Table 3.

Selection of original neuroimaging research articles in PMA, SMA, SBMA, PPS, and HSP.

References	Study design	Sample size Study participants	Raw imaging data/imaging technique	Assessment tools	Follow-up (months)	Key study findings
Progressive muscular atrophy
Agosta et al. (1)	Cross-sectional, Prospective, Multi-center, Case-control	ALS n = 56 UMN phenotype n = 31 LMN phenotype n = 14	MRI Cortical thickness DTI	ALSFRS-R MMSE RCPM CET WCST WCFST RAVLT BADA HDRS FBI ALS-FTD questionnaire Phonemic and semantic fluency test Digit span forwards and backwards	N/A	- 36% LMN phenotype had cognitive impairment - Cortical thinning of bilateral precentral gyrus, insular and cingulate cortices, and frontotemporal regions. - WM degeneration detected in the corpus callosum and frontotemporal tracts, including the uncinate, cingulum, and superior longitudinal fasciculi. - These findings were associated with cognitive or behavioral symptoms, especially WM changes.
Basaia et al. (4)	Cross-sectional, Prospective, Multi-center, Case-control	ALS n = 173 PLS n = 38 PMA n = 28	MRI DTI Resting-state fMRI Global brain network analysis Functional connectivity analysis	MMSE RAVLT Digit span forward and backward Stroop test CET WCFST WCST RCPM Phonemic and semantic fluency Italian battery for the assessment of aphasic disorders. HDRS Beck depression inventory FBI ALS-FTD Questionnaire	N/A	- In PMA, structural and functional connectomes were preserved.
Kew et al. (45)	Cross-sectional, Prospective, Single-center, Case-control	ALS n = 6 LMN phenotype n = 5	Resting-state PET Task-based PET - Motor task: moving joystick with right hand	N/A	N/A	- There was no difference in regional cerebral blood flow between LMN phenotype and controls at rest. - During motor task, there was increased activation of perisylvian areas in both ALS and LMN.
Mitsumoto et al. (35)	Longitudinal, Prospective, Single-center, Case-control	PMA n = 9 PLS n = 6 ALS n = 49	MRI DTI MRS	ALSFRS-R Finger and foot tapping Motor unit number estimation Transcranial magnetic stimulation	Every 3-months for 15-months	- In PMA, there was modest reduction in NAA/tCr ratio in the primary motor cortex.
Quinn et al. (46)	Cross-sectional, Prospective, Single-center	ALS n = 20 PMA n = 5	MRS	ALSFRS MMSE Letter-fluency index	N/A	- In PMA, there was greater NAA/Cr in the dorsolateral prefrontal cortex compared to ALS.
Raaphorst et al. (47)	Cross-sectional, Prospective, Multi-center, Case-control	ALS n = 21 PMA n = 18	Task-based fMRI - Letter fluency - Category fluency	ALSFRS-R UMN score HADS Dutch national adult reading test MMSE Digit span forwards and backwards WAIS-R letter-number sequencing Modified WCST Category and letter fluency Stroop test RAVLT Rivermead behavioral memory test Doors test Boston naming test Judgment of line orientation test Differential aptitude test Mental rotation task	N/A	- There was impaired letter fluency in PMA and ALS. - The letter fluency task showed lower activation in the inferior frontal gyrus in PMA and ALS. - No differences detected during category fluency.
Van der Graaff et al. (41)	Longitudinal, Prospective, Multi-center, Case-control	PMA n = 12 PLS n = 12 ALS n = 24	MRS	ALSFRS-R Finger and foot tapping speed	6-months	- In PMA, there was no difference in N-acetylaspartate, N-acetyl aspartylglutamate levels in the primary motor cortex at baseline. There was a significant decrease in these levels at follow-up.
Van der Graff et al. (42)	Longitudinal Prospective, Multi-center, Case-control	PMA n-12 ALS n = 12 PLS n = 12	MRI Whole brain voxel-based analysis DTI	ALSFRS-R Finger-tapping speed Vital capacity	6-months	- In PMA, there was FA reduction in extra-motor WM inferior frontal gyrus, dorsolateral prefrontal cortex, corpus callosum, hippocampus, and fornix. - DTI abnormalities were modest compared to PLS.
Spinal muscular atrophy
De Borba et al. (48)	Cross-sectional, Prospective, Single-center, Case-control	SMA type III (n = 19) SMA type IV (n = 6)	MRI Cortical thickness GM volumetry	MRC muscle strength evaluation SMAFRS	N/A	The volume of cerebellar lobules VIIIB, IX and X were significantly smaller in patients with SMA.
Mendonça et al. (49)	Longitudinal, Prospective, Single-center	SMA type 0 (n = 3)	Qualitative MRI	N/A	1-3 years	Mild progressive global brain atrophy, predominantly WM and supratentorial structures with relative preservation of the cerebellum.
Querin et al. (50)	Cross-sectional, Prospective, Single-center, Case-control	SMA type III (n = 19) SMA type IV (n = 6)	MRI Cortical thickness DTI ROI analysis	MRC muscle strength evaluation	N/A	There was increased GM density in primary motor cortex. No white matter pathology was identified.
Spinal and bulbar muscular atrophy (Kennedy's disease)
Garaci et al. (51)	Cross-sectional, Prospective, Single-center	SBMA n = 8	MRI DTI TBSS	ALSFRS	N/A	- Loss of WM integrity, including frontal region, that correlated with disability and disease duration.
Karitzky et al. (52)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 9	MRS	N/A	N/A	- Reduced NA/Cho ratio in the brainstem and reduced NA/Cho and NAA/Cr ration in the motor regions. This did not correlate with number of CAG repeats.
Kassubek et al. (53)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 18	MRI VBM	MRC muscle strength evaluation	N/A	- Subtle decreases in GM volume and extensive WM atrophy, most pronounced in the frontal areas.
Lai et al. (54)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 10	[18]F-FDG PET	N/A	N/A	- Frontal glucose hypometabolism was detected.
Mader et al. (55)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 10	MRS	N/A	N/A	- There was increased myo-inositol and macromolecular detected in the motor area. - The NAA/Cr ratio correlated with number of CAG repeats.
Pieper et al. (56)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 8	MRI VBM DTI	N/A	N/A	- Subtle changes in central WM tract integrity. - The GM and WM volume was unaffected.
Unrath et al. (40)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 20 HSP n = 24 PLS n = 25	MRI DTI	N/A	N/A	- In SBMA, extra-motor WM alterations detected within the limbic system or its network including precuneus, temporal lobe, and left inferior frontal lobe.
Post-Polio syndrome
Bruno et al. (57)	Cross-sectional, Prospective, Single-center	PPS n = 22		Self-reported severity of daily fatigue and subjective problems with attention, cognition and memory	N/A	- Small discrete hyperintense signal in reticular formation, putamen, medial leminiscus or WM tracts identified in 55% of those with high levels of fatigue and in none of those with low levels of fatigue.
Demir et al. (58)	Cross-sectional, Retrospective, Single-center	PPS n = 11	Qualitative MRI	N/A	N/A	- Qualitative MRI were reported normal.
Shing et al. (59)	Cross-sectional, Prospective, Single-center, Case-control	PPS n = 36	MRI Cortical thickness Subcortical GM DTI ROI analysis	ECAS FrSBe Fatigue severity scale Piper fatigue scale HADS	N/A	- Limited cortical atrophy (cingulate gyrus and temporal pole), limited subcortical atrophy (left nucleus accumbens) and no WM degeneration were detected despite prevalent extra-motor symptoms.
Shing et al. (60)	Cross-sectional, Prospective, Single-center, Case-control	PPS n = 36 ALS n = 88	MRI Morphometry DTI TBSS ROI analysis.	MRC muscle strength evaluation ALSFRS-R	N/A	- No GM or WM degeneration detected. - Increased GM volume in cerebellar, brainstem and occipital lobe regions and increased WM integrity in pyramidal, mesial temporal and cerebellar tracts.
Trojan et al. (61)	Cross-sectional, Prospective, Single-center, Case-control	PPS n = 42 MS n = 49	MRI Normalized brain volume	Fatigue severity scale Centers for epidemiological studies depression scale	N/A	- In PPS, no significant whole brain atrophy detected. - No association between brain volume and fatigue.
Hereditary spastic paraplegia
Aghakhanyan et al. (62)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 12	MRI DTI TBSS	N/A	N/A	- There was reduced FA with preferential involvement of frontal regions in an anteroposterior pattern.
Agosta et al. (63)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 44	MRI VBM DTI TBSS	SPRS MMSE Verbal and spatial span Memory prose RCFT TMT RCPM Paced Auditory Serial Addition Task Phonemic and semantic fluency Beck Depression Inventory	N/A	- The distribution of extra-motor WM degeneration involving cerebellar, limbic, corticocortical and interhemispheric regions was similar in pHSP and cHSP. It correlated with cognitive impairment.
Duning et al. (64)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 6	MRI Volumetry DTI	Digital symbol substitution WMS-R Digital span forward and backward TMT CWIT Letter fluency RCFT RALVT	N/A	- Structural MRI and brain volumetry were normal. - Loss of WM integrity in corticospinal tract and frontal regions in those with longer disease duration.
Erichsen et al. (65)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 8	MRS Volumetry ROI analysis	WAIS-R Digit symbol substitution Digit span forward and backwards Stroop test “2 and 7 selective attention test” Paced Auditory Serial Addition Test CVLT-T score Continuous Visual Memory Test RCFT Controlled Word Fluency Test	N/A	- There was reduced Cho/Cr ratio in motor cortex that was associated with some cognitive measures.
Faber et al. (66)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 25	MRI Cortical thickness Deep GM volumes DTI	ACE-III Neuropsychiatric Inventory SPRS	N/A	- The loss of WM integrity at the fornix and corpus callosum correlated with cognitive measures. - Basal ganglia atrophy and limited cortical thinning involving motor, limbic and parietal cortices.
França et al. (67)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 5	MRI VBM DTI TBSS	N/A	N/A	- Significant gray matter atrophy involving the thalamus and basal ganglia but not in the cerebral cortex. - Reduced FA involving subcortical white matter of the temporal and frontal lobes, cingulated gyrus, cuneus, striatum, corpus callosum, and brainstem.
Kassubek et al. (68)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 33	MRI Brain parenchymal fractions	Mini Mental Status Scale	N/A	- Global brain volume reduction involving GM and WM that was more pronounced in cHSP than pHSP.
Koritnik et al. (69)	Cross-sectional, Prospective, Single-center, Case-control	- HSP n = 12	Task-based fMRI Finger tapping	N/A	N/A	- There was altered cortical activation during the motor tasks.
Liao et al. (70)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 12	Resting state fMRI	SPRS	N/A	- The baseline neural activity and connectivity were altered in frontal regions including insula, pre-central, orbitofrontal, superior, and middle frontal gyrus.
Lindig et al. (71)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 15	MRI VBM DTI TBSS	SPRS	N/A	- Widespread GM and WM degeneration involving corpus callosum, thalamus, parieto-occipital, upper brainstem, cerebellum, and corticospinal tracts. - There was a correlation between DTI metrics and disease duration and severity.
Montanaro et al. (72)	Longitudinal, Prospective, Single-center, Case-control	HSP n = 31	MRI VBM DTI TBSS MRS	SPRS	28.9 ± 8.4 months	- There was widespread WM degeneration and reduced GM volume in right pre-frontal cortex and thalamus. - Follow-up imaging did not detect significant changes.
Oguz et al. (73)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 4	MRI DTI TBSS	N/A	N/A	- There were widespread WM alterations involving both the motor and extra-motor regions.
Pan et al. (74)	Cross-sectional, Prospective, Single-center	HSP n = 5	MRI DSI TBSS	MMSE WAIS-III Modified Ashworth Scale Tendon Reflex Grading Scale	N/A	- There was global loss of WM integrity, most marked in prefrontal and motor regions of corpus callosum.
Rezende et al. (75)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 11	MRI Volumetry DTI TBSS	SPRS	N/A	- No volumetry analyses abnormalities detected. - Reduced FA in corticospinal tracts and corpus callosum correlated with disease severity.
Scheuer et al. (76)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 18	MRI [18]F-FDG PET	Modified Disability Scale RH Basic Battery Proverb Interpretation Associate Learning and Retention of 15 Word Pairs Digit Span Forwards and Backwards Sentence Repetition Symbol Digit Modalities Test TMT Block Design Test Visual Gestalt Test Danish Adult Reading Test WAIS List Learning Test Recognition memory tests Street Completion Test WCST	N/A	- There was decreased regional cerebral blood flow in the left fronto-temporal cortex. In the more disabled patients, more extensive changes were noted. - Neuropsychological tests showed impaired recognition memory of faces. The PET imaging findings were not associated with severe cognitive impairment.
Stromillo et al. (77)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 10	MRI Normalized brain volumes MRS	MMSE 4-grade severity scale of patients' autonomy walking abilities	N/A	- Widespread structural and metabolic brain alterations. - Lower global brain volumes and diffusely decreased values in cortical regions compared to controls. - Reduced brain volume and altered NAA/Cr ratio in the corona radiata correlated with disability scores.
Tomberg et al. (78)	Cross-sectional, Prospective, Single-center, Case-control	HSP n = 9	Task-based fMRI Flexion and extension of the right-hand fingers and right ankle	Modified Ashworth Scale	N/A	- There was altered cortical sensorimotor network function that may reflect damage in the corticospinal tract or compensatory mechanisms.
Unrath et al. (40)	Cross-sectional, Prospective, Single-center, Case-control	SBMA n = 20 HSP n = 24 PLS n = 25	MRI DTI	N/A	N/A	- In HSP, extra-motor WM alterations were detected within the frontal regions and limbic system and its projectional fibers.
Warnecke et al. (79)	Cross-sectional, Prospective, Single-center	HSP n = 6	Qualitative MRI DTI	Neuropsychological testing	N/A	- Qualitative MRI showed cerebellar atrophy and mild frontal cerebral atrophy. There was loss of WM integrity in corticospinal tracts, frontal lobes, and midbrain. This was thought to contribute to the impaired attention and executive function.

ACE-III, Addenbrooke's cognitive examination III; ALS, amyotrophic lateral sclerosis; ALSFRS-R, amyotrophic lateral sclerosis functional rating scale revised; BADA, battery for the aphasic deficit analysis; CET, cognitive estimation task; Cho/Cr, Choline/creatinine; CWIT, color word interference test; CVLT, California verbal learning test; DTI, diffusion tensor imaging; ECAS, Edinburgh cognitive and behavioral ALS screen; FA, fractional anisotropy; FBI, frontal behavioral inventory; [¹⁸]F-FDG PET, fluorodeoxyglucose positron emission tomography; fMRI, functional magnetic resonance imaging; FrSBe, frontal systems behavior scale; GM, gray matter; HADS, hospital anxiety and depression scale; HDRS, Hamilton depression rating scale; HSP, hereditary spastic paraparesis; pHSP, pure HSP; cHSP, complicated HSP; LMN, lower motor neuron; mI/Cr, myo-inositol/creatine; MMSE, mini-mental state examination; MRC, medical research council; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA/Cho, N-acetylaspartate/choline; NAA/Cr, N-acetylaspartate/creatine; NAA/tCr, N-acetylaspartate/total creatine; PET, positron emission tomography; PLS, primary lateral sclerosis; RAVLT, Rey auditory verbal learning test; RCFT, Rey's complex figure test; ROI, region of interest; RCPM, Raven's colored progressive matrices; SMAFRS, spinal muscular atrophy functional rating scale; SPRS, spastic paraplegia rating scale; TBSS, tract-based spatial statistics; TMT, trail making test; UMN, upper motor neuron; VBM, voxel-based morphometry; WAIS, Wechsler adult intelligence scale; WCFST, Weigl color-form sorting test; WCST, Wisconsin card sorting test; WM, white matter; WMS-R, Weshcsler memory scale-revised.