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Five‐Year Lower Extremity Function is Associated with White Matter Abnormality in Older Adults
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"......worse initial WMT structure may predict decline in physical performance over time......Our findings suggested that white matter lesions might partially explain mobility disorders in older adults and DTI parameters of WMTs related to learning, memory, or motor control might be able to predict physical performance declines in a later period. Further longitudinal studies on paired DTIs and physical performance data at each time point are still needed to elucidate the relationship between DTI changes and physical performance evolution in older adults.Our DTI results suggest that the microstructure characteristics of some brain regions that are often involved in memory function28 can also be associated with alterations in physical performance. These results support the findings of Verwer et al.,38 who reported that poorer physical performance was associated with abnormality of white matter network regardless of the presence of vascular brain injury.
Jan 8 2021 Jnl of the American Geriatrics Society
Abstract
Objective
To explore associations between changes of lower extremity function (LEF) parameters over a 5‐year period and diffusion tensor imaging (DTI) parameters of white matter tracts among community‐dwelling older adults.
Design
A secondary analysis on image and physical function data collected from the Multidomain Alzheimer's Preventive Trial (MAPT).
Participants
208 older adults (aged 75 ± 4 years, with spontaneous memory complaint or limited instrumental daily living activity or slow gait speed, 60% female) of the MAPT‐magnetic resonance imaging (MRI) ancillary study. The time interval between a participant's enrolment and MRI scan was on average 110 ± 97 days.
Measurements
Forty‐eight white matter tracts (WMTs) were measured. LEF parameters (measured after the MRI scan) were assessed as the short physical performance battery (SPPB) score, gait speed, and chair stands time over a 5‐year period. Mixed‐effects models were performed to explore the associations between baseline DTI values and the progression of LEF parameters. Bonferroni correction was applied for multiple comparison correction.
Results
The progression of LEF was associated with 35 baseline DTI parameters from 24 WMTs. Higher baseline DTI parameter values were related to more decreases in SPPB score and gait speed, and greater increases in chair stands time. Bilateral uncinate fasciculus was associated with all LEF parameters. Other WMTs in cingulum, cerebral and cerebellar peduncle, internal capsule, and corpus callosum also showed close connections with LEF changes.
Conclusions
Our findings show that DTI parameters of some WMTs are associated with the 5‐year decline in LEF, suggesting that alterations in WMT integrity (evaluated by DTI parameters) might be used to explore potential causes of impaired mobility in older adults when no clear explanations can be found.
INTRODUCTION
Decreased lower extremity function (LEF) is one of the overt characteristics during aging and it has been closely linked to disability1, 2 and mortality.3-5 Changes of LEF are multifactorial, yet the relationship with the brain structure remains unknown. White matter lesion is one of the main brain structural changes during aging and appears to be part of the physiopathologies of mobility disorders in older adults through a possible connection with cognitive decline and other risk factors.6, 7
The integrities of white matter tracts (WMTs) can be evaluated by diffusion tensor imaging (DTI). Decreased white matter integrity and increased myelin damage, which are commonly found during the aging process, have been associated with increased axial (AxD), mean (MD), and radial diffusivity (RD) values as well as decreased fractional anisotropy (FA) values.8, 9 DTI parameters of multiple WMTs have been connected to abnormal gait pattern10-15 and chair stands performance.16 Yet, most of the current studies on DTI of WMTs and LEF performances are cross‐sectional, and the relationship between WMT integrities and the evolution of physical performance still remains unclear. A DTI‐based estimation of over time changes in LEF will be helpful to better understand aging‐related LEF decline as a function of WMT integrity. Moreover, considering that LEF, especially gait speed, is determined by complex movements which involve neuromuscular coordination, aging‐related declines in physical functions are not only associated with muscle strength17 and bone status,18 but with central nervous system as well.19, 20 It is, thus, possible that in clinical practice, when there is impaired mobility in older adults but no muscle or bone cause is found, changes in central nervous system might also be a potential explanation.
Therefore, this study aimed at examining the association between the evolution of LEF over a 5‐year period and baseline DTI parameters in WMTs among community‐dwelling older adults. We hypothesized that higher baseline MD, AxD, and RD levels and lower FA levels might be associated with higher impairment in LEF over time.
Study Population
Participants (n = 1,679, aged 70 years and older) were recruited in MAPT with any of the following criteria: (1) expressing spontaneous memory complaint, (2) having limitation in at least one instrumental activity of daily living, and (3) demonstrating slow gait speed (i.e., lower than 0.8 m/s). Those participants underwent cognitive and functional assessments, including measurements of LEF, at baseline, the 6th month and each year during 5 years.
The MAPT sample size of 1,679 was determined as described in Andrieu et al.22 The present study was a secondary analysis on the MAPT study and we included 208 MAPT participants (aged 75 ± 4 years), who performed the baseline MRI scans and for whom DTI parameters were available and exploitable (Figure 1).
Main Outcome Measure
The LEF was assessed using the short physical performance battery (SPPB),3 which comprises three performance‐based physical tests: a 4‐m walking test at usual pace, a timed 5‐repetition chair stands at maximum speed, and three standing balance tests with increased difficulties.3 Each performance has a score of 0 to 4 with a higher score representing a better performance. A final SPPB score was calculated by summing the score of each performance.
We used three outcome measures for the LEF parameters: the SPPB total score (from 0 to 12, higher is better), 4‐m usual gait speed (in m/s), and the 5‐repetition chair stands performance (in seconds). Moreover, only data of these three outcomes assessed after the MRI scan were used in our analysis. Time intervals (TIs, in days) between the first MRI scan and SPPB measurements over the 5‐year period were calculated and used as covariates.
RESULTS
3.1 Characteristics of Participants
The 208 participants in this study had an average age of 75 years and 60% of them were female (Table 1). Almost three quarters of these participants presented at least one vascular risk. 65% of the 208 participants (n = 136) completed the baseline MRI scan within the first 6 months after the enrolment in the study; the remaining participants (35%, n = 72) completed the MRI scan within 12 months. The average TI between a participant's enrolment and the baseline MRI scan was 110 ± 97 days. Descriptive data of physical performance over the 5‐year period are presented in Supplementary Table S1.
DISCUSSION
To the best of our knowledge, this is the first study that examined associations between DTI parameters and the progression of LEF, which was assessed by three complementary and validated parameters (the SPPB score, the gait speed and the chair stands time) over a 5‐year period among older adults. We found that all the three parameters that characterized the LEF were associated with only two DTI parameters on the UNC: the RD of the left UNC and the MD of the right UNC, implying that the UNC tract might be closely associated with the LEF. Additionally, specific DTI parameters were negatively associated with SPPB score and gait speed, and positively associated with chair stands time, indicating that worse initial WMT structure may predict decline in physical performance over time. We further estimated a delay of 12 years to observe a reduction of .5 points of the SPPB total score. Although the SPPB is scored by one point, a decline of .5 point is considered as clinically relevant.26 These changes in the DTI parameters appeared to be very early in the time course of motor dysfunctions.
Previous studies about WMTs DTI parameters and LEF performances were mainly cross‐sectional analyses on gait patterns and only focused on the FA parameter, which is an indicator of the WMT microstructure change.8 Bruijn et al.12 compared the gait data between young and older adults and found that lower FA value in the left SLF was associated with smaller step widths and weaker stability. Tian et al.14 analyzed the walking variability in older adults and reported that FA values of the SLF and the UNC were reversely associated with mean lap time in fast walking. Recent studies on other DTI parameters (MD, AxD, and RD) have identified more WMTs, such as cingulum (cingulate gyrus),10 cerebral peduncle,10 posterior corona radiata,11 posterior limb of internal capsule,10 and splenium of corpus callosum,11 to be closely associated with gait performance. In consistence with previous findings, all these WMTs demonstrated close associations the evolution of gait speed in our results. Although other tracts such as corticospinal tract (CST),12 anterior thalamic radiation12, 15 and anterior corona radiata14, 27 were also identified in previous studies, none of those tracts were found with significance in our results.
In respect of chair stands performance, Demnitz et al.16 studied 387 adults (mean age 69 years) and reported that decreased RD and AxD values in bilateral anterior corona radiate and the genu of corpus callosum were associated with better performance (shorter time) in the chair stands test. None of these tracts were connected with chair stands time in our population. Instead, the RD and MD values of bilateral UNC were identified. The UNC is a long‐range association fiber connecting the frontal and temporal lobes, and it has been linked with episodic memory functions. Dysfunctions of the tract may cause cognitive problems and disrupt the acquisition of certain types of learning and memory such as reversal learning, semantic memory and social‐emotional processing.28 Therefore, the identification of UNC might be related to the fact that our participants were older adults with clinical frailty criteria defined as at‐risk to develop cognitive decline due to the presence of a slowing of the gait speed or a memory cognitive complaint without dementia. Since the MD is sensitive to cellularity, edema, and necrosis, and the RD is associated with dysmyelination and diameter or density changes in axonal,8 our results indicated a possible relationship between decreased chair stands performance and declined learning and memory abilities reflected by alterations in corresponding WMTs.
Besides analysis on gait speed and chair stands time, our study also examined DTI parameters with the SPPB score, which has never been reported before. Negative associations between SPPB score and AxD, MD, and RD values of the SCC, the SLF and the UNC have been identified in our results. After adjusting for the analyses on different MRI sites, the UNC was still significantly associated with over time changes of SPPB score. The SCC is the posterior part of the corpus callosum and consists of forceps major, which connects the occipital lobes. Clinical studies have found that patients with SCC lesions demonstrate multiple memory and motor control impairments such as confusion, ataxia, seizure and increased muscle tones.29, 30 The SLF consists of four components, among which the dorsal component (SLF I) connects the supplementary motor cortex and the ventral component (SLF III) terminates in the ventral premotor and prefrontal regions. Therefore, the SLF is believed to be associated with working memory and motor regulation.31 Since the DTI parameter AxD is indicative of a broad range of white matter changes and axonal injuries,32-35 the negative associations between the AxD values of the SCC and the SLF with the evolution of physical function in a later time not only indicates continuous neural degeneration during aging but also implies that older adults with more SCC or SLF damage (higher AxD values) will experience a greater loss in LEF with the time.
Although higher FA values were associated with better white matter integrity,8, 9 our results showed that higher FA values in five tracts (right cingulum (hippocampus), bilateral inferior, and superior cerebellar peduncle) were connected with a greater loss in gait speed. Notably, four of the identified tracts are from the cerebellum, a key player of the motor system, indicating that cerebellum might be a very special brain region where FA has to be interpreted differently. Yet, further studies are still needed to explore the relationship between cerebellum tracts and physical performance.
CST contains projection fibers originated from multiple motor‐related cerebral areas such as the primary and secondary motor cortices. Yet, our results did not show any association between the integrity of baseline CST and over time changes of physical performance. Such findings were consistent with previous DTI studies on gait speed and chair stands in older adults.10-16 A possible explanation might be that the CST integrity is quite stable across age span in non‐dementia adults.36, 37
Our DTI results suggest that the microstructure characteristics of some brain regions that are often involved in memory function28 can also be associated with alterations in physical performance. These results support the findings of Verwer et al.,38 who reported that poorer physical performance was associated with abnormality of white matter network regardless of the presence of vascular brain injury. Our work adds insight into the mechanism of mobility decline in older adults from the WMT aspect. Although the clinical implications of these findings are still needed to be determined, it is possible to think that WMT integrity (evaluated by DTI parameters) might be used to explore potential causes of impaired mobility in older adults when no clear explanations can be found.
Despite the associations between baseline DTI parameters and over time changes of physical performance demonstrated in our results, it is important to note that this is a secondary analysis from a randomized controlled trial, which means the MAPT study was not designed to test the associations between WMT in the brain and physical performance deterioration. A well‐powered study specifically designed to investigate the associations between WMTs and physical performance would help to confirm our findings. Moreover, the DTI assessments were performed at different time points over the first year of the study. The lack of longitudinal data of the DTI parameters also impeded us from exploring the association between changes in DTI and changes in physical performance. Even though we can expect similar findings on older adult populations similar to the MAPT study sample (in particular, community‐dwelling older adults with spontaneous memory complaint), caution must be taken when generalizing our findings to other populations.
To conclude, the current study analyzed associations between DTI parameters in 48 WMTs and a 5‐year evolution of LEF in older adults. Thirty‐five DTI parameters from 24 WMTs were closely connected to changes of SPPB scores, gait speed or chair stands time over the five‐year period, and the MD and RD values in the UNC tract were significantly associated with all functional parameters. Our findings suggested that white matter lesions might partially explain mobility disorders in older adults and DTI parameters of WMTs related to learning, memory, or motor control might be able to predict physical performance declines in a later period. Further longitudinal studies on paired DTIs and physical performance data at each time point are still needed to elucidate the relationship between DTI changes and physical performance evolution in older adults.
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