“Doctor, I can’t read and write my Chinese name!”

“Doctor, I can’t read and write my Chinese name!”

Speaker: Dr Christie Li Supervisor: Dr James Luk

Inter-hospital Geriatric Meeting

30 March 2012

1

History

• M/61

• Social drinker, non-smoker. • Married with no children. • University level of education. • Occupation: accountant, worked as a treasurer of an

international organization before he retired 7 years ago (~54 years old).

2

Family History

• Mother: Parkinson’s disease diagnosed in her 80s. • Father: Died of ischemic heart disease. • 7 siblings.

• No family history of neurodegenerative disease. • No family history of psychiatric illness.

• Referred from TWH clinic because of deterioration

in reading and writing.

3

History of present illness

• Informant: wife.

• 7 years ago (around the time of retirement). – Difficulty in writing Chinese (including his name) and reading Chinese.

• 5-7 years ago.

– Difficulties in reading newspaper and emails. – Problem in spelling names in English. – Speak slowly but fluently.

4


• Significant impairment in recognition

– Failure to recognize “water” but able to describe that is transparent.

– Unable to recognize the fork (need the wife to give him the fork). – Unable to recognize faces (causing some social embarrassment). – Unable to recognize bank notes. – Unable to name colors (while buying clothes).

5

History of present illness • 2 years ago (memory impairment):

– Repeated questioning. – Misplacement of important items (e.g. wallets). – Missed appointments. – Forget to turn off the gas stove.

• No confabulation.

• Judgment problem. – Engagement in high risk investment in Mainland China.

6

History of present illness • Change in personality.

• Verbally aggressive and physically aggressive to his wife even for trivial matters.

• Marital conflict.

• No delusion or hallucination. • No features of depression. • No over-eating. • No evidence of obsession or compulsion or stereotyped

behavior. • No evidence of social dis-inhibition.

7


• No developmental language impairment. • No history of encephalitis. • No family history of early onset dementia. • No history of usage of illicit drugs. • Wife as the only sexual partner. • No evidence of increase in sexual desire.

8

Physical examination • BP 126/72 mmHg, P 73 bpm. • Right handed. • No obvious hearing impairment. • Visual acuity both eyes of 20/70 (eyeglasses on). • Confrontation test normal. • Fundoscopy – normal. • No parkinsonism signs. • No focal neurological deficit • No primitive reflex • Cardiovascular, respiratory and abdominal examination –

normal.

9

So far… • 61/M, with high level of education. • Use Chinese as the mother language.

• Progressive cognitive impairment over 7 years (i.e. onset

age 54 years old) affecting social function. – Language (e.g. difficulty in reading emails). – Agnosia (e.g. recognition of wrong person). – Memory (e.g. missed appointments). – Judgment impairment (e.g. high risk investment). – Change in behavior (e.g. marital conflict).

• Conclusion at this stage: suffered from dementia delineate the cause and type of dementia. 10

Overview of dementia • ICD-10.

• A syndrome due to disease of the brain, • Usually of a chronic or progressive nature. • Disturbance of multiple higher cognitive functions. • Consciousness is not clouded. • Significant impairment in social or occupational functioning.

• The impairments in cognitive function are commonly accompanied and

occasionally preceded by deterioration in emotional control, social behavior or motivation.

11

Mini-Mental State Examinations (MMSE) = 29/30

12

Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog = 8.67)

– Word recall (6/10) – Naming (1/5) – Commands (0/5) – Constructional praxis

(1/5) – Ideational praxis (0/5) – Orientation (0/8)

– Word recognition (0.67/12)

– Instruction remembering (0/5)

– Spoken language ability (0/5)

– Word finding difficulty (0/5)

– Comprehension (0/5) 13

Consist of 11 items to assess memory, orientation, language and praxis function

Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog = 8.67)

Score: 4/12

14

Neuropsychological profile

Test performed on 25/04/2011 by Dr. Wilson Tsui, Clinical psychologist, QMH

Test Performed Score of our patient Cut-off

Global Cognitive Functioning (CDRS) 135/144 Abnormal if <112

Attention (CDRS) 35/37 Abnormal if < 29

Memory (CDRS) 22/25 Abnormal if < 18

Boston Naming Test Moderately to severely impaired --

Category fluency Animal (13 in one min) Transportation (14 in one min)

Normal > 15 Normal > 10

Visual Perception and construction (CDRS)

5/6 Abnormal if < 3

Executive function (CDRS) 36/39 Abnormal if < 28

CDRS = Chinese Dementia Rating Scale

15

Investigations

• Normal complete blood picture. • Normal liver and renal biochemistries. • Vitamin B12 and folate – normal. • Thyroid function test – normal. • Venereal Disease Research Laboratory: non-reactive.

16

Magnetic Resonance Imaging (MRI)

Mild cerebral atrophy without any evidence of stroke or structural lesions like tumor identified.

Purpose: To exclude secondary causes

17

Approach to language problem

Let’s first have a look at some video clips on our patient’s performance…

18

Confrontational naming

19

Confrontational naming

20

Surface dyslexia

21

Scene Description

24

Alexia

25

No problem with repetition

26

Traditional concept • Expressive dysphasia (Broca’s dysphasia).

– Non-fluent & hesitant speech. – Preserved comprehension. – Poor hand-writing.

• Receptive dysphasia (Wernicke’s dysphasia). – Impaired comprehension. – Fluent but non-sensical speech.

• Conductive aphasia. – Repetition is poor. – Normal comprehension, fluent but non-sensible speech.

Reference: 3rd edition of Neurology and Neurosurgery illustrated 27

Network concept

Reference: Rohrer JD. Knight WD. Warren JE. Fox NC. Rossor MN. Warren JD, et al; Word-finding difficulty: a clinical analysis of the progressive aphasias. Brain. 131(Pt 1):8-38, 2008 Jan.

Planning of message

Word retrieval, verbal stores, sensory and motor mapping of stored words

Grammar and phonology

Phonetics and articulation

28

Analysis of our patient’s speech

• Generation of a message. • Conceptual content and vocabulary of message. • Structure of message –grammar and phonology. • Motor programming of speech – phonetics,

articulation and prosody.


29

Analysis of the speech

• No difficulty in initiation of speech. • Fluent speech. • Anomia. • Evidence of semantic paraphasia. • Grammar – no problem. • No phonemic paraphasia. • No problem with articulation or prosody.

30

What are the differential diagnoses?

31

Two major diagnostic categories

• Frontotemporal dementia

– Primary progressive aphasia (PPA). – Semantic dementia.

• Atypical presentation of Alzheimer’s

disease.

32

Classification of FTD

Frontotemporal dementia

Behavioral variants Primary progressive aphasia

1. Progressive non-fluent aphasia (PNFA).

2. Logopenic aphasia (LA)

3. Semantic dementia (SD)

33

Frontotemporal dementia (FTD) – behavioral variant

• Apathetic features. – Emotional blunting. – Loss of empathy. – Neglect of personal hygiene. – Selfishness.

• Disinhibited features. – Irritability. – Over-eating. – Altered food preference. – Hoarding. – Loss of social graces.

•Stereotyped-compulsive features (motor, verbal), wandering, pacing. •Impairment in executive function. •Average age: 50-60 years old.

Reference: Seelaar H. Rohrer JD. Pijnenburg YA. Fox NC. van Swieten JC, et al; Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. Journal of Neurology, Neurosurgery & Psychiatry. 82(5):476-86, 2011 May

34

MRI

35

Primary progressive aphasia

• Gradual, progressive loss of a specific language

functions.

• Relative sparing of other cognitive during the initial course of disease (1st 2 years).

Reference: Harciarek M, Kertesz A, et al; Primary progressive aphasias and their contribution to the contemporary knowledge about the brain-language relationship. Neuropsychol Rev. 2011 Sep;21(3):271-87. 36

Semantic Dementia (SD) • Loss of semantic knowledge with impairment in naming

and comprehension. • Progressively lose the meaning of words. • Circumlocution. • Affect less familiar words first. • Difficulties in defining words. • Repeatedly ask the meaning.

• Fluent and repeat well. • Semantic paraphasia with super-ordinate substitution.


Semantic Dementia (SD)

• Defective object recognition. – Various sensory modalities (vision, tactility, olfaction, and gustation). – Less familiar objects affected first.

• Impairment in recognition of faces (prosopagnosia)

• Different forms of agnosia.


Semantic Dementia (SD) • Read by phonology instead of

meaning.

• Surface dyslexia. – Impairment when reading aloud

irregular Chinese characters (unpredictable correspondence between their components and the pronunciation of the character as a whole).

• Surface dysgraphia (impaired

spelling).



• Behavioral and personality changes. – Disinhibition. – Irritability. – Special food preference. – Lack of empathy. – Utilization behavior, mental

inflexibility, compulsions.



• Onset time: 55–70 years of age.

• No treatment available.

– Behavioral disturbances may require anti-psychotic or anti-depressants.


Logopenic variant (lv PPA) • Moderately impaired

confrontation naming. • Difficulty in repeating sentences

and longer phrases. • Slowed speech with word finding

pauses. – Phonemic paraphasia

(mispronunciation). – No agrammatism.

• Intact single word comprehension.

• Frequently have episodic memory impairment and arithmetic abilities (Most had AD-type pathology).


Non-fluent variant PPA • Non-fluent speech

(effortful & halting). • Anomia. • Problems with

articulation. • Agrammatism. • A significant shortage of

verbs.

• Apraxia of speech. • Impaired motor planning and

sequencing.

• Poor repetition.

• Well preserved single-word comprehension and object knowledge.

• Impaired writing with lots of grammatical errors.

• Pathology: tauopathy.

Reference: Harciarek M, Kertesz A, et al; Primary progressive aphasias and their contribution to the contemporary knowledge about the brain-language relationship. Neuropsychol Rev. 2011 Sep;21(3):271-87.

43

PPA – speech output • Semantic dementia – fluent

but circumlocution, frequent asking about meaning.

• Overlapping features are common.

• Logopenic aphasia – slowed speech, frequent pauses, anomia, no grammar problem.

• Progressive non-fluent aphasia – non-fluent, effortful, grammar problems and anomia.


Genetic Risk • 30-50% with positive family history for bv-FTD.

• Lower frequency for PPA.

• Autosomal dominant.

• ~ 50% of the familial cases:

– Microtubule associated protein tau (MAPT) gene (mean age of onset 55 years old).

– Progranulin (PGRN) gene (mean age of onset 60 years old).

Reference: Seelaar H. Rohrer JD. Pijnenburg YA. Fox NC. van Swieten JC, et al; Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review. Journal of Neurology, Neurosurgery & Psychiatry. 82(5):476-86, 2011 May

45

However we can also consider from another angle of view…

46

Temporal &occipital lobe signs and symptoms

• Memory impairment from history.

• Alexia (reading difficulty).

• Agnosia [including color agnosia].

47

Parietal Lobe function

• Agraphia. – Confrontation writing using

common words as stimuli 2/10.

• Finger agnosia. • Constructional apraxia.

• No left-right disorientation. • No neglect. • No acalculia.

48

Frontal lobe signs

• History: verbal and physical aggressiveness. • No primitive reflexes. • No evidence of preservation. • No anosmia.

49

Alzheimer’s disease – atypical presentation

50

Let’s revise features of typical Alzheimer’s Disease

51

Alzheimer’s disease • NINCDS-ADRDA McKhann et al. 1984 • National Institute of Neurological Communicative Disorders and Stroke –

Alzheimer Disease and Related Disorders Association.

• Dementia. • Established by clinical exam. • Documented by MMSE (or similar examination). • Confirmed by other neuropsychological tests. • Deficits in > 2 areas of cognition. • Progressive loss of memory and cognitive functions. • Significant impairment in social or occupational functioning.

52

Alzheimer’s disease • NINCDS-ADRDA McKhann et al. 1984 • National Institute of Neurological Communicative Disorders and Stroke –

Alzheimer Disease and Related Disorders Association.

• No disturbance in consciousness. • Age of onset between 40 and 90. • Absence of systemic disorders or other brain diseases. • Impaired ADLs and altered behavior patterns. • Laboratory tests:

– Progressive atrophy on CT brain/MRI. – Normal LP. – Normal or non-specific slowing on EEG.

53

Clinical Features of Alzheimer’s Disease

Reference: KC Chiu et al; Clinical Features of Alzheimer’s Disease in a regional memory clinic in Hong Kong; J HK Geriatr Soc 2002; 11:21-27

54

Atypical AD

Reference: Alladi S, Xuereb J, Bak T, Nestor P, Knibb J, Patterson K, Hodges JR, et al; Focal cortical presentations of Alzheimer's disease. Brain. 2007 Oct;130(Pt 10):2636-45.

Progressive Aphasia (56%)*

Mimicking Frontotemporal dementia (6%)*

Posterior cortical atrophy (20.6%)*

Mimicking corticobasal degeneration (18%)*

PNFA Logopenic aphasia Semantic dementia

1. Occipitotemporal syndrome

•Alexia (inability to read). •Visual agnosia. •Prosopagnosia (problem with facial perception). 2. Biparietal variants 3. Visual variants

* (%) total number = 34 patients with atypical AD

55

Any ways to differentiate between the two?

56

Two major diagnostic categories

• Frontotemporal dementia

– Primary progressive aphasia (PPA). – Semantic dementia.

• Atypical presentation of Alzheimer’s

disease.

57

Summary of methods

• Structural.

– MRI.

• Functional. – FDG-PET (metabolism). – SPECT (blood flow).

• Pathology.

– PiB PET. – CSF biomarkers.

58

Structural neuroimaging – MRI Brain

59

Our patient: no hippocampal atrophy or left anterior temporal lobe atrophy

60

Asymmetric left temporal lobe atrophy in a patient with semantic dementia

Reference: Hodges JR, Patterson K, et al; Semantic dementia: a unique clinicopathological syndrome; Lancet Neurol. 2007 Nov;6(11):1004-14.

Alzheimer’s disease


Bilateral hippocampal atrophy

TH

HH

CF

Score Width of choroid

fissure (CF)

Width of temporal

horn (TH)

Height of hippocampal

formation (HH)

0 N N N

1 ↑ N N

2 ↑↑ ↑ ↓

3 ↑↑↑ ↑↑ ↓↓↓

4 ↑↑↑ ↑↑↑ ↓↓↓

Scheltens Ph, et al; Journal of Neurology, Neurosurgery and Psychiatry 1992; 55:967-972

61

Functional Imaging – Fluorodeoxyglucose (FDG)

Positron Emission Tomography (PET)

62

FDG-PET brain of our patient

Bilateral hypometabolism over the temporoparietal lobe 63

FDG-PET CT brain of AD patients

• Typical findings:

• Hypometabolism in the posterior cingulate gyrus, parietotemporal cortices and the frontal lobes in advanced disease

Reference: Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, Reiman EM, Holthoff V, Kalbe E, Sorbi S, Diehl-Schmid J, Perneczky R, Clerici F, Caselli R, Beuthien-Baumann B, Kurz A, Minoshima S, de Leon MJ, et al; Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J Nucl Med. 2008 Mar;49(3):390-8.

64

FDG-PET brain of bv-FTD patients

• Patients present with prominent hypometabolism of the frontal and anterior temporal cortices.

Reference: 1. Mosconi Let al; Multicenter standardized 18F-FDG PET diagnosis of mild cognitive impairment, Alzheimer's disease, and other dementias. J

Nucl Med. 2008 Mar;49(3):390-8. 2. Ishii K, et al; Clinical application of positron emission tomography for diagnosis of dementia. Ann Nucl Med. 2002 Dec;16(8):515-25.

65

FDG-PET brain of FTD- SD patient

Reference: Josephs KA, Duffy JR, Fossett TR, Strand EA, Claassen DO, Whitwell JL, Peller PJ, et al; Fluorodeoxyglucose F18 positron emission tomography in progressive apraxia of speech and primary progressive aphasia variants. Arch Neurol. 2010 May;67(5):596-605.

The hypometabolism is localized to the left anteromedial temporal lobe.

66

Pathology Imaging Pittsburgh compound B (PiB)

Positron Emission Tomography (PET)

67

PiB imaging of our patient

68

PiB PET Imaging • PiB = N-methyl[11C]2-(40-

methylaminophenyl)-6-hydroxybenzothiazole.

• Detect amyloid deposition in the brain.

• AD patients: 2-fold higher PIB retention in frontal, parietal and temporal cortices and striatum.

• FTD: absence of PIB retention.

Reference: Engler H, Santillo AF, Wang SX, Lindau M, Savitcheva I, Nordberg A, Lannfelt L, Långström B, Kilander L, et al; In vivo amyloid imaging with PET in frontotemporal dementia. Eur J Nucl Med Mol Imaging. 2008 Jan;35(1):100-6.

69

Cerebrospinal fluid (CSF) biomarkers

70

Basic principles • CSF is in direct contact with the extracellular space of central

nervous system.

• Biochemical changes in the brain can be reliably reflected by corresponding changes in the CSF.

• Biomarkers are associated with the disease (diagnosis, monitoring).

References: 1. Parnetti L, Lanari A, Silvestrelli G, Saggese E, Reboldi P et al. Diagnosing prodromal Alzheimer’s disease: Role of CSF biochemical

markers; Mechanisms of Aging and Development 2006 Feb; 127(2):129-32. 2. Anoop A, Singh PK, Jacob RS, Maji SK, et al; CSF Biomarkers for Alzheimer's Disease Diagnosis. Int J Alzheimers Dis. 2010 Jun

23;2010. 71

Typical CSF findings Alzheimer’s disease Frontotemporal

dementia Beta-amyloid protein

(Aβ-42). • Amyloid plaque..

Reduced levels of Aβ-42. •Reduced clearance of beta-amyloid from brain. •Enhanced aggregation & deposited in the plaque.

Aβ-42 is either normal or reduced.

Phosphorylated-tau (P-tau) e.g. at

threonine-181 • Neurofibrillary tangles.

Increased level of P-tau 181. •Hyperphosphorylation of tau.

Normal P-tau.

Total Tau. • Neuronal death.

Increased level of tau due to neuronal death.

Total tau is normal/ increased/ decreased.

Reference: 1. Anoop A, Singh PK, Jacob RS, Maji SK, et al; CSF Biomarkers for Alzheimer's Disease Diagnosis. Int J Alzheimers Dis. 2010 Jun 23;2010.

2. Reference: Seelaar H, Rohrer JD, Pijnenburg YA, Fox NC, van Swieten JC, et al; Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review; J Neurol Neurosurg Psychiatry. 2011):476-86.

72

Effectiveness in differentiation

• 164 patients. – 60 AD, 15 PCA. – 27 bv-FTD, 19 SD, 26 PNFLA. – 17 psychiatric diagnoses.

• Best biomarker is P-tau/ Aβ-42. • Distinguishing AD from bv-FTD.

– Sensitivity 91.7%, specificity 92.6%.

• Distinguishing AD from SD. – Sensitivity 92.6%, specificity 84.2%.

• Less effective in differentiating AD from PCA and PNFLA.

Reference: de Souza LC, Lamari F, Belliard S, Jardel C, Houillier C, De Paz R, Dubois B, Sarazin M, et al; Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer's disease from other cortical dementias. J Neurol Neurosurg Psychiatry. 2011 Mar;82(3):240-6. 73

Progress of our patient

74

Summary of our patient • M/61 presented with symptoms for 7 years, initially language

impairment followed by memory impairment.

• Differential diagnosis: – Frontotemporal lobar dementia –Semantic dementia – Atypical presentation of Alzheimer’s disease

• Diagnosis of Alzheimer’s disease with atypical presentation

is confirmed by PET-CT brain scan – FDG-PET: functional imaging. – PiB: pathological marker.

75

Summary of our patient

• Patient refused lumbar puncture • CSF Biomarker NOT done

• ApoE E4 status: pending.

• Treatment: – Cholinesterase inhibitor: Rivastigmine patch 4.6 mg/24 hr

daily – Other treatment to be considered later

– Memantine – Vitamin E

76

Biomarkers in the clinical diagnosis of AD

Biomarkers Sensitivity Specificity

MRI –qualitative rating 81% 67%

MRI – quantitative hippocampal volumes*

84-89% 85-90%

SPECT brain scan 63% 93%

FDG PET brain scan 93% 63%

Beta-amyloid (PiB) PET brain scan**

90% 90%

CSF p-tau/Aβ42 ratio 92% 98%

77

*Mak HK, Chu LW. Efficacy of voxel-based morphometry with DARTEL and Standard Registration as imaging biomarkers in Alzheimer's disease patients and cognitively normal older adults at 3.0 Tesla MR imaging. J Alzheimers Dis. 2011;23:655-664. ** Mormino EC et al. 2009

Management of Alzheimer’s disease

78

Management of AD Goal of treatment : Enhance / maintain : • Cognition, • Global function, • Mood /behavior, and • Quality of life (including activities of daily

living (ADL) and caregiver burden).

Notes: using both quantitatative objective measures & qualitative evaluations; ADL=Activity of daily living

79

Drug Treatment Standard Therapy of AD in 2011

• 1st line: Cholinesterase inhibitor • Oral or Transdermal (Patch)

• Add memantine MMSE<15 (& agitation) • +/- vitamin E (unless CVS ds., DM) • CV risk factors • MCI (mild cognitive impairment) – no proven

treatment (practice option) 1.Clinical Practice Guidelines: American Academy of Neurology's Dementia Guidelines (Doody et al, Neurology 2001)

2. Clinical Practice Guidelines: American College of Physicians & Am Coll Family Physicians (Qaseem et al, Ann Int Med 2008)

3. Practice Guideline for treatment of AD. American Psychiatric Association (Rabins et al, 2007) 80

Cholinesterase Inhibitors Enhance cholinergic neurotransmission Delay breakdown of acetylcholine.

Mild to moderate Alzheimer’s disease; severe AD Delay symptoms decline - Cognitive, behaviour and

ADL Mean decline in disease course deferred by 6 months An improvement in cognition and other endpoints

approx. 2-3x placebo response Non-cognitive benefit- increase in attention and

apathy Responders in substantial proportion

modest benefits, ~40% to up to 60% of patients 81

Cholinesterase Inhibitors Adverse effects

• Adverse effects (e.g. GI) approx. 2-3x that in placebo patients – Anorexia, nausea, vomiting, diarrhoea, weight loss, dizziness,

headache, bradycardia – Dose dependent & AE often subside with reduced dosage in most

patients – Transdermal rivastigmine – little GI adverse effects

• Contraindications – uncontrolled asthma, angle-closure glaucoma, sick

sinus syndrome, and left bundle-branch block.

82

Memantine Moderate-severe AD

An uncompetitive N-Methyl D-Aspartate (NMDA) receptor antagonist Block glutamate over- stimulation (excitotoxicity) which may result in neuronal damage (calcium overload)

Memantine (5-20mg/d) for moderate-severe AD e.g. MMSE <15 (particularly w/ agitation or aggression) Less decline in cognitive, functional and global function

(28 weeks) Adverse effect: Not common Dizzy, sedation, fatigue, constipation

83 Reisberg et al, 2003

Vitamin E Treatment for AD

Antioxidant: Vitamin E 800 to 2000 iu/day Vitamin E 2000 iu/day; 2 yrs Rx with selegiline, vitamin

E, both or placebo (Sano M et al 1997) RCT (n=341) moderately severe AD Outcome: (Time to) Death, institutionalization, loss of

ability to perform basic ADL or severe dementia (CDR 3)

Selegiline, Vit E or both (no additive effect) slow or delay the disease progression - better survival

and functional status No benefit on cognition function

Adverse effects - same as placebo 84 •After adjusting for baseline scores: median time to endpoint - vit E 670 days; selegiline 655 days; combined Rx 585 days, vs. Placebo 440 days

Thank you

85

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“Doctor, I can’t read and write my Chinese name!”