Total and Regional White Matter Lesions Are Correlated With Motor and Cognitive Impairments in Carriers of the FMR1 Premutation

Abstract

This study explores the relationships between hemispheric and cerebellar white matter lesions and motor and cognitive impairments in male carriers of Fragile-X Mental Retardation 1 ( FMR1 ) premutation alleles, and in a subgroup of these carriers affected with Fragile X-Associated Tremor/Ataxia syndrome (FXTAS). Regional and total white matter hyperintensities ( wmhs ) on MRI, assessed using semiquantitative scores, were correlated with three motor rating scales (ICARS, UPDRS, Tremor), and neuropsychological measures of non-verbal reasoning, working memory and processing speed, in a sample of 30 male premutation carriers aged 39–81 years, and separately in a subsample of 17 of these carriers affected with FXTAS. There were significant relationships between wmhs in the infratentorial region and all three motor scales, as well as several cognitive measures—Prorated IQ, Matrix Reasoning, Similarities, and the Symbol Digit Modalities Test (SDMT), in the total sample of carriers, as well as in the FXTAS group separately. This shows that whms within the infratentorial region correlates across the categories of clinical status with a range of motor and cognitive impairments. In the FXTAS group, there was a highly significant relationship between supratentorial (periventricular) lesions and parkinsonism, and between both periventricular and supratentorial deep white matter and ICARS ataxia score. These findings further support the relevance of white matter changes in different brain regions to the motor and cognitive deficits across the spectrum of premutation involvement. Future longitudinal studies using larger sample sizes will be necessary to examine the factors that lead to conversion to a greater extent of neurological involvement as seen in the progression across the FXTAS spectrum.

Differential Progression of Motor Dysfunction Between Male and Female Fragile X Premutation Carriers Reveals Novel Aspects of Sex-Specific Neural Involvement

“…Our data on progression of the premutation-associated changes from sub-symptomatic to clinical forms, especially in females, may have an important impact on future research, as well as on clinical approaches, because it introduces the concept of continuity. Combined with earlier evidence for the existence of subclinical neural or metabolic changes in both male and female carriers over a broad age range (Tassone et al, 2012 ; Wang et al, 2012 , 2013 , 2017 ; Battistella et al, 2013 ; Shelton et al, 2016 ; Loesch et al, 2017 , 2018 ; Hocking et al, 2019 ; O'Keeffe et al, 2019 ), these data have shown that the focus of such research should be on trajectories rather than on the final outcome of the premutation-associated process. The most recent study, based on a wide range of metabolic and proteomic biomarkers, showed a decline of mitochondrial activities in pre-symptomatic female PM carriers, leading the authors to the conclusion that the development of neurodegeneration or other clinical symptoms in older carriers could be linked to a lifetime accumulation of cellular damage, aggravated by the aging process (Napoli et al, 2020 ).…”

Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

“…We used cultured lymphoblasts from a larger sample of carriers. Although we strongly emphasised the concept of a continuum of clinical and neuropathological changes in all PM carriers ( 2 , 6 , 62 ), here we distinguish between these two subgroups (FXTAS and non-FXTAS), with the intention of exploring the trajectory of cellular changes evolving from non- FXTAS to diagnosable FXTAS-as indicative of the potentially much more informative longitudinal approach.…”

Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages

“…Cognitive evaluations showed that both SCA2 patients and preSCA subjects had significant lower scores than CTR in SDMT. SDMT has not been extensively used in SCAs, but is has been proposed as a cognitive outcome measures in several neurological disorders, including Huntington disease, Friedreich ataxia and Fragile X-Associated Tremor/Ataxia syndrome (40)(41)(42). SDMT is a measure of speed and efficiency in multiple cognitive processes involving memory, word retrieval, and executive function.…”