Table 1. topology of GM pathology in MS.

Study	Studied numbers and MS type	Method	Affected GM region	Main findings
Bö et al.5	5 SPMS 1 PPMS	immunohistochemistry	Frontal cortex Parieto-occipital cortex	The presence, distribution and extent of WM changes were independent of the extent of GM pathology
Bö et al.7	10 SPMS 7 PPMS 3 RRMS, 7 NC	immunohistochemistry	Cingulate gyrus Superior frontal gyrus Paracentral lobule Superior temporal gyrus	Demyelination more pronounced in cerebral cortex (especially cingulate gyrus) than in WM
Gilmore et al.12	36 MS 12 NC	immunohistochemistry	Spinal cord: upper cervical, lower cervical, upper thoracic and lower thoracic and lumber levels.	The proportion of GM demyelination was larger than WM demyelination at each of the five spinal cord levels
Gilmore et al.13	11 SPMS 2 PPMS 1 RRMS 3 NC	immunohistochemistry	Motor cortex Cingulate gyrus Cerebellum Thalamus Cervical level spinal cord Thoracic level spinal cord Lumbar level spinal cord	GM demyelination most extensive in spinal cord and cerebellum, while WM demyelination was most prominent in the spinal cord
Kutzelnigg et al.9	11 AMS 6 RRMS 15 PPMS 20 SPMS 15 AD	immunohistochemistry	Cerebral GM and WM	Active, focal, inflammatory lesions in the WM in patients with acute MS and RRMS, while diffuse abnormalities (with active microglia) in the WM and GM lesions were more typical in SPMS and PPMS
Kutzelnigg et al.16	5 AMS 3 RRMS 19 SPMS 10 PPMS 3 chronic MS 8 NC 34 hypoxia patients	immunohistochemistry	Cerebellum	Extensive cerebellar demyelination in particularly SPMS and PPMS patients. GM demyelination in cerebellum was similar to or even exceeding demyelination in the cerebral GM.
Huitinga et al.14	15 SPMS 2 PPMS 14 NC	immunohistochemistry	hypothalamus	Significant number of lesions in hypothalamus and adjacent structures. Both active and chronic active lesions were found in WM. Signs of demyelination in paraventricular nuclei and supraoptic nuclei
Geurts et al.11	9 SPMS 7 PPMS 1 RRMS 1 chronic MS 6 NC	immunohistochemistry	Hippocampus	High number of lesions, both mixed intrahippocampal-perihippocampal lesions and isolated intrahippocampal lesions
Papadopoulos et al.17	38 SPMS 7 PPMS 7 NC	immunohistochemistry	Hippocampus	Average demyelination 30.4%. Lesions were often chronic and subpially or subependymally located. Gross hippocampal atrophy, neuronal shrinkage and synaptic, axonal, and neuronal loss
Dutta et al.10		Immunohistochemistry, microarray assay and western blots	Hippocampus Motor cortex	Demyelinated hippocampi had minimal neuronal loss but significant decreases in synaptic density and neuronal proteins essential for axonal transport, synaptic plasticity, glutamate neurotransmission, glutamate homeostasis and memory/learning
Vercellino et al.19	3 RRMS 3 SPMS 6 NC	immunohistochemistry	Cingulate gyrus Temporal lobe Insula Frontal cortex	Great variation in extent of GM demyelination between patients and brain regions. Cingulate gyrus most affected. Neuronal loss and signs of apoptosis in GM lesions of patients with prominent GM demyelination
Vercellino et al.21	1 AMS 6 RRMS 7 SPMS 6 ALS 6 NC	immunohistochemistry	Thalamus Caudate Putamen Pallidum Claustrum Amygdala Hypothalamus Substantia nigra Mammilary bodies Globus pallidus	GM lesions most often seen in thalamus and caudate, but were also present in putamen, pallidum, claustrum, amygdale, hypothalamus and substantia nigra. Most lesion were mixed GM/WM lesions and had sometimes immune cell infiltrates. Neuronal loss and atrophy seen in GM lesions and in myelinated gray matter.
Peterson et al.18	50 MS 7 NC	immunohistochemistry	Cerebral cortex and white matter	Cortical demyelination involving neurite transection, neuronal death by apoptosis and reduced inflammation compared with WM lesions
Wegner et al.20	22 MS 17 NC	immunohistochemistry	Superior frontal gyrus precentral gyrus postcentral gyrus middle frontal gyrus superior temporal gyrus middle temporal gyrus	Neocortical thinning of 10% in MS independent of GM lesions. Type I lesions show significant glial, neuronal and synaptic loss
Kooi et al.15	7 SPMS 4 PPMS 3 ND MS 10 AD	immunohistochemistry	Hippocampus	An unaltered activity and protein expression of acetylcholinesterase, but a decrease of activity and protein expression of acetylcholintransferase in MS
Schmierer et al.73	21 MS	MRI/immunohistochemistry	Cerebral cortex and white matter	36 GM lesions detected (16 type I, 0 type II, 18 type III, 2 type IV). Twenty-eight GM lesions were visible on 9.4 Tesla T2 weighted MRI (15 type I, 11 type III and 2 type IV).
Geurts et al.44	5 SPMS 2 PPMS 2 ND MS	MRI/immunohistochemistry	Cerebral cortex and white matter	A total of 98 GM lesions were found (27 type I, 12 type II, 41 type III, 10 type IV, 8 deep GM) and 70 WM lesions. T2SE MRI images only depicted 3% of the intracortical lesion, while the 3D FLAIR images showed 5%.

AMS, acute MS or Marburg’s type of MS; SPMS, secondary progressive MS; PPMS, primary progressive MS; chronic MS, SPMS or PPMS; ND, MS subtype not determined; ALS, amyotrophic lateral sclerosis; AD, Alzheimer disease NC, non-neurological control.