The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS

O’Keefe, Joan A.; Guan, Joseph; Robertson, Erin; Biskis, Alexandras; Joyce, Jessica; Ouyang, Bo; Liu, Yuanqing; Carnes, Danielle; Purcell, Nicollette; Berry‐Kravis, Elizabeth; Hall, Deborah A.

doi:10.1007/s12311-020-01199-3

Cited by 14 publications

(17 citation statements)

References 74 publications

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“…If these findings are upheld with greater numbers and/or replication, they would align with those from a previous study of neuroimaging abnormalities in premutation carriers, in which executive dysfunction and cognitive processing scores were decreased in correlation with white matter changes in the frontocerebellar region of the brain [19]. Interestingly, increased cognitive "load" during standardized walking protocols significantly impairs gait in premutation carriers [45,46], further highlighting the role of changes in frontocerebellar pathways and functional connectivity in the development of cognitive and motor symptom decline in this population.…”

Section: Discussionsupporting

confidence: 71%

Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome

Famula

Ferrer

Hagerman

et al. 2022

J Neurodevelop Disord

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Background Carriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention. Methods This was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm “converters,” 15 Pm “nonconverters,” 15 Nc) that were one-one matched on age, education, and socioeconomic status. Results Compared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters. Conclusions Accelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.

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Section: Discussionsupporting

confidence: 71%

Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome

Famula

Ferrer

Hagerman

et al. 2022

J Neurodevelop Disord

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“…Pre‐existing conditions related to poor balance and/or atypical gait patterns, mobility, paretic conditions, and bone/muscle weakness (including conditions such as arthritis, osteoporosis, or cerebral palsy) are falls risk factors for people with intellectual disabilities (Bahiraei et al, 2019; Bruckner & Herge, 2003; Cahill et al, 2014; Chiba et al, 2009; Choi et al, 2020; Finlayson et al, 2014; Hale et al, 2007; Hsieh et al, 2012; O'Keefe et al, 2021; Oppewal et al, 2014; Oppewal & Hilgenkamp, 2019; Pal et al, 2014; Wagemans & Cluitmans, 2006).…”

Section: Resultsmentioning

confidence: 99%

Preventing falls at home among people with intellectual disabilities: A scoping review

Doherty

Benedetto

Harris

et al. 2023

Research Intellect Disabil

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Background Falls are common among people with intellectual disabilities. Many falls happen within the home. Our scoping review aimed to identify evidence for falls‐risk factors and falls‐prevention interventions for this population. Method We conducted a multi‐database search to identify any type of published study that explored falls‐risk factors or falls‐prevention interventions for people with intellectual disabilities. Following a process of (i) title & abstract and (ii) full‐text screening, data was extracted from the included studies and described narratively. Results Forty‐one studies were included. Risks are multifactorial. There was limited evidence of medical, behavioural/psychological, or environmental interventions to address modifiable risk factors, and no evidence of the interventions' cost‐effectiveness. Conclusions Clinically and cost effective, acceptable and accessible falls‐prevention pathways should be available for people with intellectual disabilities who are at risk of falls from an earlier age than the general population.

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“…Recent studies of the gait in individuals with FXTAS demonstrate significant balance problems that are worse when the patient is walking fast or turning, or when given a dual task of walking with problem solving [38 ▪▪ ,39]. In addition, when walking and performing a mental task, the patient will prioritize gait over the cognitive task so a better cognitive performance may occur more often when seated than with walking [38 ▪▪ ].…”

Section: Psychiatric and Neuropsychological Studiesmentioning

confidence: 99%

Fragile X-associated tremor/ataxia syndrome: pathophysiology and management

Hagerman

2021

Current Opinion in Neurology

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Purpose of review The purpose of this paper is to review the prevalence, pathophysiology, and management of fragile X-associated tremor/ataxia syndrome (FXTAS). Recent findings The pathophysiology of FXTAS involves ribonucleic acid (RNA) toxicity due to elevated levels of the premutation-expanded CGG (eoxycytidylate-deoxyguanylate-deoxyguanylate)-repeat FMR1 mRNA, which can sequester a variety of proteins important for neuronal function. A recent analysis of the inclusions in FXTAS demonstrates elevated levels of several proteins, including small ubiquitin-related modifiers 1/2 (SUMO1/2), that target molecules for the proteasome, suggesting that some aspect(s) of proteasomal function may be altered in FXTAS. Recent neuropathological studies show that Parkinson disease and Alzheimer disease can sometimes co-occur with FXTAS. Lewy bodies can be found in 10% of the brains of patients with FXTAS. Microbleeds and iron deposition are also common in the neuropathology, in addition to white matter disease (WMD) and atrophy. Summary The premutation occurs in 1:200 females and 1:400 males. Penetrance for FXTAS increases with age, though lower in females (16%) compared to over 60% of males by age 70. To diagnose FXTAS, an MRI is essential to document the presence of WMD, a primary component of the diagnostic criteria. Pain can be a significant feature of FXTAS and is seen in approximately 50% of patients.

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The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS

Cited by 14 publications

References 74 publications

Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome

Neuropsychological changes in FMR1 premutation carriers and onset of fragile X-associated tremor/ataxia syndrome

Preventing falls at home among people with intellectual disabilities: A scoping review

Fragile X-associated tremor/ataxia syndrome: pathophysiology and management

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