Dr Christopher Mark Davison Consultant Old Age Psychiatrist North Tyneside General Hospital ▪ ▪ Cases ▪ Exams ▪ Images AIMS

▪ Describe the clinical presentation and course of the common degenerative of late life, particularly AD and DLB ▪ Introduce the concept of mild cognitive impairment as a possible early presentation of dementia ▪ Encourage the use of operationalised diagnostic criteria for these disorders ▪ Raise awareness of less common causes of degenerative dementia that may be encountered in the practice of old age psychiatry LEARNING OUTCOMES

▪ Be able to diagnose the dementia and aetiological subtypes, using systematic methods and with an awareness of the probable diagnostic accuracy ▪ Understand the issues around diagnosing dementia at an early stage and to know the approach to assessment that will best assist in this. ▪ Understand the specific importance of accurate diagnosis for optimal management of each of the common disorders WHAT IS DEMENTIA? WHAT IS DEMENTIA?

▪ Clinical syndrome with multiple and persisting cognitive impairments ▪ Memory plus other cognitive functions affected ▪ Impairment lasting 6 months

▪ Functional impairment in daily living e.g. inability to make a cup of tea, putting clothes on wrong

▪ Exclusion of other conditions interfering with cognitive function ▪ ▪ ▪ Hypothyroid etc. WHAT IS DEMENTIA?

▪ Memory plus other cognitive functions affected

▪ Functional impairment or decline from premorbid function WHAT IS DEMENTIA?

▪ Can be progressive e.g. Alzheimer's dementia

▪ Can be static e.g. secondary to head injury WHAT IS DEMENTIA?

▪ Degenerative Dementia in old age is huge problem

▪ Risk doubles every five years over age of 65 © Luigi Novi / Wikimedia Commons

▪ 850,000 people in UK affected by dementia

▪ Numbers set to grow significantly – 1 million by 2021

▪ Costs 17 billion pounds ▪ DSM 5: ▪ Dementia ▪ = Major Neurocognitive Disorder UK DEMENTIA PREVALENCE

▪ DSM 5: ▪ Dementia ▪ = Major Neurocognitive Disorder CAUSES OF DEMENTIAS Parkinsons Disease Fronto-temporal dementia dementia Dementia with Lewy Bodies

Alzheimer’s

Huntingtons disease disease Mixed dementia Rare causes PROGRESSIVE DEMENTIAS

Alzheimer's Disease 50%

Mixed Other Causes Alzheimer's/ 10% Vascular Disease 10%

Vascular Disease Dementia with 10% Lewy Bodies 20% CASE STUDY

▪ 69 year old lady ▪ 3 year history of progressive worsening of short term memory ▪ On a couple of occasions put electric kettle on gas hob ▪ Keeping out of date food in fridge and missing appointments ▪ On clinical assessment: ▪ MOCA 22/30. Mood apathetic and some depression ▪ Experienced musical hallucinations. Doesn’t think memory is that bad. ▪ Physically well otherwise CASE STUDY

▪ 81 year gentleman ▪ 1 year history of progressive worsening of short term memory ▪ Nominal - mild ▪ On clinical assessment: ▪ MMSE 19/30. Reduced verbal fluency. ▪ High BP – but treated ▪ Mild MI when 74 ▪ History of prostate cancer ▪ Physically slightly stooped. No focal neurological signs. ▪ At research clinic has CSF sample – high tau and low beta amyloid

AD: NINCDS-ADRDA CRITERIA

▪ Dementia established by clinical examination and cognitive examination e.g. MMSE ▪ Deficits in two or more areas of cognition ▪ Progressive worsening of memory / other cognitive functions ▪ No disturbance of consciousness ▪ Onset between 45 and 90 (most often >65) ▪ No systemic or other disorders which could account for progressive cognitive deficits AD: NINCDS-ADRDA CRITERIA

▪ Supported by ▪ Impaired activities of daily living or altered behaviours ▪ Family history of Alzheimer’s ▪ Cerebral atrophy on CT head scan and progressive atrophy noted with serial scans or normal CT AD: NINCDS-ADRDA CRITERIA

▪ Other clinical features ▪ Plateaus in course of progression ▪ Associated behavioural and psychological symptoms ▪ Depression ▪ ▪ Incontinence ▪ Delusions ▪ Hallucinations ▪ Verbal, emotional or physical outbursts ▪ Weight loss ▪ Neurological signs (especially advanced AD) ▪ Increased muscle tone, myoclonus, gait disorder, seizures

McKhann et al. 1984;34:939-944. ▪ Timeline of neuropathology and symptoms in AD BIOMARKERS IN AD BIOMARKERS IN AD

▪ Neuroimaging

▪ Structural

▪ PET – metabolism (FDG) and amyloid load (PIB) BIOMARKERS IN AD

▪ CSF sampling

▪ High total tau ▪ High phosphorylated tau ▪ Low beta amyloid (A-Beta40 and A-Beta42)

▪ Predictive of Alzheimer’s BIOMARKERS IN AD NEW DIAGNOSTIC CRITERIA FOR AD

ADD WORKGROUP, MCKHANN ET AL, ALZHEIMER’S AND DEMENTIA, 2011 ▪ Probable AD: ▪ Dementia (amnestic or non-amnestic presentation) ▪ Gradual onset ▪ Evidence decline/ progression ▪ No related / CVD on imaging/ presence of DLB/FTD etc ▪ Probable AD with evidence of AD pathological process: ▪ Evidence neuronal injury (MRI, FDG PET, CSF tau) ▪ Alterations in A-beta (Amyloid PET or CSF) ▪ AD like profile (history and course) ▪ Possible AD with evidence of AD pathological process: ▪ Meet criteria for another dementia but AD biomarker positive ▪ Pathophysiologically proved AD: ▪ Meet clinical criteria and autopsy positive

BIOMARKERS IN AD CASE STUDY

▪ 63 year old retired physics teacher ▪ Complaining of blurring of vision and seeing lights, with a normal ophthalmic examination ▪ CT head was normal ▪ She re-attended one year later complaining of subjective short term memory difficulties and “bumping into things”. Struggling to dress herself and gets easily confused ▪ On examination, no neurological signs ▪ MMSE 22/30. Deficits in visuo-spatial, writing, calculation and following command. Memory intact ▪ Has finger , left-right disorientation POSTERIOR CORTICAL ATROPHY

▪ Atypical variant of AD ▪ Also called Benson's syndrome ▪ Characterised by posterior atrophy ▪ Affects occiptial and areas ▪ Tend to have well preserved memory and language ▪ However often progressive, dramatic and relatively selective decline in vision and/or skills such as , writing and arithmetic ▪ Can present with Gerstmann’s syndrome ▪ /: deficiency in the ability to write ▪ /: difficulty in learning or comprehending mathematics ▪ Finger agnosia: inability to distinguish the fingers on the hand ▪ Left-right disorientation ▪ Can also present with ▪ Also Balint’s syndrome ▪ inability to perceive the visual field as a whole () ▪ difficulty in fixating the eyes (ocular apraxia) ▪ inability to move the hand to a specific object by using vision (optic ataxia)

▪ Often younger onset than AD CASE STUDY

▪ 72 year old gentleman ▪ 1 year history of worsening of short term memory ▪ Frequent falls ▪ Occasionally sees “a pink elephant” out of the corner of his eye and the stripped carpet tends to “ripple like the sea”. ▪ On cognitive assessment: ▪ MOCA 27/30 DEMENTIA WITH LEWY BODIES

▪ Dementia with Lewy bodies (DLB) is a common cause of dementia Alzheimer's Disease 50%

Mixed Other Causes Alzheimer's/ ▪ DLB is related to 10% Vascular Disease Parkinson’s disease 10% Vascular Disease Dementia with 10% Lewy Bodies 20% DEMENTIA WITH LEWY BODIES MCKEITH 2005 ▪ Evidence of dementia of sufficient magnitude to interfere with normal social and occupational function.

▪ Core features (at least 2) ▪ Fluctuating cognition with pronounced variations in attention and alertness ▪ Recurrent visual hallucinations which are typically well formed and detailed ▪ Spontaneous features of parkinsonism

▪ Suggestive features ▪ REM sleep behaviour disorder ▪ Severe neuroleptic / antipsychotic sensitivity ▪ Low dopamine transporter uptake in demonstrated by SPECT or PET imaging DEMENTIA WITH LEWY BODIES FOURTH CONSENSUS REPORT OF THE DLB CONSORTIUM 2017 ▪ Evidence of dementia of sufficient magnitude to interfere with normal social and occupational function.

▪ Core clinical features ▪ Fluctuating cognition with pronounced variations in attention and alertness ▪ Recurrent visual hallucinations which are typically well formed and detailed ▪ REM sleep behaviour disorder ▪ One or more Spontaneous features of parkinsonism ( bradykinesia, rest tremor, rigidity) DEMENTIA WITH LEWY BODIES FOURTH CONSENSUS REPORT OF THE DLB CONSORTIUM 2017

▪ Supportive clinical features ▪ Severe antipsychotic sensitivity ▪ Repeated Falls ▪ Syncope or other transient episodes of unresponsiveness ▪ Severe Autonomic dysfunction eg constipation, orthostatic hypotension, urinary incontinence ▪ ▪ Hyposmia ▪ Hallucinations in other modalities ▪ Systematized delusions ▪ Apathy ▪ Anxiety ▪ Depression DEMENTIA WITH LEWY BODIES FOURTH CONSENSUS REPORT OF THE DLB CONSORTIUM 2017

▪ Indicative Biomarkers ▪ Reduced dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging ▪ Abnormal ( low uptake) on 123Iodine MIBG myocardial scintigraphy ▪ Polysomnographic confirmation of REM sleep without atonia

Supportive Biomarkers

▪ Relative preserved medial structures on CT/MRI ▪ Generalized low uptake on SPECT/PET perfusion/metabolism scan with reduced occipital activity +- cingulate sign on FDG PET imaging ▪ Prominent slow wave activity on EEG with periodic fluctuations in pre alpha/ theta range DEMENTIA WITH LEWY BODIES

▪ Supportive features ▪ Falls and syncope ▪ Unexplained loss of consciousness ▪ Autonomic dysfunction ▪ Hallucinations in other modalities ▪ Systematized delusions ▪ Depression ▪ Preserved medial temporal lobe structures on CT/MRI ▪ Generalised low uptake on HMPOA SPECT/PET perfusion scan with reduced occipital activity ▪ Prominent slow wave activity on EEG with temporal lobe transient sharp waves DEMENTIA WITH LEWY BODIES

▪ Probable DLB ▪ A) 2 or more core clinical feature +- indicative biomarker ▪ B) 1 core clinical feature with one or more indicative biomarker

▪ Possible DLB ▪ A) 1 core clinical feature with no indicative biomarker ▪ B) One or more indicative biomarker with no clinical features DEMENTIA WITH LEWY BODIES: NEUROPSYCHOLOGICAL PROFILE ▪ DLB and AD equally impaired on composite batteries ▪ e.g. MMSE, CAMCOG ▪ AD worse than DLB on immediate and delayed recall ▪ e.g. episodic memory ▪ DLB worse than AD for : ▪ attention e.g. reaction time, digit vigilance ▪ visuospatial performance e.g. clock drawing ▪ visual perception e.g. fragmented letters AD DLB

MMSE 18/30 MMSE 20/30 Orientation 5/10 Orientation 8/10 Short term memory 0/3 Short term memory 2/3 DEMENTIA WITH LEWY BODIES: NEUROPSYCHOLOGICAL PROFILE FLUCTUATING COGNITION IN DLB

minute to minute / hour by Lucidity and hour capable task variation performance

Cognitive baseline time

Transient Communication Glazed / interruption in difficulties switched off awareness MEDIAL TEMPORAL LOBE ATROPHY IN DLB AND AD SUBJECTS MATCHED FOR GLOBAL IMPAIRMENT

AD

DLB

Absence of medial temporal lobe atrophy is more common in DLB (40-60%) than AD (10%) Barber et al. Neurology. 2000;54:1304-1309. NEUROLEPTIC SENSITIVITY IN DLB

▪ Increased mortality 2-3x in 50% - no predictors ▪ Atypicals seem similar to conventional anti-psychotics but no RCT evidence! ▪ Tolerance of anti-psychotics does not exclude DLB ▪ Anti-psychotic challenge is not advocated ▪ Anti-psychotics do not affect DA transporter uptake imaging REM SLEEP BEHAVIOUR DISORDER

▪ High specificity for a diagnosis of Lewy body disease / - synucleinopathy when associated with neurodegenerative disease ▪ A potential risk indicator for LB disease ▪ A useful diagnostic marker ▪ An important treatment target DOPAMINE TRANSPORTER IMAGING AS A DIAGNOSTIC BIOMARKER FOR DLB

Sensitivity for probable DLB v probable AD was 78% and specificity 90%. Independent of age, MMSE or UPDRS.

Note: A negative DaTSCAN does not exclude a diagnosis of DLB! (20% will be negative!) DIAGNOSTIC CRITERIA FOR PD DEMENTIA 2007 2007 SEP 15;22(12):1689-707)

▪ Parkinson’s disease ▪ Dementia ▪ > 1 cognitive domain ▪ ADL > motor and autonomic deficits ▪ Associated clinical features ▪ Cognitive – attention, executive, visuospatial, memory, language ▪ Behavioural – apathy, personality and mood, hallucinations (v), delusions, daytime sleepiness ▪ Exclusions include other conditions causing confusion or unknown time course of motor/cognitive symptoms DLB AND PDD ARE SIMILAR WITH RESPECT TO: ▪ Cognitive profile ▪ Fluctuating cognition ▪ Extrapyramidal features ▪ Neuropsychiatric symptoms ▪ Cholinergic and dopaminergic deficits ▪ Neuroleptic sensitivity ▪ Response to cholinesterase inhibitors CASE STUDY A

▪ A 51-year-old male lawyer began to embezzle money at work using the money to buy pornographic materials via the internet. Also noted to be inappropriate at work to female staff

▪ His work had dramatically deteriorated, and rather than working with his clients, he spent most of the day at work shuffling papers, magazines or downloading pornography onto his computer

▪ Subsequently fired and not working. Over past year has last interest and tends not to speak

▪ He developed a strong desire for potato chips and gained 6 kgs

▪ His manners deteriorated, and he stuffed his mouth, often choking at the dinner table CASE STUDY A

▪ Upon examination, the patient was profoundly apathetic and indifferent

▪ MOCA 27/30 missing one point each for the name of the hospital, the season and for spelling "world" backwards

▪ Verbal fluency, abstract thinking and performance on Luria motor task were impaired

▪ Basic neurologic examination revealed pathologically brisk jaw jerks. Palmo-mental reflex evident.

▪ Fasciculations, as well as subtle atrophy and weakness, were evident in the arms and legs.

▪ Plantar responses were flexor. CASE STUDY A

▪ Progression

▪ Within six months, the patient was even more apathetic and unable to speak. ▪ Swallowing liquids became difficult, and aspiration became frequent. ▪ Died 9 months after diagnosis as a result of pneumonia

▪ Pathology

▪ Extensive gliosis and spongiform changes of the frontal cortex. ▪ Ubiquitin and TDP-43-positive, tau-negative inclusions were seen in the dentate gyrus of the hippocampus. ▪ Diagnosis of FTD-MND was diagnosed CASE STUDY B

▪ A successful architect began to have trouble finding names for people and objects.

▪ He continued to design buildings but had trouble filling out paper orders, making frequent spelling mistakes.

▪ Surprisingly, he was caught stealing a shiny necklace from a client's home.

▪ While at home he began to play solitaire compulsively for 6 hours per day.

▪ He developed a new interest in squash, and his game steadily improved. He stopped working as an architect but obtained a courier job and learned and remembered a complex route for delivering packages.

▪ There was no family history of dementia. CASE STUDY B

▪ MOCA score was 24/30.

▪ Speech was fluent but somewhat lacking specific nouns.

▪ Comprehension was mildly impaired due to deficits in understanding some words.

▪ The items missed were two of three words on memory, naming of the watch and pen, and two items on the three-step command.

▪ Neurologic examination was normal CASE STUDY B

▪ Progression ▪ Subsequently, deficits in recognizing faces of others became apparent, and he was unaware when his wife became upset. ▪ Four years after diagnosis, comprehension for spoken and written language had disappeared, and he called all people and items in his environment "thing." ▪ Subtle problems with swallowing emerged 5 1/2 years after diagnosis, and the patient died 6 months later.

Pathology Extensive atrophy of the anterior temporal lobes, orbitofrontal and medial frontal cortex was evident Extensive spongiosus, gliosis and neuronal loss were evident in these frontotemporal regions. Ubiquitin-positive inclusions were evident in the frontal and anterior temporal lobes Diagnosis: Semantic dementia FTD: MANCHESTER-LUND CRITERIA

▪ CORE SYMPTOMS (all must be present)

▪ insidious onset and gradual progression ▪ early decline in social interpersonal conduct ▪ early impairment in regulation of personal conduct ▪ early emotional blunting ▪ early loss of insight FTD: MANCHESTER-LUND CRITERIA

▪ SUPPORTIVE SYMPTOMS

▪ Behavioural disorder: ▪ decline in personal hygiene and grooming ▪ mental rigidity and inflexibility ▪ distractibility and impersistence ▪ hyperorality and dietary change ▪ utilization behaviour

▪ Speech and language: ▪ altered speech output (aspontaneity and economy of speech, press of speech) ▪ of speech, echolalia, perseveration, mutism FTD: MANCHESTER-LUND CRITERIA

▪ SUPPORTIVE SYMPTOMS

▪ Physical signs: primitive reflexes, incontinence, akinesia, rigidity, tremor, low/labile blood pressure

▪ Investigations: ▪ • : impaired tests; no amnesia or perceptual deficits ▪ • EEG: normal on conventional EEG despite clinically-evident dementia ▪ • brain imaging: predominant frontal and/or anterior temporal abnormality FTD: MANCHESTER-LUND CRITERIA

▪ Dementia of frontal lobe type ▪ Semantic dementia ▪ Progressive non-fluent aphasia ▪ FTD with motor neurone disease ▪ FTD with parkinsonism ▪ Chr 17 ▪ Chr 3 ▪ No linkage established ▪ 69 year old previously highly functional lady presents with a 3 month history of rapid decline in short term memory and displays confusion. She is quite paranoid and needs to be admitted under MHA section

▪ MOCA is 20/30

▪ She has problems with her balance and co-ordination and has occasional “jerks”

▪ Dementia100% ▪ Myoclonus 80% ▪ Pyramidal signs 50% ▪ Cerebellar signs 50% ▪ Extrapyramidal signs 50% ▪ Less common:cortical visual defects,LMNL,abnormal extraocular movt.,sensory defects,seizures,vestibular disturbance,autonomic dysfunction ▪ Mean survival five months ▪ EEG:characteristic periodic sharp-wave complexes superimposed on slow background rhythm present in>90%

▪ MRI: T2 hyperintense signal in basal ganglia in 80%

▪ CSF:Elevated levels of protein 14-3-3 without pleocytosis in 96% ▪ Kuru ▪ Familial Creutzfeldt-Jacob disease ▪ Gerstmann-Straussler-Scheinker disease ▪ Familial fatal insomnia ▪ New variant Creutzfeldt-Jacob disease

CASE STUDY

▪ An 80 year old nursing home resident has fluctuating confusion, recurrent urinary incontinence and apathy.

▪ Nursing staff are finding it more difficult to get the gentleman up and mobile as his walking and gait has deteriorated.

▪ He scores 14/30 on his MMSE and seems slowed in his thinking

▪ The gentleman’s gait is shuffling and he is stooped but there is no rigidity or tremor CASE STUDY NORMAL PRESSURE HYDROCEPHALUS

▪ Symptoms ▪ Gait dysfunction ▪ Unsteadiness and impaired balance ▪ “magnetic gait” ▪ May mimic Parkinsonian gait but no tremor ▪ Urinary incontinence – urgency and detrusor hyper-reflexia ▪ Cognitive impairment – subcortical / dysexecutive NORMAL PRESSURE HYDROCEPHALUS

▪ Investigations

▪ Structural scan ▪ Lumbar puncture (Miller-Fisher test) ▪ In most cases, CSF pressure is usually above 155 mmH2O ▪ Clinical improvement after removal of CSF (30 mL or more) has a high predictive value for subsequent success with shunting ▪ A "negative" test - very low predictive accuracy. Many patients may improve after a shunt in spite of lack of improvement after CSF removal

HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) INVESTIGATIONS

▪ Exclude opportunist infection ▪ CNS imaging ▪ atrophy in basal ganglia & frontal white matter ▪ Look for other causes (B12 / folate deficiency, HCV, syphilis, TFT) ▪ Check CSF HIV Viral Load ▪ Cognitive screening tools ▪ Cheaper & more available alternative than formal neuropsychological testing, but inferior ◆ Flashbulb Memory ◆ Flashbulb Memory

◆ A detailed and vivid memory that is stored on one occasion and retained for a lifetime. Usually, such memories are associated with important historical or autobiographical events

Autobiographical / Declarative

◆ ApoE ◆ ApoE

◆ apolipoprotein e gene

ApoE on chromosome 19 has been implicated in late-onset Alzheimer’s disease ◆ Go / No Go ◆ Go / No Go

Ask the patient to place a hand on the table. Tap under the table. Tell the patient to raise one finger when you tap once and not to raise the finger when you tap twice. Show the patient how it’s done and then do the test.

Frontal / Impulse control Perseveration ? Which lobe Perseveration ? Which lobe

Frontal (Lateral orbitofrontal cortex or inferior prefrontal convexity (Brodmanns area) ◆ Gerstmann Syndrome ◆ Gerstmann Syndrome

◆ Dominant Parietal Lode lesion

•Agraphia or dysgraphia •Acalculia or dyscalculia •Finger agnosia •Left-right disorientation ◆ Stroop Test – Tests what? ◆ Stroop Test – Tests what?

◆ Processing Speed / Attention ◆ Prefrontal Non Dominant ◆ Subcortical Dementias

◆ Cortical ◆ Subcortical Dementias

◆ Parkinson's disease dementia, ◆ Huntington's disease ◆ AIDS dementia complex

◆ Cortical

◆ AD ◆ CJD ◆ FTD ◆ HIV Ring Lesion ◆ ◆ HIV Ring Lesion ◆ Toxoplasmosis