Amyotrophic lateral sclerosis with upper motor neuron predominance: diagnostic accuracy of qualitative and quantitative susceptibility metrics in the precentral gyrus.

OBJECTIVE: The study aims at comparing the diagnostic accuracy of qualitative and quantitative assessment of the susceptibility in the precentral gyrus in detecting amyotrophic lateral sclerosis (ALS) with predominance of upper motor neuron (UMN) impairment. METHODS: We retrospectively collected clinical and 3T MRI data of 47 ALS patients, of whom 12 with UMN predominance (UMN-ALS). We further enrolled 23 healthy controls (HC) and 15 ALS Mimics (ALS-Mim). The Motor Cortex Susceptibility (MCS) score was qualitatively assessed on the susceptibility-weighted images (SWI) and automatic metrics were extracted from the quantitative susceptibility mapping (QSM) in the precentral gyrus. MCS scores and QSM-based metrics were tested for correlation, and ROC analyses. RESULTS: The correlation of MCS score and susceptibility skewness was significant (Rho = 0.55, p < 0.001). The susceptibility SD showed an AUC of 0.809 with a specificity and positive predictive value of 100% in differentiating ALS and ALS Mim versus HC, significantly higher than MCS (Z = -3.384, p-value = 0.00071). The susceptibility skewness value of -0.017 showed specificity of 92.3% and predictive positive value of 91.7% in differentiating UMN-ALS versus ALS mimics, even if the performance was not significantly better than MCS (Z = 0.81, p = 0.21). CONCLUSION: The MCS and susceptibility skewness of the precentral gyrus show high diagnostic accuracy in differentiating UMN-ALS from ALS-mimics subjects. The quantitative assessment might be preferred being an automatic measure unbiased by the reader. CLINICAL RELEVANCE STATEMENT: The clinical diagnostic evaluation of ALS patients might benefit from the qualitative and/or quantitative assessment of the susceptibility in the precentral gyrus as imaging marker of upper motor neuron predominance. KEY POINTS: • Amyotrophic lateral sclerosis diagnostic work-up lacks biomarkers able to identify upper motor neuron involvement. • Susceptibility-weighted imaging/quantitative susceptibility mapping-based measures showed good diagnostic accuracy in discriminating amyotrophic lateral sclerosis with predominant upper motor neuron impairment from patients with suspected motor neuron disorder. • Susceptibility-weighted imaging/quantitative susceptibility mapping-based assessment of the magnetic susceptibility provides a diagnostic marker for amyotrophic lateral sclerosis with upper motor neuron predominance.

Editorial Comment: Iron-sensitive MR imaging of the primary motor cortex to differentiate hereditary spastic paraplegia from other motor neuron diseases.

KEY POINTS: • Conventional and advanced MR techniques may aid in the diagnosis of motor neuron disease.• Iron-sensitive MR imaging of the primary motor cortex may reveal changes to help differentiate hereditary spastic paraplegia (HSP) from UMM predominant amyotrophic lateral sclerosis (UMN-ALS) and primary lateral sclerosis (PLS).• Additional research in this area is necessary.

In vivo hypothalamic regional volumetry across the frontotemporal dementia spectrum.

BACKGROUND: Frontotemporal dementia (FTD) is a spectrum of diseases characterised by language, behavioural and motor symptoms. Among the different subcortical regions implicated in the FTD symptomatology, the hypothalamus regulates various bodily functions, including eating behaviours which are commonly present across the FTD spectrum. The pattern of specific hypothalamic involvement across the clinical, pathological, and genetic forms of FTD has yet to be fully investigated, and its possible associations with abnormal eating behaviours have yet to be fully explored. METHODS: Using an automated segmentation tool for volumetric T1-weighted MR images, we measured hypothalamic regional volumes in a cohort of 439 patients with FTD (197 behavioural variant FTD [bvFTD]; 7 FTD with associated motor neurone disease [FTD-MND]; 99 semantic variant primary progressive aphasia [svPPA]; 117 non-fluent variant PPA [nfvPPA]; 19 PPA not otherwise specified [PPA-NOS]) and 118 age-matched controls. We compared volumes across the clinical, genetic (29 MAPT, 32 C9orf72, 23 GRN), and pathological diagnoses (61 tauopathy, 40 TDP-43opathy, 4 FUSopathy). We correlated the volumes with presence of abnormal eating behaviours assessed with the revised version of the Cambridge Behavioural Inventory (CBI-R). RESULTS: On average, FTD patients showed 14% smaller hypothalamic volumes than controls. The groups with the smallest hypothalamic regions were FTD-MND (20%), MAPT (25%) and FUS (33%), with differences mainly localised in the anterior and posterior regions. The inferior tuberal region was only significantly smaller in tauopathies (MAPT and Pick's disease) and in TDP-43 type C compared to controls and was the only regions that did not correlate with eating symptoms. PPA-NOS and nfvPPA were the groups with the least frequent eating behaviours and the least hypothalamic involvement. CONCLUSIONS: Abnormal hypothalamic volumes are present in all the FTD forms, but different hypothalamic regions might play a different role in the development of abnormal eating behavioural and metabolic symptoms. These findings might therefore help in the identification of different underlying pathological mechanisms, suggesting the potential use of hypothalamic imaging biomarkers and the research of potential therapeutic targets within the hypothalamic neuropeptides.

Iron-sensitive MR imaging of the primary motor cortex to differentiate hereditary spastic paraplegia from other motor neuron diseases.

OBJECTIVES: Hereditary spastic paraplegia (HSP) is a group of genetic neurodegenerative diseases characterised by upper motor neuron (UMN) impairment of the lower limbs. The differential diagnosis with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) can be challenging. As microglial iron accumulation was reported in the primary motor cortex (PMC) of ALS cases, here we assessed the radiological appearance of the PMC in a cohort of HSP patients using iron-sensitive MR imaging and compared the PMC findings among HSP, PLS, and ALS patients. METHODS: We included 3-T MRI scans of 23 HSP patients, 7 PLS patients with lower limb onset, 8 ALS patients with lower limb and prevalent UMN onset (UMN-ALS), and 84 ALS patients with any other clinical picture. The PMC was visually rated on 3D T2*-weighted images as having normal signal intensity, mild hypointensity, or marked hypointensity, and differences in the frequency distribution of signal intensity among the diseases were investigated. RESULTS: The marked hypointensity in the PMC was visible in 3/22 HSP patients (14%), 7/7 PLS patients (100%), 6/8 UMN-ALS patients (75%), and 35/84 ALS patients (42%). The frequency distribution of normal signal intensity, mild hypointensity, and marked hypointensity in HSP patients was different than that in PLS, UMN-ALS, and ALS patients (p < 0.01 in all cases). CONCLUSIONS: Iron-sensitive imaging of the PMC could provide useful information in the diagnostic work - up of adult patients with a lower limb onset UMN syndrome, as the cortical hypointensity often seen in PLS and ALS cases is apparently rare in HSP patients. KEY POINTS: • The T2* signal intensity of the primary motor cortex was investigated in patients with HSP, PLS with lower limb onset, and ALS with lower limb and prevalent UMN onset (UMN-ALS) using a clinical 3-T MRI sequence. • Most HSP patients had normal signal intensity in the primary motor cortex (86%); on the contrary, all the PLS and the majority of UMN-ALS patients (75%) had marked cortical hypointensity. • The T2*-weighted imaging of the primary motor cortex could provide useful information in the differential diagnosis of sporadic adult-onset UMN syndromes.

Combining structural and metabolic markers in a quantitative MRI study of motor neuron diseases.

OBJECTIVE: To assess the performance of a combination of three quantitative MRI markers (iron deposition, basal neuronal metabolism, and regional atrophy) for differential diagnosis between amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). METHODS: In total, 33 ALS, 12 PLS, and 28 healthy control (HC) subjects underwent a 3T MRI study including single- and multi-echo sequences for gray matter (GM) volumetry and quantitative susceptibility mapping (QSM) and a pseudo-continuous arterial spin labeling (ASL) sequence for cerebral blood flow (CBF) measurement. Mean values of QSM, CBF, and GM volumes were extracted in the motor cortex, basal ganglia, thalamus, amygdala, and hippocampus. A generalized linear model was applied to the three measures to binary discriminate between groups. The diagnostic performances were evaluated via receiver operating characteristic analyses. RESULTS: A significant discrimination was obtained: between ALS and HCs in the left and right motor cortex, where QSM increases were respectively associated with disability scores and disease duration; between PLS and ALS in the left motor cortex, where PLS patients resulted significantly more atrophic; between ALS and HC in the right motor cortex, where GM volumes were associated with upper motor neuron scores. Significant discrimination between ALS and HC was achieved in subcortical structures only combining all three parameters. INTERPRETATION: While increased QSM values in the motor cortex of ALS patients is a consolidated finding, combining QSM, CBF, and GM volumetry shows higher diagnostic potential for differentiating ALS patients from HC subjects and, in the motor cortex, between ALS and PLS.

Widespread subcortical grey matter degeneration in primary lateral sclerosis: a multimodal imaging study with genetic profiling.

BACKGROUND: Primary lateral sclerosis (PLS) is a low incidence motor neuron disease which carries a markedly better prognosis than amyotrophic lateral sclerosis (ALS). Despite sporadic reports of extra-motor symptoms, PLS is widely regarded as a pure upper motor neuron disorder. The post mortem literature of PLS is strikingly sparse and very little is known of subcortical grey matter pathology in this condition. METHODS: A prospective imaging study was undertaken with 33 PLS patients, 117 healthy controls and 100 ALS patients to specifically assess the integrity of subcortical grey matter structures and determine whether PLS and ALS have divergent thalamic, hippocampal and basal ganglia signatures. Volumetric, morphometric, segmentation and vertex-wise analyses were carried out in the three study groups to evaluate the integrity of thalamus, hippocampus, caudate, amygdala, pallidum, putamen and accumbens nucleus in each hemisphere. The hippocampus was further parcellated to characterise the involvement of specific subfields. RESULTS: Considerable thalamic, caudate, and hippocampal atrophy was detected in PLS based on both volumetric and vertex analyses. Significant volume reductions were also detected in the accumbens nuclei. Hippocampal atrophy in PLS was dominated by dentate gyrus, hippocampal tail and CA4 subfield volume reductions. The morphometric comparison of ALS and PLS cohorts revealed preferential medial bi-thalamic pathology in PLS compared to the predominant putaminal degeneration detected in ALS. Another distinguishing feature between ALS and PLS was the preferential atrophy of the amygdala in ALS. CONCLUSIONS: PLS is associated with considerable subcortical grey matter degeneration and due to the extensive extra-motor involvement, it should no longer be regarded a pure upper motor neuron disorder. Given its unique pathological features and a clinical course which differs considerably from ALS, dedicated research studies and disease-specific therapeutic strategies are urgently required in PLS.

Three-dimensional surface display using 123I-IMP in a case of motor neuron disease with dementia.

A case of motor neuron disease with dementia is presented. A brain CT showed atrophic changes mainly in the left frontal cortex, and 123I-IMP SPECT disclosed a decrease in 123I-IMP uptake in the frontal regions. To distinguish a subregion related to dementia from that related to motor system disorders, a three-dimensional surface display with 123I-IMP was reconstructed. The imaging method clearly demonstrated cortical hypoperfusion in the inferomedial frontal cortex and the motor-sensory cortex. These findings suggest that dementia may be due to the former lesion and motor system disorders due to the latter lesion, respectively.