Myelin imaging in amyotrophic and primary lateral sclerosis

Figures & data

Table I. Clinical features and functional scores of the study participants.

Diagnosis	Age at scan	Sex	Symptom onset	Duration (months)	MRI interval (months)	ALSFRS-R baseline, follow-up		UMN score baseline, follow-up		Baseline rate of progression	TMT B – A (seconds	ACE (max 100)	Verbal fluency (max 7)
													Letter	Category
ALS01	65	M	BO	30	7.4	43	43	13	11	0.17	41	98	6	7
ALS02	67	M	RUL	70	5.7	35	35	3	3	0.19	–	96	4	7
ALS03	70	M	RUL	46	7.8	27	27	6	5	0.46	–	90	4	7
ALS04	61	M	LLL	34	8.0	28	21	7	3	0.59	50	91	6	6
ALS06	67	F	BO	63	6.3	33	–	13	–	0.24	9	–	–	–
ALS07	77	M	BO	57	6.5	27	26	10	10	0.37	73	73	–	–
ALS08	64	M	LLL	88	6.7	28	28	1	1	0.23	68	87	6	4
ALS09	55	F	RLL	50	–	23	–	9	–	0.49	31	95	5	7
ALS11	49	F	RUL	80	6.0	29	29	5	5	0.24	–	97	5	7
ALS12	41	M	LUL	41	6.9	26	23	15	15	0.54	27	99	6	7
ALS13	69	M	LUL	33	5.3	39	34	4	4	0.27	29	93	5	6
ALS14	48	F	RLL	135	9.7	30	30	10	10	0.13	41	92	5	6
ALS15	61	M	RUL	141	–	23	–	1	–	0.18	–	93	6	7
ALS16	56	F	LLs	65	7.4	27	24	3	3	0.32	–	99	7	7
ALS18	46	F	RLL	21	7.3	32	18	12	12	0.77	10	97	6	7
ALS19	56	F	LLL	98	7.9	31	30	3	4	0.17	21	100	7	7
ALS20	49	M	LLL	28	6.2	35	31	15	15	0.46	–	–	5	5
ALS21	76	M	RLL	14	6.0	34	28	7	11	1.00	63	85	5	6
ALS22	76	M	Trunk	61	–	43	–	3	–	0.08	54	98	6	6
ALS24	55	M	RLL	15	–	42	–	12	–	0.41	23	97	6	7
ALS25	75	M	LLL	81	–	35	–	13	–	0.16	46	76	6	5
ALS26	52	F	RLL	20	–	38	–	11	–	0.51	19	93	4	6
ALS27	64	F	RUL	8	–	18	–	14	–	3.94	–	–	–	–
ALS mean (SD)	61 (11)	9F:14M		56 (36)	7 (1)	32 (7)	28 (6)	8 (5)	8 (5)	0.52 (0.78)	38 (20)	92 (7)	5 (1)	6 (1)
PLS01	63	F	LLL	92	7.3	32	27	15	15	0.17	30	98	6	7
PLS02	45	F	LLs	180	–	35	–	15	–	0.07	27	77	5	6
PLS03	77	F	LLs	62	7.2	34	32	10	10	0.22	70	96	7	5
PLS04	77	F	BO	155	–	30	–	15	–	0.12	18	92	5	5
PLS05	64	M	RLL	184	6.3	20	18	15	15	0.15	–	98	–	–
PLS06	70	M	RLL	366	7.4	29	27	13	15	0.05	45	94	5	5
PLS07	65	F	LLL	260	–	28	–	15	–	0.08	42	–	4	3
PLS mean (SD)	66 (11)	5F:2M		186 (103)	7 (1)	30 (5)	26 (14)	14 (2)	14 (8)	0.12 (0.06)	39 (18)	93 (8)	5 (1)	5 (1)
Control	66	M	–	–	–	–	–	–	–	–	24	100	7	7
Control	38	F	–	–	–	–	–	–	–	–	23	93	7	7
Control	46	M	–	–	–	–	–	–	–	–	36	97	7	7
Control	68	F	–	–	–	–	–	–	–	–	14	99	7	7
Control	38	F	–	–	–	–	–	–	–	–	15	98	5	7
Control	56	F	–	–	–	–	–	–	–	–	12	100	7	7
Control	46	M	–	–	–	–	–	–	–	–	20	99	7	7
Control	65	F	–	–	–	–	–	–	–	–	17	98	5	7
Control	66	M	–	–	–	–	–	–	–	–	23	100	7	7
Control	72	M	–	–	–	–	–	–	–	–	16	99	7	7
Control	45	F	–	–	–	–	–	–	–	–	10	98	7	7
Control	64	F	–	–	–	–	–	–	–	–	19	99	7	7
Control mean (SD)	56 (12)	7F:5M									19 (7)	98 (2)	7 (1)	7 (0)

ACE: Addenbrookes Cognitive Examination; BO: bulbar onset; LUL: left upper limb; LLL: left lower limb; LLs: bilateral lower limb onset; RUL: right upper limb; RLL: right lower limb; TMT: Trail-Making Test; UMN: upper motor neuron. Bold type: p < 0.05.

Figure 1. Reductions in MWF for PLS patients compared to healthy controls (A, significant reductions in orange with trends in blue), and PLS patients compared to ALS patients (B, significant reductions in red with trends in dark blue). Increases in IE-water T2 for PLS patients compared to healthy controls (C, non-significant trends in light blue) and ALS patients compared to healthy controls (D, significant increases in red-yellow with trends in green). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Table II. Spearman rank correlation coefficient and p-values for correlations between clinical measures and mcDESPOT MWF (top) and IE-water T2 (bottom) across the entire TBSS skeleton.

	ALSFRS-R		Disease duration		Progression rate		ACE		TMT		Letter fluency		Category fluency
	R	p	R	p	R	p	R	p	R	p	R	p	R	p
MWF
ALS	−0.39	0.06	0.06	0.73	0.15	0.50	0.54	0.01	−0.49	0.05	0.22	0.36	0.40	0.09
PLS	0.00	1.00	0.21	0.64	−0.32	0.48	−0.40	0.50	−0.49	0.33	−0.62	0.27	0.30	0.62
Combined	−0.26	0.17	−0.12	0.55	0.24	0.20	0.42	0.04	−0.49	0.02	0.13	0.56	0.48	0.02
IE-water T2
ALS	0.17	0.44	−0.04	0.85	−0.14	0.51	−0.65	0.002	0.66	0.005	−0.21	0.38	−0.65	0.003
PLS	−0.11	0.82	0.00	1.00	0.11	0.82	0.40	0.50	0.43	0.40	0.41	0.49	−0.10	0.87
Combined	0.09	0.64	0.05	0.80	−0.15	0.43	−0.52	0.008	0.57	0.005	−0.12	0.57	−0.65	0.0006

ACE: Addenbrookes Cognitive Examination; TMT: Trail-Making Test.

Figure 2. Regional white matter tract correlations, notably including the anterior corpus callosum and frontal projections, between lower ACE scores and reduced MWF in ALS patients (A), and increased IE-water T2 in ALS patients (B). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Figure 3. Regional white matter tract correlations, notably including anterior corpus callosum and frontal projections, between higher TMT B-A scores (reflecting dysexecutive function) and reduced MWF in the ALS group (A), in the ALS and PLS patients combined (B); IE-water T2 increases in ALS patients (C) and IE-water T2 increases in the combined group (D). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Figure 4. Regional white matter tract correlations, with a notable involvement of frontal lobe projections, between reduced category fluency and decreased MWF in ALS patients (A), decreased MWF in all patients (B), increased IE-water T2 in ALS patients only (C), and increased IE-water T2 in all patients (D). All p-values corrected for multiple comparisons. Images displayed by radiological convention.

Table III. Features that support PLS as a distinct pathological entity to ALS.

Characteristic
Clinical features
Extreme length of survival from symptom onset
UMN-only involvement
Exclusively leg or bulbar-onset
No consistent FTD overlap
Genetics
Single familial pedigree (54), without ALS-like cases
Not described in most familial ALS pedigrees
Neuropathology
Profound atrophy of motor cortex with marked Betz cell loss

Table IV. Neuropathological studies in PLS.

n	Phenotype caveats	Main findings	Ref
8		Noted sub-clinical LMN involvement in 6/8	(55)
1	‘ALS’ long-survivor (12 years)	Upper CST, CC, and extra-motor tract degeneration with myelin pallor in ALS; long-survivor, presumed PLS, case showed no spinal cord changes	(56)
1		Profound PMC atrophy with marked Betz cell loss; loss of myelin throughout cerebral CST	(24)
3		Loss of myelin noted particularly in the PLIC	(32)
1		Changes limited to PMC, with profound loss of Betz cells	(4)
1	Less than 4 years from symptom onset	Myelin pallor throughout cerebral pyramidal tracts	(57)
1	Prominent cognitive involvement	Marked degeneration of frontal and temporal lobe tracts in addition to CST	(41–43)
1	Prominent cognitive involvement	Ubiquitin + ve skeins and Bunina bodies	(58)
2		TDP-43 + ve cytoplasmic inclusions in hypoglossal nuclei and glia of one of the cases	(59)

CC: corpus callosum; CST: corticospinal tract; FTD: frontotemporal dementia; LMN: lower motor neuron; PMC: primary motor cortex; UMN: upper motor neuron; PLIC: posterior limb of internal capsule.

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