Acetyl-dl-leucine in cerebellar ataxia ([18F]-FDG-PET study): how does a cerebellar disorder influence cortical sensorimotor networks?

Abstract

Objective The aim of the study was to deepen our insights into central compensatory processes of brain networks in patients with cerebellar ataxia (CA) before and with treatment with acetyl-dl-leucine (AL) by means of resting-state [18F]-FDG-PET brain imaging. Methods Retrospective analyses of [18F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B). Group subtraction analyses, e.g., for responders and non-responders, comparisons with healthy controls and correlation analyses of regional cerebral glucose metabolism (rCGM) with symptom duration, ataxia (SARA) and quality of life (QoL) scores were calculated. Results Prior to treatment rCGM was consistently downregulated at the cerebellar level and increased in multisensory cortical areas, e.g., somatosensory, primary and secondary visual (including V5, precuneus), secondary vestibular (temporal gyrus, anterior insula), and premotor/supplementary motor areas. With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group. A positive correlation of ataxia improvement with rCGM was found in visual and vestibular cortices, a negative correlation in cerebellar and brainstem areas. QoL showed a positive correlation with rCGM in the cerebellum and symptom duration in premotor and somatosensory areas. Conclusions Central compensatory processes in CA mainly involve multisensory visual, vestibular, and somatosensory networks as well as premotor/primary motor areas at the cortical level. The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms.

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options

“…A case series of patients with cerebellar ataxia of various origins treated with ADLL suggested a clinically significant benefit of the treatment [221,222] that has also been supported by neuro-metabolic studies [223][224][225]. However, the evidence for the efficacy of ADLL is somewhat contradictory with a negative placebo-controlled clinical trial that failed to show the improvement in cerebellar ataxia signs and symptoms [226].…”

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine

“…N -acetyl- l -leucine, a modified amino acid, is used in the treatment of vertigo. Its mechanism of action involves the activation of cerebral glucose metabolism in the cerebellum and other regions of the brain 119 , 120 . Notably, N -acetyl- l -leucine has also shown promise in delaying disease progression and extending the lifespan of Npc1 −/− mice 121 .…”

Structural and connectivity parameters reveal spared connectivity in young patients with non-progressive compared to slow-progressive cerebellar ataxia

“…Such compensation mechanisms have been already proposed in several neurological diseases. For example, Becker-Bense et al ( 8 ) revealed a compensatory strategy in the multisensory visual network of adult ataxic patients with vestibular and oculomotor symptoms, while a compensative role played by the cerebellum on the basal ganglia dysfunctions has been observed in patients with Parkinson’s disease ( 9 , 10 ). Recently, a wider number of works has pointed out the fundamental role of the cerebellum-basal ganglia interplay for balance, motor control and coordination ( 11 ).…”