executive function• Bradyphrenia• Retrieval > encoding difficulty • Visuospatial dysfunction• PD motor features (in AD it’s axial)

Lewy Body Dementia

Core Features:1. Fluctuating cognition2. Visual hallucinations3. Spontaneous parkinsonism

Suggestive features:4. REM sleep behaviour disorder5. Neuroleptic sensitivity6. Low dopamine transporter uptake (PET/ SPECT)

Management of LBD/ PDD

• Cholinergic deficit in DLB• Rivastigmine improved cognition and behaviour in

DLB cf to placebo in a 20-week study (McKeith et al, 2000)

• Rivastigmine –treated patients with PDD had better cognitive and global scores than placebo at 24 weeks (Emre et al, 2004)

• Agitated psychotic and behavior – clozapine or quetiapine

• REM Sleep behavior disorder – clonazepam, CEIs

Vascular dementia

1. Dementia (decline from previous higher level of functioning)

2. Cerebrovascular disease:– focal neurologic signs consistent with previous stroke

(even with negative stroke history)– evidence of relevant cerebrovascular disease by CT or

MRI scan3. A clear temporal relationship– Onset< 3 months/ abrupt cognitive decline/stepwise

progressionNational Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences [NINDS-AIREN], 1993

clinical subtypes of VaD

1. Multi-infarct dementia – large complete cortical or subcortical infarcts

2. Strategic infarct dementia – single infarct in functionally critical areas e.g. angular gyrus, thalamus, PCA

3. Subcortical ischemic VaD– Lacunar states– Binswagner syndrome– CADASIL– Cerebral amyloid angiopathy

Clinical presentation of VaD

Cognitive• Slow processing• Executive dysfunction• Memory impairment

(retrieval deficit)• Depression • Apathy

Motor• Focal cortical impairments• Pseudobulbar palsy• Extrapyramidal signs

Frontotemporal dementias

• Common cause of presenile (<60 yr) dementia• Genetic advances and pathology suggest these

are multiple and independent illnesses• Pathology: Tau or TDP 43 inclusions

(tauopathy)• Cholinergic pathways relatively spared• Overlap with Amyotrophic Lateral Sclerosis,

Frontotemporal dementia- behavioural variant

• Disinhibition• Apathy• Lack of empathy• Loss of emotional reactivity• Lack of respect to personal space• Rude comments about others• Perseveration• Compulsive behaviors• Hyperorality and hypersexuality

Autoimmune encephalopathies

J Neuropsychiatry Clin Neurosci. 2011;23(1):90-97.

Steroid responsive encephalopathy with autoimmune thyroiditis (SREAT)

• Relapsing and remitting cognitive and behavioral changes

• Tremor, transient aphasia, myoclonus, seizures, gait ataxia

• No other detectable cause; MRI normal in 70%• Usually euthyroid • Abnormal elevation of anti-TPO +/- anti-TG

Elevated CSF protein (75%), cells (25%) and anti-TPO

CJD

1. Sporodic 80-90%– Peak age 55-75 years– Mean survival 7 months

2. Genetic 10%– Autosomal dominant– Family history

3. Iatrogenic– Corneal and dural grafts, GH

Variant CJD is different from CJD

MRI in CJD

CJD – cortical ribbon sign &Hockey stick sign (arrows)

vCJD –Pulvinar sign