An introduction to Alzheimer s related dementias Dr Ryan Fuller

1. An introduction to Alzheimer’s & related dementias Dr Ryan Fuller

2. What do we mean by dementia? Chronic brain failure (progressive) Cognitive impairment (intellect) Functional impact (persistent & pervasive) (distress – subjective &/ or objective)

3. What do we mean by dementia? Impaired memory (Amnesia) + 1 : Aphasia Apraxia Agnosia Dysexecutive syndrome Decline from previous level (baseline) function Severe - interferes with daily function & independence          

4. What do we mean by dementia?

5. What do we mean by functional decline?

6. What do we mean by functional decline?

7. What do we mean by functional decline?

8. Why bother? Diagnosis is not straight forward Some dementias are reversible! Some dementias have specific treatment So specific (subtype) clinical diagnosis is important

9. Why bother? Common “treatable” dementias: Biological Urinary tract infections Chest infections Constipation Dehydration Iatrogenic – polypharmacy toxicity / side effects Vitamin B12/ Thiamine / Calcium deficiency Anaemia Sensory impairment – cataracts, hearing loss Impaired mobility – arthritis, ankle oedema

10. Why bother? Common “treatable” dementias: Psychological Acute stress reaction Bereavement Depressive disorder Social Loss of family support Resettlement syndrome Caregiver stress Financial difficulty

11. Why bother? Rarer “treatable” dementias: Normal pressure hydrocephalus Frontal meningioma

12. Normal Pressure Hydrocephalus CSF increases – brain swelling Ataxia Incontinence Dementia

13. Normal Pressure Hydrocephalus

14. Normal Pressure Hydrocephalus

15. Frontal meningioma Slow growing brain tumour – swelling Pressure effects depend on site

16. Frontal meningioma

17. Frontal meningioma

18. Frontal meningioma

19. Dementia “label” is not adequate  AD can be considered for cholinesterase inhibitors VaD course modified by risk factor intervention DLB diagnosis may prevent life-threatening neuroleptic medication use Specific support to patients & caregivers is more effective if disease has a specific name

20. Diagnosis is complex There is no simple test Dementia is a syndrome diagnosed by clinicians Syndrome = collection of symptoms / criteria set by experts Clinician = health professional face : face with patients Accurate diagnosis needs experienced clinicians

21. Classification Historical Age Pathological (microscopic) Clinico-pathological

22. Historical - the dementia concept 18th Century: ‘Psychosocial incompetence’ regardless of age, reversibility or pathological antecedents (very broad clinical & legal use) 19th Century: ‘Cognitive paradigm‘ irreversible disorder (mainly in the elderly) intellectual functions (particularly memory) (narrowed down) 20th Century: “severe early-onset” senile dementia (Alzheimer’s) ‘Non-cognitive features’ hallucinations, delusions & behavioral deficits (partially modified 1980s)

23. Classification Historical Age Pathological (microscopic) Clinico-pathological

24. Dementia classification by age

25. What are the different types of AD?

26. EOAD

27. Classification Historical Age Clinico-pathological Pathological (microscopic)

28. Clinico-pathological dementias Cortical vs Subcortical

29. Cortex & subcortex

30. Cortex & subcortex

31. Cortex & subcortex

32. Clinico-pathological dementias

33. Clinico-pathological dementias

34. Classification Historical Age Clinico-pathological Pathological (microscopic)

35. Pathological - (structural) dementias Alzheimer’s (AD) 75 % Vascular (VaD) 15 – 25 % Lewy body (LBD) 10 – 20 % Frontotemporal (FTD) 10 - 15 %

36. Dementia subtype prevalence across the lifespan

37. Pathological - (structural) dementias Alzheimer’s (AD) 75 % Vascular (VaD) 15 – 25 % Lewy body (LBD) 10 – 20 % Frontotemporal (FTD) 10 - 15 %

38. Alzheimer’s disease 1901: 51yo woman, Auguste D, admitted to Frankfurt asylum Cognitive & language deficits, disorientation, depression, Auditory hallucinations, delusions, paranoia & aggression Studied by Dr Alois Alzheimer (1864–1915) 1903: Alzheimer moved to Munich medical school to work with Emil Kraepelin - foremost German psychiatrists of era 1906: Auguste D died & her brain was sent to him for PM examination “paucity of cells in the cerebral cortex” (atrophy) “clumps of filaments between the nerve cells” (plaques) 1910: Kraepelin coined the term 'Alzheimer's disease' a term still used to refer to commonest cause of senile dementia

39. Alzheimer’s disease

40. Alzheimer’s disease

41. Alzheimer’s disease In his original presentation, Alzheimer discussed Auguste D's cognitive & non-cognitive deficits At post mortem he found plaques, tangles & Arteriosclerotic changes in her brain “The clinical interpretation of this Alzheimer’s disease is still unclear. remains uncertain. Although the anatomical findings suggest that we are dealing with a particularly serious form of senile dementia. The fact is that this disease sometimes starts as early as the late forties” (Kraepelin) However, Kraepelin omitted Auguste D's arteriosclerotic changes, hallucinations, delusions & other psychiatric symptoms

42. Alzheimer’s disease Prevalence 5 % > 65 , roughly doubles every 5 years Reliable data lacking in developing countries (incl.SA) 10/66 study in Free State 5% Risk factors Age Female gender Strong family history + young onset 32 – 64 Testing possible Chr 14 Pre-senelin 1 (point mutations & deletions) Chr 1 Pre-senelin 2 Chr 21 APP (likely to be very rare cause) ApoE4 1 allele = 4x risk but not causative, not diagnostic, & not predicative Head injury Cerebrovascular RF AIDS

43. Alzheimer’s disease

44. Alzheimer’s disease

45. Alzheimer’s disease

46. Alzheimer’s disease

47. Alzheimer’s disease

48. Pathological - (structural) dementias Alzheimer’s (AD) 75 % Vascular (VaD) 15 – 25 % Lewy body (LBD) 10 – 20 % Frontotemporal (FTD) 10 - 15 %

49. Vascular dementia Group of syndromes caused by different mechanisms resulting in vascular lesions in the brain Diagnosis is complex because: Pathological changes result from range of causes Temporal relationship between cerebral insults & dementia often unclear Cerebrovascular disease common in elderly & in AD Classification (NINDS, AIREN,1993) 1). Small vessel disease with dementia 2). Multi-infarct dementia 3). Strategic single infarct dementia 4). Hypoperfusion (eg. cardiac arrest) 5). Haemorrhagic dementia 6). Other mechanisms         

50. Vascular dementia Prevalence less than AD Reliable SA data lacking Developed countries (Harvey et al, 1998) 60 – 64 0.3% 65 – 69 0.7% 70 – 79 2.5% 80 – 89 4.2% Likely to be much higher

51. Vascular dementia History Abrupt onset, step-wise deterioration Cerebrovascular RF: hypertension, smoking, CVS disease, diabetes, ? cholesterol (Cortical lesions) Aphasia + visuoperceptual & visuospatial deficits Deficits may be focal, memory less affected Examination Focal neurological signs, broad-based small stepping gait CVS RF+ Investigations (to reduce RF & emboli) ECG, echocardiogram, carotid artery ultrasound, Neuroimaging [crucial MRI for infarcts & white matter (subcortical) lesions] Muscle biopsy & genetic testing possible for notch 3 mutations (CADASIL family history) [Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts & Leucoencephalopathy] – “lacunar” infarcts, small arteries

52. Vascular dementia Diagnosis (DSM-IV) Similar to AD but with: Focal neurological symptoms Neuroimaging signs of multiple infarcts in the cortex (ICD-10) TIA or successive small strokes Vascular risk factors Focal neurological signs & symptoms Neuroimaging confirmation of vascular lesions

53. Vascular dementia

54. Vascular dementia

55. Vascular dementia

56. Vascular dementia

57. Vascular dementia

58. Pathological - (structural) dementias Alzheimer’s (AD) 75 % Vascular (VaD) 15 – 25 % Lewy body (LBD) 10 – 20 % Frontotemporal (FTD) 10 - 15 %

59. Lewy Body Dementia (LBD = DLB) Cognitive deficits >> parkinsonism Similar to Parkinson’s disease dementia Lewy body clumps in neurons [alpha-synuclein & ubiquitin protein] Detectable in post-mortem brain biopsies         

60. Lewy Body Dementia Lewy bodies 7 – 25 nanometer diameter filaments Similar to NFTs

61. Lewy Body Dementia Cortical intraneuronal LBs Rare NFTs Plaques may be present AD-like dementia

62. Lewy Body Dementia Diagnosis (McKeith et al, 1996) Attention, frontal sub-cortical skills & Visuospatial deficits Amnesia less marked Probable diagnosis (2/3) fluctuating cognition visual hallucinations parkinsonism (tremor, rigidity, bradykinesia) Supporting features Falls, syncope, TIAs, neuroleptic sensitivity, delusions & hallucinations, Sleep disturbance & nightmares

63. Parkinson’s dementia

65. Lewy Body Dementia BAP Drug Treatments in Old Age Psychiatry Professor Ian McKeith, 2009

66. Lewy Body Dementia Described by Okazaki 1961 Prevalence varies PM samples 15% Clinical operational criteria 10 – 23% Lewy bodies: intracellular inclusions of proteins neurofilaments cell stress response proteins

67. Lewy Body Dementia Cerebral cortex: Frontal, Temporal, Insula, Anterior Cingulate areas Majority = Cortical & Brain stem 50% fulfill AD criteria [plaques & tangles] Minority = no AD changes (young onset) Some = LB Cortical changes only

68. Neurochemistry ChAT (Choline acetyltransferase) levels lower than in AD & correlate with Cognitive impairment Hallucinations “Imbalance of central cholinergic and adrenergic neurotransmission” (Pilowski, 1996) equivalent to delirium ? (Byrne,APT,1996)

69. Why is DLB important? > Functional disability than AD [motor + autonomic impairment] 2 x care costs than AD Worse QOL than AD [1/4 caregivers rate > death]

70. Prevalence 15% all dementia autopsies Lewy bodies & Lewy neurites 1 in 7 dementia cases due to DLB 1 case DLB for every 4 AD and 2 PD

71. Diagnostic Criteria for DLB(McKeith et al, Neurology, 2005) Cognitive decline & ?social / occ. function [Attention, executive or visuo-spatial dysfunction prominent] CORE features Suggestive features

72. Diagnostic Criteria for DLB(McKeith et al, Neurology, 2005) CORE features Fluctuation Recurrent visual hallucinations Spontaneous parkinsonism Suggestive features REM sleep behaviour disorder Neuroleptic sensitivity Dopaminergic abnormalities in basal ganglia [SPECT/ PET]

73. Diagnostic Criteria for DLB(McKeith et al, Neurology, 2005) “Probable” DLB 1 core + 1 suggestive 2 suggestive “Possible” DLB 1 core 1 suggestive

74. Causes of Dementia(Alzheimer’s Society National Conference, 2007) Alzheimer’s Disease 62% Vascular Dementia 17% Mixed AD/VaD 10% Dementia with Lewy Bodies 4% (should be15%) Parkinson’s diease 2% Other 3% Greatest problem with DLB is it is under-diagnosed For every 1 case we diagnose we miss 3-4 cases

75. Neuropathological features(3rd Consortium Meeting, Neurology, 2005) Severity of Lewy-related pathology is positively correlated with DLB clinical syndrome [Limbic & Neocortical regions] Severity of AD-type pathology is negatively correlated with DLB clinical syndrome

76. Diagnostic Problems Difficulty recognising / defining “fluctuation” Failure to ask about suggestive & supportive features - RBD [trail making, attention tasks ?] - Early autonomic dysfunction

77. Diagnostic Problems Insufficient neuropsychometry Common atypical presentations Underuse of the “possible” DLB diagnosis Underuse of biomarkers MRI, SPECT – DaTSCAN, CSF

78. Alpha-synuclein Oligomer levels ? LB diseases (El-Agnaf et al, 2008) “End stage dustbin purpose to accumulate and get rid of abnormal proteins” Monomers ? Dimers ? Oligomers Toxic to dendrite spines Synapse death

79. Alpha-synuclein Oligomer levels ? LB diseases (El-Agnaf et al, 2008) LB cases – CSF levels of oligomers correlated with duration of illness (dementia or parkinsonism) Novel ELISA to detect CSF alpha-syn oligomers 84 PD & 20 DLB cases had sig. higher levels vs 80 controls & 25 tauopathy cases

80. Potential imaging markers for DLB SPECT Occipital hypoperfusion (Sens 65%, Spec for AD 65%) MRI Medial Temporal Area (Sens 40%, Spec for AD 100%) PET Dopaminergic loss in basal ganglia Flurodopa PET (sens 86%, Spec for AD 100%)

81. Potential imaging markers for DLB Dopamine transporter imaging (DaT) FP-CIT SPECT Sensitivity 78% Specificity 90% In discriminating “probable” DLB from AD Equally applicable in mild or severe dementia, all ages, with/out parkinsonism Generally acceptable to patients

82. Summary DLB common & disabling Reasonably robust system for diagnosing & classifying CSF & imaging biomarkers need development to increase detection Some symptomatic treatment success Needs regulatory trials Pathological processes driving DLB not understood so disease modifying targets unclear

83. Recommendations for DaT scans “Probable” DLB but where there is clinical uncertainty “Possible” DLB Dementia with atypical features where there is clinical uncertainty

84. Pathological - (structural) dementias Alzheimer’s (AD) 75 % Vascular (VaD) 15 – 25 % Lewy body (LBD) 10 – 20 % Frontotemporal (FTD) 10 - 15 %

85. Frontotemporal dementia

86. Frontotemporal dementia

87. Frontotemporal dementia Onset younger < 65, retain independence, not disorientated, focal deficits Behaviour socially inappropriate, disinhibition, rigidity, Memory problems later (semantic) Executive function marked Language problems isolated (non-fluent aphasia) without amnesia Visuospatial problems rarer Motor problems commoner (primitive reflexes, apraxia) Mood variable - withdrawal, impaired empathy & guilt, irritability, euphoric but problems understanding / processing / describing emotions, impulsive (suicidal risk) Psychotic symptoms jealousy, religious, bizarre delusions Somatic Appetite & weight gain (carbohydrate cravings)

89. Frontotemporal dementia Pathology Macroscopically Frontal & temporal lobe degeneration Microscopically Progressive nerve cell destruction in frontal lobe (spongiform) Tau proteins accumulate into “Pick bodies” which swell or balloon nerve cells into Pick cells and define Pick’s diseas Spinal motor neuron degeneration + inclusions  

90. Frontotemporal dementia Figure. Depiction of region-of-interest markings on representative slices for the four regions measured. MR images are coronal and axial T1-weighted magnetization-prepared rapid gradient echo images in a normal control.Figure. Depiction of region-of-interest markings on representative slices for the four regions measured. MR images are coronal and axial T1-weighted magnetization-prepared rapid gradient echo images in a normal control.

91. Frontotemporal dementia

92. Alcohol-related dementia Chronic alcoholism + dementia Alcohol use may decline after onset Wernicke-Korsackoff (thiamine def.) Confabulation +++ Present with frontal lobe deficits & mixed picture Cerebral atrophy, mamillary body atrophy Head trauma, intracranial bleeds

93. Rarer dementias HIV-associated dementia Neurosyphilis Prion disease spectrum – eg. CJD Huntington’s disease – hereditary (motor, cognitive, psychiatric deficits)

94. Summary Late presentations, ageism & neglect in clinical practice Acute on chronic with comorbid non-cognitive symptom clinical picture AD spectrum is commonest underlying pathology but degree & impact of “mixed” AD & VaD clinical picture is difficult to determine Atypical presentations: < 50 Motor symptoms Fluctuating course All cases need thorough MDT assessment & review with active cerebrovascular risk management

95. Thank You