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# Common Characteristics Between Frailty and Myotonic Dystrophy Type 1: A Narrative Review

Joana Garmendia, Garazi Labayru, Philipe de Souto Barreto, Itziar Vergara, Adolfo López De Munain, Andone Sistiaga

► To cite this version:

Joana Garmendia, Garazi Labayru, Philipe de Souto Barreto, Itziar Vergara, Adolfo López De Munain, et al.. Common Characteristics Between Frailty and Myotonic Dystrophy Type 1: A Narrative Review. Aging and disease, 2024, 10.14336/ad.2024.0950. hal-04938689

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Review

# Common Characteristics Between Frailty and Myotonic Dystrophy Type 1: A Narrative Review

Joana Garmendia¹,², Garazi Labayru¹,²,³, Philipe de Souto Barreto⁴,⁵,⁶, Itziar Vergara⁷,⁸,⁹, Adolfo López de Munain²,³,¹⁰, Andone Sistiaga¹,²,³*

¹Department of Clinical and Health Psychology and Research Methodology, Psychology Faculty, University of the Basque Country (UPV/EHU), Donostia-San Sebastián, Gipuzkoa, Spain. ²Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto Carlos III, Madrid, Spain. ³Neuroscience Area, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Gipuzkoa, Spain. ⁴Institute on Aging, Toulouse University Hospital (CHU Toulouse), Toulouse, France. ⁵Institut Hospitalo-Universitaire (IHU) HealthAge, Toulouse, France. ⁶CERPOP UMR 1295, Inserm, Université Paul Sabatier, Toulouse, France. ⁷Osakidetza Health Care Directorate, PC-IHO Research Unit of Gipuzkoa, Donostia-San Sebastián, Gipuzkoa, Spain. ⁸Primary Care Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Gipuzkoa, Spain. ⁹Red de Investigación en Cronicidad, Atención Primaria y Promoción de la Salud (RICAPPS), Spain. ¹⁰Neurology Department, Donostia University Hospital, Donostia-San Sebastián, Gipuzkoa, Spain.

[Received August 6, 2024; Revised August 29, 2024; Accepted August 29, 2024]

**ABSTRACT:** Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disorder often considered a model of accelerated aging due to the early appearance of certain age-related clinical manifestations and cellular and molecular aging markers. Frailty, a state of vulnerability related to aging, has been recently studied in neurological conditions but has received considerably less attention in neuromuscular disorders. This narrative review aims to describe 1) the common characteristics between Fried's frailty phenotype criteria (muscular weakness, slow gait speed, weight loss, exhaustion/fatigue, and low physical activity) and DM1, and 2) the psychological and social factors potentially contributing to frailty in DM1. This review gathered evidence suggesting that DM1 patients meet four of the five frailty phenotype criteria. Additionally, longitudinal studies report the deterioration of these criteria over time in DM1. Patients also exhibit psychological/cognitive and social factors that might contribute to frailty. Monitoring frailty criteria in the DM1 population could help to implement timely preventions and interventions to reduce the disease burden and severity of frailty symptoms.

**Key words:** Steinert's disease, Fried's frailty phenotype, accelerated aging, disease-related frailty, senescence, psychosocial factors

## 1. Introduction

Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, is considered a rare condition; however, it is the most common form of muscular dystrophy in adults. Clinical-based prevalence studies estimate that DM1 affects 5 to 20 per 100,000 individuals globally [1]. It is a genetic disorder inherited in an autosomal dominant manner and characterized by

molecular instability, which correlates with earlier disease onset and greater severity [2, 3]. DM1 is classically characterized by progressive muscular weakness, atrophy, and myotonia, alongside other systemic manifestations affecting various body systems, including the central nervous system (CNS), cardiac, endocrinal, ophthalmological, and gastrointestinal systems [1, 4]. DM1 patients can be classified into different phenotypes based on the age of disease onset [5]. Generally, the

*Correspondence should be addressed to: Dr. Andone Sistiaga Berrondo, University of the Basque Country, Psychology Faculty Avda. Tolosa, 70. 20018 Donostia- San Sebastián, Gipuzkoa, Spain. Email: andone.sistiaga@ehu.eus.

Copyright: © 2024 Garmendia J. et al. This is an open-access article distributed under the terms of the [Creative Commons Attribution License](https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
earlier the signs and symptoms appear, the more severe the disease. Some phenotypes include intellectual disability, leading to greater psychosocial challenges [6-8].

DM1 has been proposed as a model of premature or accelerated aging, which, as defined by Margolick and Ferrucci (2015) [9], is characterized by anatomical and functional manifestations and underlying mechanisms that mirror those observed in normal aging but occur prematurely or earlier than typically expected. In the DM1 population, patients prematurely present age-related clinical manifestations (e.g., cataracts, frontal baldness, muscle weakness, cognitive impairment, metabolic dysfunction). Cellular findings in DM1 also resemble the hallmarks of aging, including senescence inducers (telomere shortening, mitochondrial dysfunction, and oxidative stress) and senescence biomarkers (cell cycle inhibitors, senescence-associated secretory phenotype, chromatin reorganization, and microRNA), along with molecular features similar to those of segmental progeroid disorders [10-14].

In an aging population, frailty emerges as a crucial concept, defined as a state of vulnerability between robustness and disability associated with age. It is considered a potentially reversible condition [15] resulting from the cumulative decline of several physiological systems and vulnerability to internal and external stressors [16]. The frailty phenotype was first characterized by Fried [17] and includes at least three criteria: muscle weakness, slow walking speed, unintentional weight loss, exhaustion or fatigue, and low physical activity. In recent years, researchers have acknowledged the contribution of other psychological and social factors to frailty, leading to a more comprehensive and multidimensional approach to understanding the construct [18-21].

Traditionally studied in geriatrics, the concept of frailty has extended into other medical disciplines as a measure of an individual's risk profile [22]. Fried and colleagues [17] proposed two distinct paths leading to frailty: age-related and disease-related frailty, with the latter arising from chronic or acute medical events. Angioni and colleagues [23] supported this hypothesis, suggesting clinical differences and trajectories between the two paths. Neurological conditions, such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, have emerged as significant contributors to disease-related frailty, with a high prevalence of frailty observed in these conditions [24, 25]. Frailty itself serves as a risk factor for disease progression and increased vulnerability to adverse medical events [26]. Additionally, frailty not only increases the risk of developing neurological disorders [27] but also influences their clinical presentation and phenotypical expression,

being associated with adverse health outcomes [24, 28] alongside certain disease-specific features [29, 30]. However, there is very limited literature available on frailty within neuromuscular disorders [31, 32].

Due to the potential accelerated aging process in DM1 and the possible increased risk of frailty, this narrative review aims to analyze the common characteristics between Fried's frailty phenotype criteria and DM1. Additionally, considering the CNS alteration and psychosocial factors affecting DM1 patients, the second aim of this review is to address the psychological and social factors potentially contributing to frailty in DM1.

## 2. Method

Articles were searched in MEDLINE (PubMed), Scopus, and Web of Science databases until August 2024. To align the review with the stated objectives, frailty was defined using Fried's frailty phenotype criteria. To ensure the inclusion of the most recent studies since the establishment of Fried's criteria in 2001, this review considered works published from 2001 to the present (August 2024). The search strategy included the terms "DM1" or "myotonic dystrophy," combined with keywords related to Fried's frailty phenotype criteria (muscle weakness, gait speed, weight loss, exhaustion/fatigue, and physical activity) for the first aim, and psychological and social contributors to frailty for the second aim. To further expand the range of studies, a forward and backward snowballing approach was employed [33].

Inclusion criteria for this narrative review were limited to papers published in English or Spanish. Only human studies involving adult populations, both cross-sectional and longitudinal, were included. Interventional studies were considered only in exceptional cases. Exclusion criteria included case reports, conference papers, studies on myotonic dystrophy type 2, and any research studies beyond the scope of this review.

The included articles were screened by reading the abstracts, and relevant articles were comprehensively reviewed.

## 3. Results and discussion

This narrative review is divided into two sections: the first section focuses on the frailty phenotype criteria, while the second section addresses the psychological and social factors potentially contributing to frailty. As of the date of this review, there are no studies on frailty in the DM1 population. In this review, each component or factor of frailty is briefly described within the context of aging and geriatrics. Subsequently, a comprehensive examination is
conducted within the DM1 population, discussing the available literature.

## 3.1. Frailty phenotype and DM1

The studies addressing the common characteristics between Fried's frailty phenotype criteria and DM1 are summarized in Table 1 and are discussed below. Overall, the findings and conclusions from the reviewed articles were consistent and aligned, showing no discrepancies, which strengthens the presented evidence.

<table><caption>**Table 1.** Summary of the common characteristics between frailty phenotype criteria and DM1.</caption><thead><tr><th>Fried's frailty phenotype criteria</th><th>DM1</th><th>Transversal studies in DM1</th><th>Studies</th><th>Longitudinal studies in DM1</th><th>Studies</th></tr></thead><tbody><tr><td>Muscle weakness: grip strength in the lowest 20% at baseline, adjusted for gender and body mass index.</td><td>✓</td><td>-Myotonia<br/>-Low grip strength</td><td>(Hogrel et al., 2017; LoRusso et al., 2018; Moxley et al., 2007; Ozimski et al., 2021; Sugimoto et al., 2022; Thornton, 2014)</td><td>-Progressive muscle atrophy and weakness<br/>-Loss of muscle strength</td><td>(Gagnon et al., 2018; Hammarén et al., 2015; Raymond et al., 2017; Roussel et al., 2021; Sedehizadeh et al., 2017)</td></tr><tr><td>Slow gait speed: The slowest 20% of the population, based on time to walk 15 feet, adjusting for gender and standing height.</td><td>✓</td><td>-Gait disturbances: altered gait speed, step length and frequency, and cadence</td><td>(Bachasson et al., 2016; Galli et al., 2012; Kim et al., 2020; Pucillo et al., 2018; Wiles, 2005)</td><td>-Deterioration of gait parameters<br/>-Increase in walking difficulties</td><td>(Hammarén et al., 2015)</td></tr><tr><td>Weight loss: weight loss, unintentional, of ≥10 pounds in prior year</td><td>-</td><td>-No specific studies<br/>-Two phenotypes: atrophic and overweight (obesity)<br/>-Increased fat-mass (visceral adiposity)<br/>-Decreased fat-free mass<br/>-Possible contributor: dysphagia (prevalence 55%)</td><td>(Gutiérrez et al., 2020; Joosten et al., 2023; Kikuchi et al., 2022; Peric, Bozovic, et al., 2019; Pruna et al., 2011; Sedehizadeh et al., 2017)</td><td>-No specific studies<br/>-Increase on total fat-mass and a decrease in total fat-free mass<br/>-Decrease in both trunk fat-mass and fat-free mass (possible weight loss)</td><td>(Kikuchi et al., 2022; Sedehizadeh et al., 2017)</td></tr><tr><td>Exhaustion/fatigue: as indicated by self-report of exhaustion.</td><td>✓</td><td>-High prevalence of fatigue (50-90%)</td><td>(Erokhina et al., 2024; Heatwole et al., 2012; Kalkman, 2005; Laberge et al., 2020; Landfeldt et al., 2019; Menting et al., 2018; Peric, Bjelica, et al., 2019),</td><td>-Increase in fatigue levels and/or proportion of patients with fatigue over time</td><td>(Kalkman, 2005; Laberge et al., 2020; Peric, Bjelica, et al., 2019)</td></tr><tr><td>Low physical activity: A weighted score of kilocalories expended per week, based on each participant's report.</td><td>✓</td><td>-Less physically active than healthy controls<br/>-Need assistance or have difficulties performing physical activity</td><td>(Gagnon et al., 2007, 2013; Garmendia et al., 2023; Kierkegaard et al., 2011; Knak et al., 2020; Landfeldt et al., 2020; Van Heugten et al., 2018; Wiles, 2005)</td><td>-Decrease in physical activity over time</td><td>(Raymond et al., 2019)</td></tr></tbody></table>

Note. DM1 = Myotonic dystrophy type 1

### 3.1.1. Muscle weakness

Muscle weakness, a key characteristic of the frailty phenotype, is operationalized as low grip strength. Research suggests that it peaks in early adulthood, remains stable through midlife, and subsequently declines with age, typically starting at the age of 50 [34]. In older adults, grip strength is a predictor of overall strength and function [35] and is a significant indicator of current health status and physical, functional, and psychological

performance [35–38]. Additionally, it is considered a mediator in the relationship between muscle mass and frailty [39] and a predictor of morbidity and mortality [40, 41]. Although grip strength is a key component of muscle weakness, other aspects, such as lower limb strength, are also worth considering in the context of frailty.

DM1, a progressive neuromuscular condition, is typically characterized by progressive muscle weakness, atrophy, and handgrip myotonia, which refers to impaired muscle relaxation after voluntary contraction [42],
leading to weak grip strength. The muscular involvement in DM1 follows a symmetric and distal pattern, gradually progressing to proximal muscles. It commonly causes distal weakness in the upper (forearms, hands) and lower (finger flexors, ankle plantar flexors, ankle dorsiflexors) limbs, with the face, jaw, and neck muscles being the most severely affected muscle groups [4, 43].

Myotonia and distal muscular weakness are among the first signs of DM1 [1] and are frequently observed symptoms [44], typically evident during maximal grip contractions. Regarding the natural course of myotonia in DM1, certain studies suggest that the myotonia sign tends to decrease with age [11], likely due to the aggravation of muscular weakness, resulting in insufficient strength to manifest contraction and relaxation signs.

Progressive skeletal muscle atrophy and weakness can reduce muscle strength and endurance [42]. In line with this observation, DM1 patients exhibit weak grip strength and different grip force relaxation compared to healthy controls (HC) [45, 46]. Myotonia and grip strength are associated with the molecular defect of the disease (CTG expansion size) [44–47] and serve as markers of disease severity. Additionally, muscular weakness is linked to an increased risk of falls and fractures in DM1 [48, 49], with the incidence of these events being high and age-related in this population [50]. Longitudinal studies have shown a significant loss of muscle strength in various muscle groups [51–53] and a significant decline in grip strength [54, 55].

### 3.1.2. Slow gait speed

Another characteristic of the frailty phenotype is slow gait speed, which is a significant predictor of the risk of injurious falls, which can potentially lead to medical complications, such as fractures. Other gait parameters are also related to adverse clinical, cognitive, and physical health outcomes [56].

The progressive deterioration of muscles in DM1 patients can profoundly affect gait and balance, leading to commonly observed disturbances in these areas. Various studies in DM1 have reported altered gait parameters, including altered gait speed, step length and frequency, and cadence [57–60]. These gait deficiencies are closely associated with an increased risk of falls and fractures in DM1 patients (Bachasson et al., 2016; Galli et al., 2012; Kim et al., 2020; Pucillo et al., 2018), with the prevalence of falls ranging from 30-70% and fall-related fractures from 11-17% [49, 60, 63]. Additionally, individuals with DM1 experience a twofold risk of falling compared to healthy controls aged over 65.

Furthermore, a 5-year follow-up study noted significant deterioration of gait parameters and muscle strength, balance, and performance-based measures,

resulting in a significant increase in reported walking difficulties [52].

### 3.1.3. Weight loss

Unintentional weight loss or shrinking is another common feature contributing to the frailty phenotype. In the context of aging, weight loss often occurs due to reduced food intake [64]. This weight loss can be attributed to various age-related changes, such as loss of appetite, gastrointestinal alterations, metabolic changes, altered taste and smell, and psychological and social factors [65]. Additionally, illness and the effects of medications can further contribute to weight loss. This weight loss can lead to nutritional deficiencies and is often accompanied by sarcopenia, defined as the loss of skeletal muscle mass and function due to aging [66].

In the case of DM1, two distinct phenotypes can be found in patients: the atrophic phenotype and the overweight or obesity phenotype, with the latter being the most predominant. Indeed, some studies have shown that overweight and obesity are prevalent in DM1, affecting 50% and 25-50% of patients, respectively [67, 68]. Furthermore, studies on body composition in DM1 have reported alterations such as increased fat mass (FM) and visceral obesity and decreased fat-free mass (FFM), even in patients with a normal body mass index [55, 67, 69, 70]. These changes could be due to physical inactivity, poor dietary habits, and metabolic alterations such as insulin resistance [71]. These findings suggest the potential presence of both sarcopenic obesity (co-existence of sarcopenia and obesity) and osteosarcopenia (co-existence of sarcopenia and osteoporosis) in DM1 patients [72, 73].

On the other hand, concerning the atrophic phenotype, there is a lack of literature specifically addressing weight loss in DM1 patients. However, certain clinical features of the condition may contribute to unintentional weight loss. One significant feature is the high prevalence of gastrointestinal dysfunction in DM1 patients [74, 75], which includes symptoms such as dysphagia (difficulty in swallowing), abdominal pain, constipation, and diarrhea. Dysphagia, present in approximately 55% of DM1 patients [76], is not only a significant risk factor for aspiration pneumonia but can also lead to malnutrition and unintentional weight loss [77], further exacerbating nutritional deficiencies and muscle wasting associated with physical frailty.

While no longitudinal studies have addressed weight loss specifically in DM1, certain studies on body composition have yielded inconsistent results. One study reported a significant increase in total FM and a decrease in total FFM [55]. In contrast, another study with a similar follow-up period showed a significant reduction in both
trunk FM and FFM [69], suggesting the possibility of
weight loss.

3.1.4. Exhaustion/fatigue

Exhaustion or fatigue is considered a central component
of frailty and is characterized by poor endurance and
energy. The Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition, [78] defines fatigue as a state
associated with reduced physical and/or mental resources,
ranging from general lethargy to a specific burning
sensation in the muscles induced by work. Although
measures of fatigue in frailty vary, most refer to fatigue as
a general feeling of tiredness or diminished energy and
endurance rather than muscle fatigability [79, 80].

Fatigue is highly prevalent in DM1, affecting 50-90% of individuals with the condition [81-86]. This prevalence is higher than in other neuromuscular disorders [87]. Fatigue in DM1 is not necessarily related to muscular impairment, as patients with mild muscle symptoms can experience severe fatigue.

In DM1 patients, fatigue has been found to correlate with disease severity markers, such as muscular impairment and molecular defect (CTG), as well as psychological features and quality of life [82, 85, 86, 88]. Moreover, fatigue is commonly associated with another CNS-related symptom, daytime excessive sleepiness [82], a common feature within this population. Notably, in older adults, daytime sleepiness has been associated with sarcopenia, an increased risk of falls, age-related comorbidities, and mortality [89, 90].

Although inconclusive, longitudinal studies suggest
that fatigue levels and the proportion of patients with
fatigue tend to increase over time and are also associated
with age [82, 85, 87].

3.1.5. Low physical activity

Frailty phenotype is also characterized by low levels of
physical activity, which is considered one of the key
determinants of frailty [91]. Physical activity tends to
decrease with aging [92], and physical inactivity and
sedentary behavior are prevalent among older adults [93].
Lack of physical activity is considered a risk factor for
incident frailty [91, 94, 95] and is linked to reduced
muscle mass and strength [96], along with increased risk
of disease, disability, and mortality [97].

Studies have reported that DM1 patients encounter
significant physical activity or fitness challenges, often
requiring assistance [98–102]. Research indicates that
DM1 patients are less physically active compared to
healthy adults or the reference population, as measured by
objective and subjective techniques [60, 103], with half of
the studied patients meeting the minimum requirements

for WHO-recommended physical activity [104].
Sedentary DM1 patients tend to present worse functional
performance, suggesting that physical activity could have
a protective effect on the loss of functional ability [53].

In the study by Knak and colleagues [104], the low physical activity levels observed in DM1 patients are attributed to several factors, including the high prevalence of muscle weakness, fatigue, apathy, and cognitive impairment, along with other challenges such as financial difficulties or limited access to facilities. However, their study identified education as the only significant predictor of physical activity among DM1 patients [104].

In this regard, a longitudinal study reported a significant decrease in physical activity over a nine-year period among DM1 patients, with levels falling below those of healthy adults aged 55-64 at baseline [105]. The authors suggested that these changes reflect not only aging effects but also disease-specific factors inherent to DM1.

An interventional study involving cognitive behavioral therapy combined with optional graded exercise in DM1 patients significantly improved physical activity levels and exercise capacity and lowered fatigue compared to standard care alone [106]. Another study found that an activity-stimulating behavioral intervention improved the capacity for activity and participation in the intervention group, while the standard care group saw a decline. However, physical activity levels remained stable in both groups [107].

Regular physical activity is essential for maintaining
muscle strength [108]. Therefore, low physical activity in
DM1 could contribute to muscle disuse, resulting in
decreased strength and potentially leading to further
muscle atrophy. This situation exacerbates the risk of poor
health outcomes, disability, and frailty.

3.2. Psychosocial factors contributing to frailty in DM1

3.2.1. Psychological factors

While the concept of psychological frailty lacks a
universally accepted definition, a recent scoping review
[109] identified common psychological components
contributing to frailty. These components include mood
alterations (depression, sadness), cognitive alteration
(cognitive deficits, dementia), other mental health
concerns (anxiety, poor coping, and loneliness), and
fatigue-related problems (including fatigue, exhaustion,
and loss of energy).

Various studies have reported a bidirectional
relationship between psychological/cognitive function
and physical frailty [110–113]. Both psychological
symptoms and cognitive impairment or reduced cognitive
reserve can potentially increase vulnerability to stressors
and the risk of adverse health outcomes, such as neurodegenerative processes [114–116].

In DM1, alongside muscular impairment, patients often present central nervous system involvement, including brain alterations, cognitive impairment, and symptoms such as apathy, fatigue, and daytime sleepiness [117]. Concerning cognition, these patients tend to have a slightly diminished IQ and cognitive deficits across various domains [118, 119], including social cognition [120], and longitudinal studies have indicated a slow progressive decline in cognitive function [121–128], suggesting a neurodegenerative process. However, it remains challenging to determine whether these cognitive deficits in DM1 are primarily associated with disease-related alterations in early-life stages (e.g., neurodevelopmental) or are linked to an additional neurodegenerative process derived from aging.

Regarding the psychopathological profile of DM1 patients, these individuals often face chronic and progressive conditions that evoke challenging emotions such as frustration, anxiety, and sadness [8]. Various studies, including a meta-analysis [129–131], have revealed mild psychopathological problems in DM1 patients, with higher rates of mood disorders (19% depression, 17% anxiety, and 55% apathy), somatic disorders, and personality disorders compared to the healthy population. Apathy emerges as the most prevalent psychological symptom in DM1, and interestingly, recent studies in the general older adult population have linked apathy to incident frailty and disability, with apathetic individuals presenting a higher risk of being classified as pre-frail or frail [132–134].

### 3.2.2. Social factors

Social factors are also significant contributors to frailty. Frailty is associated with social vulnerability, characterized by a lack of essential social resources needed to fulfill basic social requirements. This vulnerability includes increased loneliness and social isolation, inadequate social support, reduced social participation, and declining self-management abilities [135, 136]. Social factors constitute a crucial component associated with an elevated risk of adverse medical events and mortality.

Studies consistently highlight challenges in daily activities and disrupted social participation in DM1 patients, including difficulties in recreational activities, social interactions, and employment [98–102]. Follow-up studies indicate a progressive decline in both daily and social activities in DM1 patients [105].

Other studies in DM1 also identified unmet needs in social and personal care despite adequate medical attention [137], along with indicators of socioeconomic

deprivation, such as poor academic achievement, high unemployment rates, low family income, and a greater need for social assistance compared to the healthy population [138]. Determinants of this social dysfunction in DM1 include disease-related factors (disease duration, impaired social cognition, apathy, fatigue, and muscular impairment) and environmental factors (limited social network, stigma, low educational attainment, and unemployment), all contributing to difficulties in the social domain [99, 105, 139–141].

## 4. Conclusions and future directions

This narrative review is the first study to explore the common clinical characteristics between frailty and DM1, focusing on the frailty phenotype criteria as characterized by Fried [17], along with the psychosocial factors potentially contributing to frailty.

The main finding of this review is the substantial overlap of the Fried's frailty phenotype criteria with the symptomatology characteristic of DM1. Evidence has been gathered to suggest that DM1 patients meet at least four frailty phenotype criteria. Specifically, the literature confirms that DM1 patients commonly experience muscular weakness [45, 46], slow gait speed [57–60], fatigue/exhaustion [81–85], and reduced physical activity [60, 103, 104]. However, there is no conclusive evidence supporting unintentional weight loss in DM1. Although there is a tendency towards overweight and obesity in these patients [67, 68], this does not rule out the possibility of the coexistence of overweight/obesity and weight loss. Notably, DM1 patients present both low muscle mass and high adiposity [55, 67, 69], resembling characteristics observed in sarcopenic obesity [72].

In addition, longitudinal studies in DM1 have reported a deterioration of the frailty phenotype criteria over time. Specifically, muscle weakness tends to worsen progressively [42, 51, 53, 142], and gait parameters, including speed, significantly decline [52]. Additionally, fatigue levels have been observed to increase with age [82, 85, 87], and physical activity decreases significantly over time [105] in DM1.

Beyond the physical domain, psychosocial factors, including psychological, cognitive, and social factors, could also influence the risk profile of the DM1 population. DM1 patients often show slight cognitive deficits [118] and experience a gradual decline in cognitive function over time [121–125]. Psychopathological symptoms, particularly apathy, are prevalent among these patients [129, 130]. Additionally, DM1 patients encounter challenges in social functioning, including difficulties in daily activities, reduced social participation, and lower levels of education and
employment [98–102], which tend to worsen progressively over time [105].

The primary challenge in studying frailty in DM1 lies in the potential overlap between frailty and DM1 symptomatology. Given the complex, multisystemic nature of the disease, it is difficult to conclusively attribute frailty to specific disease characteristics, the potential accelerated aging processes, or an interaction between both. As highlighted in this review, there is a notable absence of studies specifically addressing frailty in DM1. Consequently, one of the main limitations is that frailty could only be examined by separately analyzing the components of the frailty phenotype in DM1. Additionally, there is a potential bias since only articles meeting the inclusion criteria and deemed relevant to the objectives of this narrative review were included, which may have resulted in the omission of certain pertinent studies. It is also important to note that the reviewed studies were conducted on adult DM1 patients with varying phenotypes (based on age of onset), which should be considered when generalizing the conclusions. Finally, beyond the limitations of this review, it is crucial to recognize that the reviewed studies might have their own biases and limitations, such as small sample sizes, which are inherent constraints in the study of a rare disease like DM1.

Frailty is characterized by its potential reversibility in healthy older adults [15], highlighting the importance of its identification and management. However, it remains to be explored whether frailty symptoms could be reversed in clinical populations (or in the case of disease-related frailty), particularly in DM1 patients.

Studying frailty in DM1 could provide valuable insights for identifying vulnerable individuals at risk of adverse health outcomes and mortality. Moreover, monitoring and managing frailty in this clinical population could have important implications for the clinical care of these patients. Beyond the usual clinical approach of DM1 patients, identifying and stratifying them based on their frailty status could facilitate the implementation of targeted prevention and intervention programs for the most vulnerable individuals. These initiatives could aid in preventing, decelerating, and even reversing frailty, thereby potentially delaying the onset of disability in this population. Such efforts could be key in improving patients' health-related quality of life since a recent study reported that disease-related frailty might progress to disability more rapidly than age-related frailty [23].

Understanding how frailty impacts prognosis and mortality in DM1 is essential. Therefore, future research should focus on determining the prevalence of frailty in the DM1 population and its relationship with disease-specific features (molecular defect, muscular impairment,

and multisystemic involvement), and adverse health outcomes. Studies addressing common biological mechanisms between DM1, and frailty would also be of particular interest. Additionally, longitudinal studies are needed to track the natural progression of DM1 and frailty components over time and address the effects of interventions on frailty. Such research would provide valuable insights into the impact of frailty on clinical manifestations.

In summary, this narrative review has identified physical, psychological, and social features in the DM1 population that align with or are associated with frailty and support the idea of an ongoing accelerated aging process. These findings suggest a potentially higher prevalence of frailty in DM1, which may contribute to an increased risk of adverse health outcomes and mortality. Insights gained from studying frailty in DM1 patients could inform the development of effective interventions to mitigate disease progression and prevent adverse outcomes and disability in vulnerable individuals.

## Acknowledgements

This work was supported by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (Ref: 609), from the Institute of Health Carlos III co-founded by the European Union [PI22/01118 to Andone Sistiaga]; Basque Government [2022111031 to Andone Sistiaga; IT1732-22 to Joana Garmendia, Garazi Labayru, Andone Sistiaga and Adolfo López de Munain]; University of the Basque Country [PIF 20/238 to Joana Garmendia]. This work was performed in the context of the IHU HealthAge, which was benefited from funding by the Agence Nationale de la Recherche under the France 2030 program [ANR-23-IAHU-0011 to Philipe de Souto Barreto].

## References

[1] Harper P Myotonic dystrophy., 3rd ed. Saunders: London, UK; 2001.

[2] Hunter A, Tsilfidis C, Mettler G, Jacob P, Mahadevan M, Surh L, et al. (1992). The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy. J Med Genet, 29:774-779.

[3] Wenninger S, Cumming SA, Gutschmidt K, Okkersen K, Jimenez-Moreno AC, Daidj F, et al. (2021). Associations Between Variant Repeat Interruptions and Clinical Outcomes in Myotonic Dystrophy Type 1. Neurol Genet, 7:e572.

[4] Thornton CA (2014). Myotonic Dystrophy. Neurol Clin, 32:705-719.

[5] Turner C, Hilton-Jones D (2014). Myotonic dystrophy: diagnosis, management and new therapies. Curr Opin Neurol, 27:599-606.
[6] Axford MM, Pearson CE (2013). Illuminating CNS and cognitive issues in myotonic dystrophy: Workshop report. Neuromuscul Disord, 23:370-374.

[7] Bugiardini E, Meola G, Alvarez C, Angeard N, Bassez G, Day JW, et al. (2014). Consensus on cerebral involvement in myotonic dystrophy. Workshop report: May 24-27, 2013, Ferrere (AT), Italy. Neuromuscul Disord, 24:445-452.

[8] Pater R, Zaldua JG, Gallais B, Graham C, Voet N (2023). 267th ENMC International Workshop: Psychological Interventions for Improving Quality of Life in Slowly Progressive Neuromuscular Disorders. Neuromuscul Disord, S0960896623000962.

[9] Margolick JB, Ferrucci L (2015). Accelerating aging research: How can we measure the rate of biologic aging? Exp Gerontol, 64:78-80.

[10] García-Puga M, Saenz-Antoñanzas A, Gerenu G, Arrieta-Legorburu A, Fernández-Torrón R, Zulaica M, et al. (2022). Senescence plays a role in myotonic dystrophy type 1. JCI Insight, 7:e159357.

[11] Hasuike Y, Mochizuki H, Nakamori M (2022). Cellular Senescence and Aging in Myotonic Dystrophy. Int J Mol Sci, 23:2339.

[12] Hasuike Y, Mochizuki H, Nakamori M (2022). Expanded CUG Repeat RNA Induces Premature Senescence in Myotonic Dystrophy Model Cells. Front Genet, 13:865811.

[13] Mateos-Aierdi AJ, Goicoechea M, Aiastui A, Fernández-Torrón R, Garcia-Puga M, Matheu A, et al. (2015). Muscle wasting in myotonic dystrophies: a model of premature aging. Front Aging Neurosci. doi: 10.3389/fnagi.2015.00125.

[14] Meinke P, Hintze S, Limmer S, Schoser B (2018). Myotonic Dystrophy—A Progeroid Disease? Front Neurol, 9:601.

[15] Kolle AT, Lewis KB, Lalonde M, Backman C (2023). Reversing frailty in older adults: a scoping review. BMC Geriatr, 23:751.

[16] Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K (2013). Frailty in elderly people. The Lancet, 381:752-762.

[17] Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. (2001). Frailty in Older Adults: Evidence for a Phenotype. J Gerontol A Biol Sci Med Sci, 56:M146-M157.

[18] Ellwood A, Quinn C, Mountain G (2022). Psychological and Social Factors Associated with Coexisting Frailty and Cognitive Impairment: A Systematic Review. Res Aging, 44:448-464.

[19] Gobbens RJJ, Van Assen MALM (2014). The prediction of quality of life by physical, psychological and social components of frailty in community-dwelling older people. Qual Life Res, 23:2289-2300.

[20] Gobbens RJJ, Van Assen MALM (2017). Associations between multidimensional frailty and quality of life among Dutch older people. Arch Gerontol Geriatr, 73:69-76.

[21] Wang H, Wang J, Xie B, Liu B, Wang J (2021). Multi-dimensional frailty and its risk factors among older

residents in long-term care facilities in Shanghai, China. Int J Nurs Sci, 8:298-303.

[22] Belloni G, Cesari M (2019). Frailty and Intrinsic Capacity: Two Distinct but Related Constructs. Front Med, 6:133.

[23] Angioni D, Macaron T, Takeda C, Sourdet S, Cesari M, Giudici KV, et al. (2020). Can We Distinguish Age-Related Frailty from Frailty Related to Diseases? Data from the MAPT Study. J Nutr Health Aging, 24:1144-1151.

[24] Ayrignac X, Larochelle C, Keezer M, Roger E, Poirier J, Lahav B, et al. (2021). Frailty in ageing persons with multiple sclerosis. Mult Scler J, 27:613-620.

[25] McMillan JM, Michalchuk Q, Goodarzi Z (2021). Frailty in Parkinson's disease: A systematic review and meta-analysis. Clin Park Relat Disord, 4:100095.

[26] Cristofori G, Aguado Ortego R, Gómez Pavón J (2023). Concepto y manejo práctico de la fragilidad en neurología. Rev Neurol, 76:327.

[27] Ward DD, Ranson JM, Wallace LMK, Llewellyn DJ, Rockwood K (2022). Frailty, lifestyle, genetics and dementia risk. J Neurol Neurosurg Psychiatry, 93:343-350.

[28] Kelaiditi E, Andrieu S, Cantet C, Vellas B, Cesari M, the ICTUS/DSA Group (2016). Frailty Index and Incident Mortality, Hospitalization, and Institutionalization in Alzheimer's Disease: Data From the ICTUS Study. J Gerontol A Biol Sci Med Sci, 71:543-548.

[29] Baione V, Canevelli M, Belvisi D, Buscarini MC, Bellucci G, Fantozzi R, et al. (2023). Frailty and relapse activity in multiple sclerosis: A longitudinal observation. Mult Scler Relat Disord, 72:104603.

[30] Belvisi D, Canevelli M, Costanzo M, Giangrosso M, Fabbrini A, Borraccino A, et al. (2022). The role of frailty in Parkinson's disease: a cross-sectional study. J Neurol, 269:3006-3014.

[31] Alshaikh JT, Amdur R, Sidawy A, Trachiotis G, Kaminski HJ (2016). Thymectomy is safe for myasthenia gravis patients: Analysis of the NSQIP database. Muscle Nerve, 53:370-374.

[32] Strang P, Schultz T, Ozanne A (2024). Partly unequal receipt of healthcare in last month of life in amyotrophic lateral sclerosis: a retrospective cohort study of the Stockholm region. Ups J Med Sci. doi: 10.48101/ujms.v129.9856.

[33] Wohlin C (2014). Guidelines for snowballing in systematic literature studies and a replication in software engineering. Proc. 18th Int. Conf. Eval. Assess. Softw. Eng. London England United Kingdom: ACM, 1-10.

[34] Dodds RM, Syddall HE, Cooper R, Benzeval M, Deary IJ, Dennison EM, et al. (2014). Grip Strength across the Life Course: Normative Data from Twelve British Studies. PLoS ONE, 9:e113637.

[35] Bohannon RW (2019). Grip Strength: An Indispensable Biomarker For Older Adults. Clin Interv Aging, Volume 14:1681-1691.

[36] Stevens PJ, Syddall HE, Patel HP, Martin HJ, Cooper C, Aihie Sayer A (2012). Is grip strength a good marker
of physical performance among community-dwelling older people? J Nutr Health Aging, 16:769-774.

[37] Stringa N, Van Schoor NM, Hoogendijk EO, Milaneschi Y, Huisman M (2023). The phenotypic and genotypic association of grip strength with frailty, physical performance and functional limitations over time in older adults. Age Ageing, 52:afad189.

[38] Taekema DG, Gussekloo J, Maier AB, Westendorp RGJ, De Craen AJM (2010). Handgrip strength as a predictor of functional, psychological and social health. A prospective population-based study among the oldest old. Age Ageing, 39:331-337.

[39] Choe Y, Jeong J, Kim Y (2020). Grip strength mediates the relationship between muscle mass and frailty. J Cachexia Sarcopenia Muscle, 11:441-451.

[40] Cooper R, Kuh D, Hardy R, Mortality Review Group, on behalf of the FALCon and HALCyon study teams (2010). Objectively measured physical capability levels and mortality: systematic review and meta-analysis. BMJ, 341:c4467-c4467.

[41] Strand BH, Cooper R, Bergland A, Jørgensen L, Schirmer H, Skirbekk V, et al. (2016). The association of grip strength from midlife onwards with all-cause and cause-specific mortality over 17 years of follow-up in the Tromsø Study. J Epidemiol Community Health, 70:1214-1221.

[42] Ozimski LL, Sabater-Arcis M, Bargiela A, Artero R (2021). The hallmarks of myotonic dystrophy type 1 muscle dysfunction. Biol Rev, 96:716-730.

[43] LoRusso S, Weiner B, Arnold WD (2018). Myotonic Dystrophies: Targeting Therapies for Multisystem Disease. Neurotherapeutics, 15:872-884.

[44] Sugimoto M, Kuru S, Takada H, Horie R, Yamauchi K, Kubota T, et al. (2022). Characteristics of myotonic dystrophy patients in the national registry of Japan. J Neurol Sci, 432:120080.

[45] Hogrel J, Ollivier G, Ledoux I, Hébert LJ, Eymard B, Puymirat J, et al. (2017). Relationships between grip strength, myotonia, and CTG expansion in myotonic dystrophy type 1. Ann Clin Transl Neurol, 4:921-925.

[46] Moxley RT, Logigian EL, Martens WB, Annis CL, Pandya S, Moxley RT, et al. (2007). Computerized hand grip myometry reliably measures myotonia and muscle strength in myotonic dystrophy (DM1). Muscle Nerve, 36:320-328.

[47] Andersen G, Ørgreen MC, Preisler N, Colding-Jørgensen E, Clausen T, Duno M, et al. (2013). Muscle phenotype in patients with myotonic dystrophy type 1. Muscle Nerve, 47:409-415.

[48] Hammarén E, Kollén L (2021). What Happened with Muscle Force, Dynamic Stability And Falls? A 10-Year Longitudinal Follow-Up in Adults with Myotonic Dystrophy Type 1. J Neuromuscul Dis, 8:1007-1016.

[49] Jiménez-Moreno AC, Raaphorst J, Babačić H, Wood L, Van Engelen B, Lochmüller H, et al. (2018). Falls and resulting fractures in Myotonic Dystrophy: Results from a multinational retrospective survey. Neuromuscul Disord, 28:229-235.

[50] Berends J, Tieleman AA, Horlings CGC, Smulders FHP, Voermans NC, Van Engelen BGM, et al. (2019).

High incidence of falls in patients with myotonic dystrophy type 1 and 2: A prospective study. Neuromuscul Disord, 29:758-765.

[51] Gagnon C, Petitclerc É, Kierkegaard M, Mathieu J, Duchesne É, Hébert LJ (2018). A 9-year follow-up study of quantitative muscle strength changes in myotonic dystrophy type 1. J Neurol, 265:1698-1705.

[52] Hammarén E, Kjellby-Wendt G, Lindberg C (2015). Muscle force, balance and falls in muscular impaired individuals with myotonic dystrophy type 1: A five-year prospective cohort study. Neuromuscul Disord, 25:141-148.

[53] Roussel M-P, Fiset M-M, Gauthier L, Lavoie C, McNicoll É, Pouliot L, et al. (2021). Assessment of muscular strength and functional capacity in the juvenile and adult myotonic dystrophy type 1 population: a 3-year follow-up study. J Neurol, 268:4221-4237.

[54] Raymond K, Levasseur M, Mathieu J, Desrosiers J, Gagnon C (2017). A 9-year follow-up study of the natural progression of upper limb performance in myotonic dystrophy type 1: A similar decline for phenotypes but not for gender. Neuromuscul Disord, 27:673-682.

[55] Sedehizadeh S, Brook JD, Maddison P (2017). Body composition and clinical outcome measures in patients with myotonic dystrophy type 1. Neuromuscul Disord, 27:286-289.

[56] Bortone I, Sardone R, Lampignano L, Castellana F, Zupo R, Lozupone M, et al. (2021). How gait influences frailty models and health-related outcomes in clinical-based and population-based studies: a systematic review. J Cachexia Sarcopenia Muscle, 12:274-297.

[57] Bachasson D, Moraux A, Ollivier G, Decostre V, Ledoux I, Gidaro T, et al. (2016). Relationship between muscle impairments, postural stability, and gait parameters assessed with lower-trunk accelerometry in myotonic dystrophy type 1. Neuromuscul Disord, 26:428-435.

[58] Galli M, Cimolin V, Crugnola V, Priano L, Menegoni F, Trotti C, et al. (2012). Gait pattern in myotonic dystrophy (Steinert disease): A kinematic, kinetic and EMG evaluation using 3D gait analysis. J Neurol Sci, 314:83-87.

[59] Kim S, Lim Y-H, Kang K, Park D, Lee H-W, Park J-S (2020). Functional Ambulation Profile (FAP) Score as a Potential Marker of Gait Analysis in Myotonic Dystrophy Type 1. Front Neurol, 11:392.

[60] Wiles CM (2005). Falls and stumbles in myotonic dystrophy. J Neurol Neurosurg Psychiatry, 77:393-396.

[61] Filli L, Schwegler S, Meyer C, Killeen T, Easthope CS, Broicher SD, et al. (2020). Characterizing cognitive-motor impairments in patients with myotonic dystrophy type 1. Neuromuscul Disord, 30:510-520.

[62] Pucillo EM, Mcintyre MM, Pautler M, Hung M, Bounsanga J, Voss MW, et al. (2018). Modified dynamic gait index and limits of stability in myotonic dystrophy type 1. Muscle Nerve, 58:694-699.
[63] Passeri E, Sansone VA, Sconfienza LM, Messina C, Meola G, Corbetta S (2020). Fragility fractures and bone mineral density in male patients affected by type 1 and type 2 myotonic dystrophy. Neuromuscul Disord, 30:28-34.

[64] Bales CW, Ritchie CS (2002). Sarcopenia, weight loss, and nutritional frailty in the elderly. Annu Rev Nutr, 22:309-323.

[65] McDonald RB, Ruhe RodneyC (2010). Changes in Food Intake and Its Relationship to Weight Loss during Advanced Age. In: Mobbs CV, Hof PR, editors Interdiscip. Top. Gerontol. Geriatr. S. Karger AG, 51-63.

[66] Morley JE (2010). Anorexia, Weight Loss, and Frailty. J Am Med Dir Assoc, 11:225-228.

[67] Peric S, Bozovic I, Nisic T, Banovic M, Vujnic M, Svabic T, et al. (2019). Body composition analysis in patients with myotonic dystrophy types 1 and 2. Neurol Sci, 40:1035-1040.

[68] Pruna L, Chatelin J, Pascal-Vigneron V, Kaminsky P (2011). Regional body composition and functional impairment in patients with myotonic dystrophy. Muscle Nerve, 44:503-508.

[69] Kikuchi K, Satake M, Furukawa Y, Terui Y (2022). Assessment of body composition, metabolism, and pulmonary function in patients with myotonic dystrophy type 1. Medicine (Baltimore), 101:e30412.

[70] Joosten IBT, Fuchs CJ, Beelen M, Plasqui G, Van Loon LJC, Faber CG (2023). Energy Expenditure, Body Composition, and Skeletal Muscle Oxidative Capacity in Patients with Myotonic Dystrophy Type 1. J Neuromuscul Dis, 10:701-712.

[71] Mateus T, Martins F, Nunes A, Herdeiro MT, Rebelo S (2021). Metabolic Alterations in Myotonic Dystrophy Type 1 and Their Correlation with Lipin. Int J Environ Res Public Health, 18:1794.

[72] Donini LM, Busetto L, Bischoff SC, Cederholm T, Ballesteros-Pomar MD, Batsis JA, et al. (2022). Definition and Diagnostic Criteria for Sarcopenic Obesity: ESPEN and EASO Consensus Statement. Obes Facts, 15:321-335.

[73] Huo YR, Suriyaarachchi P, Gomez F, Curcio CL, Boersma D, Muir SW, et al. (2015). Phenotype of Osteosarcopenia in Older Individuals With a History of Falling. J Am Med Dir Assoc, 16:290-295.

[74] Fisette-Paulhus I, Gagnon C, Girard-Côté L, Morin M (2022). Genitourinary and lower gastrointestinal conditions in patients with myotonic dystrophy type 1: A systematic review of evidence and implications for clinical practice. Neuromuscul Disord, 32:361-376.

[75] Hilbert JE, Barohn RJ, Clemens PR, Luebbe EA, Martens WB, McDermott MP, et al. (2017). High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2. Neurology, 89:1348-1354.

[76] Gutiérrez Gutiérrez G, Díaz-Manera J, Almendrote M, Azriel S, Eulalio Bárcena J, Cabezudo García P, et al. (2020). Guía clínica para el diagnóstico y seguimiento de la distrofia miotónica tipo 1, DM1 o enfermedad de Steinert. Neurología, 35:185-206.

[77] LaDonna KA, Koopman WJ, Venance SL (2011). Myotonic dystrophy (DM1) and dysphagia: the need for dysphagia management guidelines and an assessment tool. Can J Neurosci Nurs, 33:42-46.

[78] American Psychiatric Association Diagnostic and statistical manual of mental disorders (5th ed.), 5th ed. 2013.

[79] Knoop V, Costenoble A, Vella Azzopardi R, Vermeiren S, Debain A, Jansen B, et al. (2019). The operationalization of fatigue in frailty scales: a systematic review. Ageing Res Rev, 53:100911.

[80] Theou O, Jones GR, Overend TJ, Kloseck M, Vandervoort AA (2008). An exploration of the association between frailty and muscle fatigue. Appl Physiol Nutr Metab, 33:651-665.

[81] Heatwole C, Bode R, Johnson N, Quinn C, Martens W, McDermott MP, et al. (2012). Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1). Neurology, 79:348-357.

[82] Laberge L, Gallais B, Auclair J, Dauvilliers Y, Mathieu J, Gagnon C (2020). Predicting daytime sleepiness and fatigue: a 9-year prospective study in myotonic dystrophy type 1. J Neurol, 267:461-468.

[83] Landfeldt E, Nikolenko N, Jimenez-Moreno C, Cumming S, Monckton DG, Gorman G, et al. (2019). Disease burden of myotonic dystrophy type 1. J Neurol, 266:998-1006.

[84] Menting J, Tack CJ, Bleijenberg G, Donders R, Droogleever Fortuyn HA, Fransen J, et al. (2018). Is fatigue a disease-specific or generic symptom in chronic medical conditions? Health Psychol, 37:530-543.

[85] Peric S, Bjelica B, Bozovic I, Pesovic J, Paunic T, Banovic M, et al. (2019). Fatigue in myotonic dystrophy type 1: a seven-year prospective study. Acta Myol Myopathies Cardiomyopathies Off J Mediterr Soc Myol, 38:239-244.

[86] Erokhina EK, Melnik EA, Lebedeva DD, Shamtieva KV, Peters TV, Pavlikova EP, et al. (2024). Sleep Disorders and Fatigue in Patients with Different Forms of Myotonic Dystrophy Type 1. Neurosci Behav Physiol, 54:35-40.

[87] Kalkman JS (2005). Experienced fatigue in facioscapulohumeral dystrophy, myotonic dystrophy, and HMSN-I. J Neurol Neurosurg Psychiatry, 76:1406-1409.

[88] Laberge L, Dauvilliers Y, Bégin P, Richer L, Jean S, Mathieu J (2009). Fatigue and daytime sleepiness in patients with myotonic dystrophy type 1: to lump or split? Neuromuscul Disord NMD, 19:397-402.

[89] Piovezan RD, Jadczak AD, Tucker G, Visvanathan R (2023). Daytime Sleepiness Predicts Mortality in Nursing Home Residents: Findings from the Frailty in Residential Aged Care Sector Over Time (FIRST) Study. J Am Med Dir Assoc, 24:1458-1464.e4.

[90] Soysal P, Smith L, Tan SG, Capar E, Veronese N, Yang L (2021). Excessive daytime sleepiness is associated with an increased frequency of falls and sarcopenia. Exp Gerontol, 150:111364.
[91] Sobhani A, Sharifi F, Fadayevatan R, Kamrani AAA, Moodi M, Khorashadizadeh M, et al. (2022). Low physical activity is the strongest factor associated with frailty phenotype and frailty index: data from baseline phase of Birjand Longitudinal Aging Study (BLAS). BMC Geriatr, 22:498.

[92] Milanovic Z, Jorgić B, Trajković N, Sporis, Pantelić S, James (2013). Age-related decrease in physical activity and functional fitness among elderly men and women. Clin Interv Aging, 549.

[93] Harvey J, Chastin S, Skelton D (2013). Prevalence of Sedentary Behavior in Older Adults: A Systematic Review. Int J Environ Res Public Health, 10:6645-6661.

[94] Blodgett J, Theou O, Kirkland S, Andreou P, Rockwood K (2015). The association between sedentary behaviour, moderate-vigorous physical activity and frailty in NHANES cohorts. Maturitas, 80:187-191.

[95] O'Connell ML, Coppinger T, McCarthy AL (2020). The role of nutrition and physical activity in frailty: A review. Clin Nutr ESPEN, 35:1-11.

[96] Ramsey KA, Rojer AGM, D'Andrea L, Otten RHJ, Heymans MW, Trappenburg MC, et al. (2021). The association of objectively measured physical activity and sedentary behavior with skeletal muscle strength and muscle power in older adults: A systematic review and meta-analysis. Ageing Res Rev, 67:101266.

[97] McPhee JS, French DP, Jackson D, Nazroo J, Pendleton N, Degens H (2016). Physical activity in older age: perspectives for healthy ageing and frailty. Biogerontology, 17:567-580.

[98] Gagnon C, Mathieu J, Noreau L (2007). Life habits in myotonic dystrophy type 1. J Rehabil Med, 39:560-566.

[99] Garmendia J, Labayru G, Aliri J, De Munain AL, Sistiaga A (2023). Executive functions and daily functioning in DM1: ecological assessment with Virtual Reality. Neuromuscul Disord, S0960896623007514.

[100] Kierkegaard M, Harms-Ringdahl K, Holmqvist LW, Tollbäck A (2011). Functioning and disability in adults with myotonic dystrophy type 1. Disabil Rehabil, 33:1826-1836.

[101] Landfeldt E, Nikolenko N, Jimenez-Moreno C, Cumming S, Monckton DG, Faber CG, et al. (2020). Activities of daily living in myotonic dystrophy type 1. Acta Neurol Scand, 141:380-387.

[102] Van Heugten C, Meuleman S, Hellebrekers D, Kruitwagen-van Reenen E, Visser-Meily J (2018). Participation and the Role of Neuropsychological Functioning in Myotonic Dystrophy Type 1. J Neuromuscul Dis, 5:205-214.

[103] Gagnon C, Chouinard M-C, Laberge L, Brisson D, Gaudet D, Lavoie M, et al. (2013). Prevalence of Lifestyle Risk Factors in Myotonic Dystrophy Type 1. Can J Neurol Sci J Can Sci Neurol, 40:42-47.

[104] Knak KL, Sheikh AM, Witting N, Vissing J (2020). Physical activity in myotonic dystrophy type 1. J Neurol, 267:1679-1686.

[105] Raymond K, Levasseur M, Mathieu J, Gagnon C (2019). Progressive Decline in Daily and Social Activities: A 9-year Longitudinal Study of Participation in Myotonic Dystrophy Type 1. Arch Phys Med Rehabil, 100:1629-1639.

[106] Okkersen K, Jimenez-Moreno C, Wenninger S, Daidj F, Glennon J, Cumming S, et al. (2018). Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial. Lancet Neurol, 17:671-680.

[107] Heskamp L, Okkersen K, Van Nimwegen M, Ploegmakers MJ, Bassez G, Deux J-F, et al. (2020). Quantitative Muscle MRI Depicts Increased Muscle Mass after a Behavioral Change in Myotonic Dystrophy Type 1. Radiology, 297:132-142.

[108] Vignos PJ (1983). Physical models of rehabilitation in neuromuscular disease. Muscle Nerve, 6:323-338.

[109] Zhao J, Liu YWJ, Tyrovolas S, Mutz J (2023). Exploring the concept of psychological frailty in older adults: a systematic scoping review. J Clin Epidemiol, 159:300-308.

[110] Gale CR, Cooper C, Deary IJ, Aihie Sayer A (2014). Psychological well-being and incident frailty in men and women: the English Longitudinal Study of Ageing. Psychol Med, 44:697-706.

[111] Jing Z, Li J, Wang Y, Ding L, Tang X, Feng Y, et al. (2020). The mediating effect of psychological distress on cognitive function and physical frailty among the elderly: Evidence from rural Shandong, China. J Affect Disord, 268:88-94.

[112] Liu X, Chen T, Chen S, Yatsugi H, Chu T, Kishimoto H (2022). The Relationship between Psychological Distress and Physical Frailty in Japanese Community-Dwelling Older Adults: A Cross-Sectional Study. J Frailty Aging. doi: 10.14283/jfa.2022.63.

[113] Yuan Y, Peng C, Burr JA, Lapane KL (2023). Frailty, cognitive impairment, and depressive symptoms in Chinese older adults: an eight-year multi-trajectory analysis. BMC Geriatr, 23:843.

[114] Kelaiditi E, Cesari M, Canevelli M, Abellan Van Kan G, Ousset P-J, Gillette-Guyonnet S, et al. (2013). Cognitive frailty: Rational and definition from an (I.A.N.A./I.A.G.G.) International Consensus Group. J Nutr Health Aging, 17:726-734.

[115] Navarro-Pardo E, Facal D, Campos-Magdaleno M, Pereiro A, Juncos-Rabadán O (2020). Prevalence of Cognitive Frailty, Do Psychosocial-Related Factors Matter? Brain Sci, 10:968.

[116] Sugimoto T, Arai H, Sakurai T (2022). An update on cognitive frailty: Its definition, impact, associated factors and underlying mechanisms, and interventions. Geriatr Gerontol Int, 22:99-109.

[117] Miller JN, Kruger A, Moser DJ, Gutmann L, van der Plas E, Koscik TR, et al. (2021). Cognitive Deficits, Apathy, and Hypersomnolence Represent the Core Brain Symptoms of Adult-Onset Myotonic Dystrophy Type 1. Front Neurol, 12:700796.

[118] Okkersen K, Buskes M, Groenewoud J, Kessels RPC, Knoop H, Engelen B van, et al. (2017). The cognitive
profile of myotonic dystrophy type 1: A systematic review and meta-analysis. Cortex, 95:143-155.

[119] Wu Y, Wei Q, Lin J, Shang H, Ou R (2024). Cognitive impairment, neuroimaging abnormalities, and their correlations in myotonic dystrophy: a comprehensive review. Front Cell Neurosci, 18:1369332.

[120] Leddy S, Cercignani M, Serra L, Bozzali M (2021). Social cognition in type 1 myotonic dystrophy - A mini review. Cortex J Devoted Study Nerv Syst Behav, 142:389-399.

[121] Cabada T, Díaz J, Iridoy M, López P, Jericó I, Lecumberri P, et al. (2020). Longitudinal study in patients with myotonic dystrophy type 1: correlation of brain MRI abnormalities with cognitive performances. Neuroradiology. doi: 10.1007/s00234-020-02611-9.

[122] Gallais B, Gagnon C, Mathieu J, Richer L (2017). Cognitive decline over time in adults with myotonic dystrophy type 1: A 9-year longitudinal study. Neuromuscul Disord, 27:61-72.

[123] Labayru G, Aliri J, Zulaica M, López de Munain A, Sistiaga A (2020). Age-related cognitive decline in myotonic dystrophy type 1: An 11-year longitudinal follow-up study. J Neuropsychol, 14:121-134.

[124] Modoni A, Silvestri G, Vita MG, Quaranta D, Tonali PA, Marra C (2008). Cognitive impairment in myotonic dystrophy type 1 (DM1): A longitudinal follow-up study. J Neurol, 255:1737-1742.

[125] Winblad S, Samuelsson L, Lindberg C, Meola G (2016). Cognition in myotonic dystrophy type 1: a 5-year follow-up study. Eur J Neurol, 23:1471-1476.

[126] Sansone V, Gandossini S, Cotelli M, Calabria M, Zanetti O, Meola G (2007). Cognitive impairment in adult myotonic dystrophies: A longitudinal study. Neurol Sci, 28:9-15.

[127] Fujino H, Suwazono S, Ueda Y, Kobayashi M, Nakayama T, Imura O, et al. (2023). Longitudinal Changes in Neuropsychological Functioning in Japanese Patients with Myotonic Dystrophy Type 1: A Five Year Follow-Up Study. J Neuromuscul Dis, 10:1083-1092.

[128] Gliem C, MinneropID M, Roeske S, rtner HG, Schoene-Bake J-C, Adler S, et al. (2019). Tracking the brain in myotonic dystrophies: A 5-year longitudinal follow-up study. doi: 10.1371/journal.pone.0213381.

[129] Minier L, Lignier B, Bouvet C, Gallais B, Camart N (2018). A Review of Psychopathology Features, Personality, and Coping in Myotonic Dystrophy Type 1. J Neuromuscul Dis, 5:279-294.

[130] Van Der Velden BG, Okkersen K, Kessels RP, Groenewoud J, Van Engelen B, Knoop H, et al. (2019). Affective symptoms and apathy in myotonic dystrophy type 1 a systematic review and meta-analysis. J Affect Disord, 250:260-269.

[131] Callus E, Bertoldo EG, Beretta M, Boveri S, Cardani R, Fossati B, et al. (2018). Neuropsychological and Psychological Functioning Aspects in Myotonic Dystrophy Type 1 Patients in Italy. Front Neurol, 9:751.

[132] Ayers E, Shapiro M, Holtzer R, Barzilai N, Milman S, Verghese J (2017). Symptoms of Apathy Independently Predict Incident Frailty and Disability in Community-Dwelling Older Adults. J Clin Psychiatry, 78:e529-e536.

[133] Maruta M, Shimokihara S, Makizako H, Ikeda Y, Han G, Akasaki Y, et al. (2022). Associations between apathy and comprehensive frailty as assessed by the Kihon Checklist among community-dwelling Japanese older adults. Psychogeriatrics, 22:651-658.

[134] Parrotta I, Maltais M, Rolland Y, Spampinato DA, Robert P, De Souto Barreto P, et al. (2020). The association between apathy and frailty in older adults: a new investigation using data from the Mapt study. Aging Ment Health, 24:1985-1989.

[135] Bunt S, Steverink N, Olthof J, Van Der Schans CP, Hobbelen JSM (2017). Social frailty in older adults: a scoping review. Eur J Ageing, 14:323-334.

[136] Hanlon P, Wightman H, Politis M, Kirkpatrick S, Jones C, Andrew MK, et al. (2024). The relationship between frailty and social vulnerability: a systematic review. Lancet Healthy Longev, 5:e214-e226.

[137] Holmøy AKT, Johannessen CH, Hope S, Van Walsem MR, Aanonsen NO, Hassel B (2019). Uncovering health and social care needs among myotonic dystrophy patients: Utility of the Needs and Provisions Complexity Scale. Acta Neurol Scand, 139:526-532.

[138] Laberge L, Veillette S, Mathieu J, Auclair J, Perron M (2007). The correlation of CTG repeat length with material and social deprivation in myotonic dystrophy. Clin Genet, 71:59-66.

[139] Gagnon C, Mathieu J, Jean S, Laberge L, Perron M, Veillette S, et al. (2008). Predictors of Disrupted Social Participation in Myotonic Dystrophy Type 1. Arch Phys Med Rehabil, 89:1246-1255.

[140] Gagnon C, Chouinard MC, Laberge L, Veillette S, Bégin P, Breton R, et al. (2010). Health supervision and anticipatory guidance in adult myotonic dystrophy type 1. Neuromuscul Disord, 20:847-851.

[141] Raymond K, Gagnon C, Levasseur M (2022). Multiple Case Study of Changes in Participation of Adults with Myotonic Dystrophy Type 1: Importance of Redesigning Accomplishment and Resilience. J Neuromuscul Dis, 9:731-755.

[142] Hammarén E, Kjellby-Wendt G, Kowalski J, Lindberg C (2014). Factors of importance for dynamic balance impairment and frequency of falls in individuals with myotonic dystrophy type 1 – A cross-sectional study – Including reference values of Timed Up & Go, 10m walk and step test. Neuromuscul Disord, 24:207-215.