Cortical Perfusion Alteration in Normal-Appearing Gray Matter Is Most Sensitive to Disease Progression in Relapsing-Remitting Multiple Sclerosis

S.-P. Hojjat; M. Kincal; R. Vitorino; C.G. Cantrell; A. Feinstein; L. Zhang; L. Lee; P. O'Connor; T.J. Carroll; R.I. Aviv

doi:10.3174/ajnr.A4737

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Fig 1.
Block diagram representation of the image acquisition and processing pipeline. PSIR indicates phase-sensitive inversion recovery; PD, proton density.
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Fig 2.
Representative section of T1 and perfusion images in perfusion space for the different study groups with overlays of the investigated ROIs.
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Fig 3.
Distribution of the absolute perfusion cortical lesion results in the construction of 4 different populations: Standard CL (neither CBF nor CBV outliers), CBF outliers, CBV outliers, and CBV-CBF outliers (CBV outliers that are also CBF outliers). Absolute values of cerebral blood flow and cerebral blood volume are reported on the x-axis and y-axis, respectively. Each RRMS-NI lesion (A) is represented by a circle, and RRMS-I lesion (B) is represented by a triangle.
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Fig 4.
Distribution of the absolute perfusion white matter lesion results in the construction of 4 different populations by using the interquartile range method: Standard WML (neither CBF nor CBV outliers), CBF outliers, CBV outliers, and CBV-CBF outliers (CBV outliers that are also CBF outliers). Absolute values of cerebral blood flow and cerebral blood volume are reported on the x-axis and y-axis, respectively. Each RRMS-NI lesion (A) is represented by circle, and RRMS-I lesion (B) is represented by a triangle.

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Table 1:

Participant demographic data, neurocognitive scores, and fractional brain volume^{^a}

	HC (n = 19)	RRMS-NI (n = 19)	RRMS-I (n = 20)
Demographics
Age (yr)	49.0 ± 7.1	46.4 ± 7.2	48.1 ± 4.7
Female sex (No.) (%)	14 (73.68)	15 (78.95)	12 (60)
Education (yr)	16.9 ± 2.9^{^b}	16.1 ± 1.3	14.6 ± 1.9^{^b}
Disease duration (yr)	0.0 ± 0.0	11.8 ± 5.4	11.6 ± 4.9
HADS-A (log) (median) (IQR)	3 (1–6)^{^b,^c}	6 (5–7)^{^c}	8 (7–10)^{^b}
HADS-D (log) (median) (IQR)	2 (1–3)^{^b}	3 (1,5)^{^d}	8 (6–10)^{^b,^d}
EDSS median (IQR)	NA	1.5 (1–2)^{^d}	2.5 (2–3)^{^d}
Percentage fractional brain volume
BPF	79 ± 9^{^b}	75 ± 6	72 ± 8^{^b}
fC	45.15 ± 5.12	43.43 ± 3.91	41.87 ± 5.50
fWM	31.66 ± 4.07^{^b}	29.61 ± 2.83	28.35 ± 3.5^{^b}
fCL	0.00 ± 0.00^{^b}	0.01 ± 0.01	0.01 ± 0.02^{^b}
fBG	1.35 ± 0.19	1.31 ± 0.18	1.25 ± 0.22
fTh	0.68 ± 0.12^{^b}	0.64 ± 0.14	0.55 ± 0.14^{^b}
fWML	0.00 ± 0.00^{^b}	0.67 ± 0.74	0.92 ± 0.90^{^b}
fT1 hole	0.00 ± 0.00^{^b}	0.23 ± 0.22	0.410 ± 0.506^{^b}
fCSF	21.16 ± 8.78^{^b}	24.10 ± 6.24	26.64 ± 7.32^{^b}

Note:—HADS indicates Hospital Anxiety [A] and Depression [D] Scale; EDSS, Extended Disability Status Scale; BPF, brain parenchymal fraction; fC, fractional cortical volume; fWM, fractional white matter volume; fCL, fractional cortical lesions volume; fBG, fractional basal ganglia volume; fTh, fractional thalamus volume; fWML, fractional white matter lesions volume; fTI hole, fractional T1 hole volume; fCSF, fractional CSF volume; HC, healthy controls; NA, not applicable; IQR, interquartile range.
↵a All values are means unless otherwise specified. Significant P value < .017.
↵b HC vs RRMS-I.
↵c HC vs RRMS-NI.
↵d RRMS-NI vs RRMS-I.

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Table 2:

Comparison of perfusion parameters between study groups^{^a}

	HC (n = 19)		RRMS-NI (n = 19)				RRMS-I (n = 20)
	WM	GM	WML	NAWM	CL	NAGM	WML	NAWM	CL	NAGM
CBF	21.8^{^b}	44.0^{^f}	14.4^{^d,^e}	21.5^{^d,^e}	21.4^{^c}	41.1^{^c,^d,^f}	12.5^{^d,^e}	17.0^{^b,^d,^e}	23.1^{^c}	31.7^{^c,^d,^f}
(mL/100 g per min)	(19.7–28.4)	(37.9–49.5)	(9.9–20.2)	(16.0–29.5)	(15.7–32.3)	(29.8–55.7)	(8.1–18.5)	(13.2–25.2)	(15.4–34.3)	(24.6–44.5)
CBV	1.5^{^b}	2.8^{^f}	1.1^{^d,^e}	1.6^{^d,^e}	1.4^{^c}	2.5^{^c,^d}	1.0^{^d,^e}	1.3^{^b,^d.^e}	1.7^{^c}	2.1^{^c,^d,^f}
(mL/100 g)	(1.2–1.9)	(2.1–3.2)	(0.8–1.6)	(1.2–2.1)	(1.1–2.0)	(1.9–3.4)	(0.7–1.4)	(1.0–1.7)	(1.2–2.4)	(1.7–2.7)
MTT	4.3^{^b}	3.8^{^f}	4.8^{^e}	4.6^{^e}	4.3	3.9^{^d,^f}	5.0^{^e}	4.8^{^b,^e}	4.6^{^c}	4.0^{^c,^d,^f}
(min)	(3.9–5.0)	(3.4–4.3)	(4.1–5.9)	(4.1–5.2)	(3.5–4.9)	(3.3–4.4)	(4.2–6.0)	(4.3–5.2)	(3.9–5.4)	(3.5–4.6)

Note:—HC indicates healthy controls.
↵a Normal-appearing GM and WM tissues are compared across patients with RRMS who were cognitively unimpaired and impaired and with healthy controls with corrected P < .017 (ie, .05/3) identified as significantly different. Lesion perfusion was also independently compared across disease groups and with the corresponding normal-appearing tissue within each patient group with P < .05 identified as significantly different. The values represent medians; the interquartile range for values are giving in parentheses.
↵b HC WM vs NAWM.
↵c CL vs NAGM.
↵d RRMS-NI vs RRMS-I.
↵e WML vs NAWM.
↵f HC GM vs NAGM.