Chiadi U. Onyike, MD, MHS Johns Hopkins Neuropsychiatry

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Disclosure:  PI, Baltimore site of multicenter trial of memantine for

behavioral frontotemporal dementia

▪ Results published: The Lancet Neurology, 12(2), 149–156.

 PI, Baltimore site of multicenter trial of LMTM for

behavioral frontotemporal dementia

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Content:  Spectrum of non-Alzheimer neurodegenerative diseases  Their features  Their management

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A teacher of 58 developed dysnomia and decline in spelling ability, comprehension of reading and conversation, and singing ability. Attention, planning/organization and self care were impaired, and he exhibited child-like behavior and loss of etiquette (eating some meals with his fingers). He developed anxiety. Two years into the illness, a neurologist suspected dementia. MMSE score was 27 points and the neurological exam was normal. Brain MRI showed temporal lobe atrophy.

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Neuropsychological testing 3 years later showed MMSE = 28, and impaired memory and learning, marked dysnomia, and poor word knowledge with paraphasias and regularization spelling errors. Behavior was impulsive and obstinate. Eating was gluttonous. A year later MMSE = 29. Further decline in word and object knowledge was noted…

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High prevalence  682 with MCI (n=138) or

dementia (n=270)

 43% of MCI ▪ 20% depression ▪ 15% apathy ▪ 15% irritability  75% of dementia patients ▪ 35% apathy ▪ 32% depression ▪ 30% agitation/aggression

Incidence N (%), N = 61

Mean severity score (SD)

Delusions

17 (27.9)

4.1 (3.6)

Apathy

13 (21.3)

5.6 (3.6)

Aberrant motor behavior

13 (21.3)

3.7 (2.5)

Irritability

12 (19.7)

3.8 (4.0)

Depression

11 (18.0)

4.7 (3.2)

Hallucinations

10 (16.4)

2.9 (1.3)

Agitation/aggression

10 (16.4)

6.4 (3.8)

Anxiety

9 (14.8)

3.6 (2.6)

Disinhibition

6 (9.8)

2.0 (0.9)

Elation

0 (0)

N/A

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Is it “memory loss”?

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Is it just cognition?

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What about?  Depression/anxiety  Paranoia and delusions  Hallucinations  Abnormalities of judgment

and social conduct  Compulsions

Alzheimer disease, AD

Most common cause

Cerebrovascular disease, CVD

Genetic varieties particularly

Frontotemporal degeneration, FTD

1:1 or greater ratio FTD:AD below age 50

Lewy body disease

Uncommon before age 65

Traumatic brain injury, TBI HIV/AIDS dementia

Prevalence decreased since HAART

Alcohol-related dementia

Controversial; due to nutritional deficiency?

Huntington disease, HD

Among the commonest below age 35

Prion dementias, e.g., CJD

Fulminant progression

Multiple sclerosis, MS Normal Pressure Hydrocephalus

Left: The Prague Asylum, with a view of the tower of St. Catharine Monastery. Right: Arnold Pick (1851-1924); Professor of Psychiatry and Neuropathology and Chair of Neuropsychiatry in Prague (1887-1921). He described the presenile focal dementias and aphasias that would became known as ‘Pick’s disease’.

Source: Kertesz and Kavlach, 1996

Historical timeline

Definition

1896 – case study: primary aphasia 1911 – “Pick” bodies 1923/26 – “Picks disease” 1974/75 – Types A, B and C 1975 – Semantic aphasia 1982 – Primary progressive aphasia 1986 – 1st conference, Lund, Sweden 1994 & 98 – Lund-Manchester criteria 1998 – 1st genetic locus (MAPT) 2006 & 09 – TDP43 & FUS discovery 2011 – International criteria 2011 – 7th genetic locus (C9orf72)

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“It’s hallmarks are progressive decline in [conduct]: coarsening of temperament, dispositions, judgment, and comportment; dysregulation of emotions, drives and selfcontrol; and disintegration of language and communication… Aphasia syndromes and motor syndromes are also well recognized” Onyike et al., 2011

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Insidious deterioration

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Behavioral disinhibition and asocial behavior

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Inertia and apathy

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Loss of empathy/sympathy

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Perseveration, stereotypies and compulsions

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Hyperorality, hyperphagia and/or stereotyped eating habits

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Executive dysfunction

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Focal abnormality on brain imaging

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Causal mutation

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Peak age of onset 53 – 58; range 21 – 75…

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Prevalence: 18 – 38 per 100,000

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Incidence: 3 – 4 per 100,000

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Life expectancy: 8 –10 years; ~3 years for FTD-ALS

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M>>F in most reports

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AD:FTD ratio 40%; hereditary in 10-20%

Phenotypic heterogeneity reflects biologic heterogeneity 

Syndrome to disease (phenotype:pathology) correlation is imperfect

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Syndrome to genotype correlation is also imperfect

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Syndromes not shown include affective and psychotic presentations

Gender

Onset

Clinic

Case 1

F

21

22

Case 2

M

28

Case 3

M

Case 4

Death

Features

FamHx

Tau

Ubiq

TDP43

Diagnosis

25

DEP, COGIMP

None

+

-

N

FTD17

33

37

SCHIZ

None

-

+

+

FTD-MND

?

37

46

APATH/DISIN

?

-

-

?

DLDH

M

34

39

41

BIPOLAR

None

-

+

N

FTD-U

Case 5

M

35

39

43

SCHIZ

None

-

+

+

FTD-MND

Case 6

M

37

40

44

DEP/APATH

YOD

-

+

+

FTD-U (PGRN)

Case 7

M

38

43

45

SCHIZ

FTD-MND

-

+

?

FTD-ID

Case 8

M

45

46

49

APATH

FTD17

+

+

FTD17

Case 9

M

43

49

61

COGIMP

None

-

+

+

FTD-ID

Case 10

F

?

50

63

COGIMP

YOD

+

-

N

FTD17

Case 11

M

45

50

63

COGIMP/APATH

MND*

-

+

?

FTD-U

Case 12

M

?

51

62

COGIMP

FTD17

+

-

N

FTD17

Case 13

F

50

53

64

COGIMP

LOD

-

+

?

FTD-U

Case 14

F

49

55

66

COGIMP

None

-

+

+

FTD-ID

Case 15

M

56

57

59

COGIMP/PSP

AD

+

-

N

PSP

Case 16

M

58

59

60

DISIN/COGIMP

None

-

+

+

FTD-ID

Case 17

F

59

62

65

COGIMP

None

-

+

+

FTD-MND

Implications for clinical syndromes “I wish it would dawn upon engineers that, in order to be an engineer, it is not enough to be an engineer” Jose Ortega y Gasset (Toward a Philosophy of History, 1941)

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Different clinical syndromes may represent the same disease state

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Memory is not necessarily a central characteristic of dementia

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Thus arise questions about:  Dementia definitions  How clinical phenomena relate to

diseases  Traditional professional boundaries (i.e., cognitive vs. behavioral; “organic” vs. “non-organic”)

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History:

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Cognitive state

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Unusual age at onset

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Predominance of abnormal speech

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Puzzling “atypical” features

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Unusually pronounced loss of skills

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Family history of dementia,

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Visual complaints (other than

parkinsonism, motor disorder

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Unusual prodrome, e.g., sleep problem

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Rapid progression

hallucinations)

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Motor examination 

Abnormal posture and movement

Mental state:



Frequent falls at early stage

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Poor insight

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Frequent jerking

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Apathy/indifference

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Progressive motor weakness

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Compulsions without obsessions

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Poor coordination

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Early hallucinations and/or paranoia

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Left-right asymmetry

Disease/disorder

Phenotype

Onset

Features

AD

Apathy, depression, anxiety, amnesia, dysexecutive

65+

 cognition; global atrophy; diffuse EEG slowing

FTD

 conduct, impulsive, dysexecutive, aphasia

45+

 cognition; focal EEG slowing; focal atrophy

Vascular dementia

Dysexecutive, affective disorder, psychomotor slowing, CVD

>60

 cognition; neurological signs; infarcts and gliosis on MRI

DLB

Hallucinations, paranoia, amnesia, parkinsonism

>70

 cognition; global atrophy; diffuse EEG slowing

Major depression

Intermittent depression with apathy and anhedonia