By Lucy Piper, medwireNews Reporter
medwireNews: Researchers have identified microstructural damage to the striatum in patients with sporadic amyotrophic lateral sclerosis (ALS) that could play a key role in the motor disability and cognitive deficits associated with the condition.
“Thus, our findings may have an important role in advancing our current understanding of the neurodegenerative process underlying ALS”, say Shuangwu Liu (Shandong University, Jinan, China) and colleagues
For the retrospective study, 79 patients with ALS (mean duration 20.5 months) and 53 healthy individuals were clinically assessed, had their serum neurofilament light (NfL) levels measured and underwent genetic testing to rule out genetic ALS.
The participants were Chinese, had a mean age of 52 years and 64.5% of the ALS group and 62.3% of the healthy individuals were women.
The ALS group had a mean ALS Functional Rating Scale–Revised (ALSFRS-R) score of 36.8 points, and they differed significantly from the healthy controls in having higher mean levels of serum NfL (58.3 vs 13.8 pg/mL) and greater neuropsychological impairment. The latter was shown by lower scores for the Edinburgh cognitive and behavioral ALS screen (ECAS) total (95.1 vs 114.0 points), ALS-specific (73.3 vs 88.5 points) and ALS non-specific (21.5 vs 25.5 points) measures. Patients with ALS also had significantly higher scores on the Frontal Behavioral Inventory (5.8 vs 0.2 points), the Hamilton Anxiety Rating Scale (11.3 vs 5.4 points) and the Hamilton Depression Rating Scale (7.5 v 2.6 points).
The researchers used a probabilistic nerve fibre tracking approach to segment the striatum into six subregions based on their corticostriatal connectivity using multishell diffusion magnetic resonance imaging (MRI). These included the prefrontal, motor, somatosensory, parietal, temporal, and occipital regions. These were segmented further into 12 subregions based on maximum connectivity probability with the corresponding cortical regions.
Three neurite dispersion and density imaging (NODDI) parameters for the striatal subregions were then measured, namely the neurite density index (NRI), orientation dispersion index (ODI) and isotropic volume fraction (ISO).
“The NODDI has been suggested to be more sensitive for estimating multi-compartment model and can provide important insights into the cellular pathology changes in disease conditions”, the researchers explain. “Thus, the NODDI has been gradually adopted to assess [grey matter] microstructural changes in multiple neuropsychiatric diseases.”
Liu et al found that after familywise error correction, patients with ALS had significantly lower NDI in the bilateral motor and right frontal subregions of the striatum and significantly lower ODI in the right motor and frontal subregions than the healthy individuals. They also had a significantly higher ISO in the bilateral motor and frontal subregions.
Correlation analyses showed that in the patients with ALS the NDI of the left motor striatal subregion was significantly associated with the ALSFRS-R score and with the serum NfL level, while the ISO of the right motor striatal subregion correlated significantly with ALS duration.
There was also a significant correlation among the ALS patients between the ISO of the right frontal striatal subregion and the ECAS ALS-specific score.
“Our findings may provide a comprehensive profile regarding the role of selective striatal damage in ALS patients and in vivo evidence further supporting the corticofugal axonal spread of TDP-43 [TAR DNA binding protein 43 kDa] pathology in ALS patients”, say the investigators.
They explain that TDP-43 pathology in patients with ALS can be divided into four stages according to corticofugal axonal spread, which starts in the motor cortex and disseminates sequentially to the prefrontal cortex, the striatum and then the hippocampus.
Therefore “cortical-striatum disseminate TDP-43 pathology and corresponding selective striatal subregion alterations are likely a definite feature of ALS patients”, they say, suggesting that “connectivity-based striatal microstructure alterations are likely potential neuroimaging markers for in vivo noninvasive monitoring of disease progression in future therapeutic research.”
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Eur J Neurol 2025; 32: e16577