Coexisting Lewy body disease and clinical parkinsonism

in amyotrophic lateral sclerosisShelley L. Forrest1,2, Jordan Hanxi Kim2, Clair De Sousa2, Rosie Soos2, Daniel R. Crockford2, Donna Sheedy2, Julia Stevens2, Toni McCrossin2,

Rachel H. Tan3, Heather McCann4, Claire E. Shepherd4, Dominic Rowe5,6, Matthew C. Kiernan3, Glenda M. Halliday3,4,7, Jillian J. Kril2.1Dementia Research Centre, School of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, Australia. 2Discipline of Pathology and Charles Perkins Centre, Faculty of Medicine and Heath, University of Sydney, Australia. 3Brain and

Mind Centre and Central Clinical School, Faculty of Medicine and Health, University of Sydney, Australia. 4Neuroscience Research Australia, Randwick, Australia. 5Department of Clinical Medicine, Faculty of Medicine and Health and Human Sciences, Macquarie University, Sydney,

Australia. 6Centre for MND Research, Department of Biomedical Science, Faculty of Medicine and Health and Human Sciences, Macquarie University, Sydney, Australia. 7School of Medical Sciences, The University of New South Wales, Sydney, Australia.

INTRODUCTIONAmyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of upper and lower motor neurons and

is associated with a range of clinical phenotypes. Pathologically, ALS is characterised by the phosphorylated 43kDa

TAR DNA-binding protein (pTDP-43) in motor and non-motor networks. pTDP-43 inclusions in vulnerable neuronal

and/or glial cell populations in ALS (and other neurodegenerative disorders) spread to interconnected regions as the

disease progresses. In ALS, pTDP-43 aggregates first develop in cortical and sub-cortical motor system regions before

spreading to non-motor cortical and medial temporal lobe regions in later disease stages.

Parkinsonian features have been reported in up to 30% of ALS patients and Lewy bodies, normally associated with

Lewy body disorders (LBD), have been reported in a small number of ALS cases, with unknown clinical relevance.

Based on epidemiological studies the prevalence of Parkinson’s disease (PD) in the general population is 315 per

100,000 people over the age of 40, which increases in prevalence with age affecting 428 and 1087 per 100,000 people

in the 60-69 year and 70-79 year age groups, respectively.

This study investigates the prevalence of clinically relevant LBD in a prospectively studied ALS cohort to

determine if concomitant pathology contributes to the heterogeneity of clinical features.

METHODSAll ALS cases held by the NSW Brain Tissue Resource Centre and Sydney Brain Bank were included in this study (n=99) and,

for comparison, longitudinally followed cases with pathologically confirmed LBD (n=205). ALS cases with coexisting LBD

Braak stage IV pathology, corresponding to clinical parkinsonism, were identified by screening for the presence of neuronal loss

and Lewy body formation in the substantia nigra. pTDP-43 pathology, Lewy bodies and Alzheimer’s disease neuropathologic

change were staged according to standardised criteria. A retrospective review of clinical files was performed for each case with

coexisting LBD to determine age of symptom onset, disease duration, clinical features and whether the presence of a genetic

abnormality was investigated during life. Cases with abnormal GGGGCC hexanucleotide repeat expansions in C9orf72 are

confirmed pathologically by aggregating dipeptide repeat proteins including poly-GA. Any case identified with poly-GA inclusions

in the cerebellar granular neurons and/or molecular layer were screened for a genetic abnormality in C9orf72.

Text Column 1

DEMOGRAPHIC AND CLINICAL FINDINGS

NEUROPATHOLOGICAL FINDINGSAll cases had loss of upper and/or lower motor neurons, and corticospinal tract degeneration.

Comparison of neuropathological features in ALS cases with coexisting LBD to pure ALS cases revealed a similar

morphology and distribution of pTDP-43 inclusions and Lewy bodies. No pTDP-43/a-synuclein co-expression observed.

Sample Text Column 1

ABN 90 952 801 237 | CRICOS Provider 00002J

Patient

1 2 3 4 5 6

Clinical diagnosis

Sex

Age at death (y)

Age at onset (y)

Duration (y)

Family history

Known genetic abnormality

TDP-43 stage

Braak Lewy body stage

Thal Ab phase

Braak NFT stage

CERAD neuritic plaque

ABC score

AD neuropathologic change

MND/SALS

M

82

74

8

No

None

-

IV

0

I

0

A0B1C0

Not AD

MND/SALS

M

81

80

1

No

None

3

IV

4 or 5

III

C

A3B2C3

Intermediate

MND/SALS

M

72

70

2

No

None

3

IV

1 or 2

I

B

A1B1C2

Low AD

MND/SALS

F

64

62

2

No

None

3

IV

0

I

0

A0B1C0

Not AD

MND/PD

M

70

66

4

No

None

3

VI

1 or 2

II

0

A1B1C0

Low AD

MND

M

66

61

5

No

None

2

IV

0

II

0

A0B1C0

Not AD

Patient

1 2 3 4 5 6

Clinical diagnosis

Region affected first

Side affected first

First symptom/s

Extrapyramidal signs

MND/SALS

Unknown

Unknown

Unknown

-

MND/SALS

Lower limb

Unknown

Muscle

weakness and

falls

Parkinsonism

(PD), MSA

MND/SALS

Bulbar

-

Facial droop

and speech

difficulty

-

MND/SALS

Bulbar

-

Dysarthria

-

MND/PD

Lower limb

Left

-

Parkinsonism

(PD)

MND

Lower limb

Right

-

-

AD = Alzheimer’s disease; CERAD = Consortium to Establish a Registry for Alzheimer’s disease; MND = motor neuron disease;

NFT = neurofibrillary tangle; PD = Parkinson’s disease; SALS = sporadic amyotrophic lateral sclerosis.

Demographic and neuropathologic staging in cases with coexisting ALS and LBD.

Clinical features in ALS cases with coexisting LBD.

Case demographics No. of

cases

Age at onset (y),

mean SD (range)

Disease duration (y),

mean SD (range)

M:F

ALS cases with coexisting LBD

ALS

LBD Braak stage IV

6

93

205

69 7 (61 - 80)

65 11 (35 - 85)

64 14 (37 – 87)

4 3 (1 – 8)

3 3 (1 – 17)

13 9 (1 – 47)

5:1

57:36

147:59

MND = motor neuron disease; MSA = multiple system atrophy; PD = Parkinson’s disease; SALS = sporadic ALS.

CONCLUSIONSThe prevalence of clinically relevant LBD in ALS is higher than the general population, which has implications for clinical

and neuropathological diagnoses and the identification of biomarkers. While coexisting LBD comprises a small

proportion of ALS cases, concomitant proteinopathies may underlie the clinical heterogeneity observed in ALS.

Acknowledgements This study was conducted by ForeFront and funded by the National Health and Medical Research Council of Australia (1132524). Sydney

Brain Bank is supported by the NHMRC of Australia, UNSW and NeuRA. NSW Brain Tissue Resource Centre is supported by the National Institute on Alcohol and

Alcoholism of the National Institutes of Health (R28 AA012725) and The University of Sydney.

20 mm50 mm

pTDP43, hypoglossal nucleus (HGN) pTDP43, HGN

20 mm20 mm

a-synuclein, substantia nigraH&E, substantia nigra