Gait Change in Dual Task as a Behavioral Marker to Detect Mild Cognitive Impairment in Elderly Persons: A Systematic Review and Meta-analysis.

OBJECTIVES: To systematically summarize the evidence of gait tests as screening tools for mild cognitive impairment (MCI). DATA SOURCES: Electronic database searches were conducted in PubMed, EBSCO, Cochrane, Web of Science, Ovid, China National Knowledge Infrastructure, WanFang, and SinoMed, and studies published before November 30, 2018, were included. STUDY SELECTION: Synonyms of MCI, gait, and cognitive-motor interference (CMI) were searched. Studies that analyzed gait change of people with MCI in single- or dual-task gait tests were included. DATA EXTRACTION: The quality of the included studies was assessed with Downs and Black methodological quality appraisal tools. Study characteristics, participants' characteristics, test descriptions, and results were extracted from the included studies. DATA SYNTHESIS: Twenty-two studies involving 1928 participants were included. Meta-analysis showed that gait velocity difference in dual task (effect size [ES]=-0.89) were more obvious than in single task (ES=-0.74) between older adults with and without MCI, and the ES increased with the complexity of cognitive load (countdown by 1s, ES=-0.83; verbal fluency, ES=-0.96; serial reduction by 7s, ES=-1.26). The dual-task cost of gait velocity showed high sensitivity (ES=0.90) in detecting MCI. Meta-regression analysis demonstrated strong criterion-related validity between the CMI of gait velocity and the Montreal Cognitive Assessment score. CONCLUSIONS: In comparison with the single-task gait test, gait change under cognitive load is more pronounced in older adults with MCI. CMI of gait velocity can be a potential screening tool for MCI in elderly persons.

Individual variability of cerebral autoregulation, posterior cerebral circulation and white matter hyperintensity.

KEY POINTS: Cerebral autoregulation (CA) is a key mechanism to protect brain perfusion in the face of changes in arterial blood pressure, but little is known about individual variability of CA and its relationship to the presence of brain white matter hyperintensity (WMH) in older adults, a type of white matter lesion related to cerebral small vessel disease (SVD). This study demonstrated the presence of large individual variability of CA in healthy older adults during vasoactive drug-induced changes in arterial pressure assessed at the internal carotid and vertebral arteries. We also observed, unexpectedly, that it was the 'over-' rather than the 'less-reactive' CA measured at the vertebral artery that was associated with WMH severity. These findings challenge the traditional concept of CA and suggest that the presence of cerebral SVD, manifested as WMH, is associated with posterior brain hypoperfusion during acute increase in arterial pressure. ABSTRACT: This study measured the individual variability of static cerebral autoregulation (CA) and determined its associations with brain white matter hyperintensity (WMH) in older adults. Twenty-seven healthy older adults (13 females, 66 ± 6 years) underwent assessment of CA during steady-state changes in mean arterial pressure (MAP) induced by intravenous infusion of sodium nitroprusside (SNP) and phenylephrine. Cerebral blood flow (CBF) was measured using colour-coded duplex ultrasonography at the internal carotid (ICA) and vertebral arteries (VA). CA was quantified by a linear regression slope (CA slope) between percentage changes in cerebrovascular resistance (CVR = MAP/CBF) and MAP relative to baseline values. Periventricular and deep WMH volumes were measured with T2-weighted magnetic resonance imaging. MAP was reduced by -11 ± 7% during SNP, and increased by 21 ± 8% during phenylephrine infusion. CA demonstrated large individual variability with the CA slopes ranging from 0.37 to 2.20 at the ICA and from 0.17 to 3.18 at the VA; no differences in CA were found between the ICA and VA. CA slopes measured at the VA had positive correlations with the total and periventricular WMH volume (r = 0.55 and 0.59, P < 0.01). Collectively, these findings demonstrated the presence of large individual variability of CA in older adults, and that, when measured in the posterior cerebral circulation, it is the higher rather than lower CA reactivity that is associated with WMH severity.

Central artery stiffness, baroreflex sensitivity, and brain white matter neuronal fiber integrity in older adults.

Cerebral hypoperfusion elevates the risk of brain white matter (WM) lesions and cognitive impairment. Central artery stiffness impairs baroreflex, which controls systemic arterial perfusion, and may deteriorate neuronal fiber integrity of brain WM. The purpose of this study was to examine the associations among brain WM neuronal fiber integrity, baroreflex sensitivity (BRS), and central artery stiffness in older adults. Fifty-four adults (65 ± 6 years) with normal cognitive function or mild cognitive impairment (MCI) were tested. The neuronal fiber integrity of brain WM was assessed from diffusion metrics acquired by diffusion tensor imaging. BRS was measured in response to acute changes in blood pressure induced by bolus injections of vasoactive drugs. Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). The WM diffusion metrics including fractional anisotropy (FA) and radial (RD) and axial (AD) diffusivities, BRS, and cfPWV were not different between the control and MCI groups. Thus, the data from both groups were combined for subsequent analyses. Across WM, fiber tracts with decreased FA and increased RD were associated with lower BRS and higher cfPWV, with many of the areas presenting spatial overlap. In particular, the BRS assessed during hypotension was strongly correlated with FA and RD when compared with hypertension. Executive function performance was associated with FA and RD in the areas that correlated with cfPWV and BRS. These findings suggest that baroreflex-mediated control of systemic arterial perfusion, especially during hypotension, may play a crucial role in maintaining neuronal fiber integrity of brain WM in older adults.

Life-long aerobic exercise preserved baseline cerebral blood flow but reduced vascular reactivity to CO2.

PURPOSE: To examine the potential benefits of life-long aerobic exercise on brain health, in particular cerebrovascular function. MATERIALS AND METHODS: Ten Masters athletes (MA) (seven males, three females; 74.5 ± 5.8 years) and 10 sedentary elderly individuals (SE) (eight males, two females; 75.4 ± 5.6 years) were recruited and baseline cerebral blood flow (CBF) and cerebral vascular reactivity (CVR) to CO2 were measured on a 3T MRI scanner. Nine sedentary young subjects were also recruited to serve as a control group to verify the age effect. RESULTS: When compared to the SE group, MA showed higher CBF in posterior cingulate cortex/precuneus, which are key regions of the default-mode-network and are known to be highly sensitive to age and dementia. CVR in the MA brains were paradoxically lower than that in SE. This effect was present throughout the brain. Within the MA group, individuals with higher VO2max had an even lower CVR, suggesting a dose-response relationship. CONCLUSION: Life-long aerobic exercise preserved blood supply in the brain's default-mode-network against age-related degradation. On the other hand, its impact on the cerebral vascular system seems to be characterized by a dampening of CO2 reactivity, possibly because of desensitization effects due to a higher lifetime exposure.

Masters athletes exhibit larger regional brain volume and better cognitive performance than sedentary older adults.

PURPOSE: To investigate differences in the age-related decline in brain tissue concentration between Masters athletes and sedentary older adults. MATERIALS AND METHODS: Twelve Masters athletes (MA) (three females, age = 72.4 ± 5.6 years, endurance training >15 years), 12 sedentary elderly (SE) similar in age and educational level (four females, age = 74.6 ± 4.3 years), and nine young controls (YC) (four females, age = 27.2 ± 3.6 years) participated. T1-weighted high-resolution (1 × 1 × 1mm(3) ) images were acquired. Voxel-based analysis was conducted to identify clusters showing tissue concentration differences with t-tests. Cognitive function was assessed using a standard clinical battery focused on executive function and memory. RESULTS: Two MA and two SE were unable to complete the magnetic resonance imaging (MRI) study. Both SE and MA showed lower gray matter (GM) concentrations than YC in the superior, inferior and middle frontal gyrus, superior temporal gyrus, postcentral gyrus, and the cingulate gyrus (PFDR-corrected < 0.001) and lower white matter (WM) concentrations in the inferior frontal gyrus and precentral gyrus (PFDR-corrected < 0.005). Notably, MA showed higher GM and WM concentrations than SE in the subgyral, cuneus, and precuneus regions related to visuospatial function, motor control, and working memory (PFDR-corrected < 0.005). After controlling for estimated intelligence, MA outperformed SE on tasks of letter (P < 0.01) and category (P < 0.05) fluency. CONCLUSION: Life-long exercise may confer benefits to some aspects of executive function and age-related brain tissue loss in the regions related to visuospatial function, motor control, and working memory in older adults.

Looking for low vision: Predicting visual prognosis by fusing structured and free-text data from electronic health records.

INTRODUCTION: Low vision rehabilitation improves quality-of-life for visually impaired patients, but referral rates fall short of national guidelines. Automatically identifying, from electronic health records (EHR), patients with poor visual prognosis could allow targeted referrals to low vision services. The purpose of this study was to build and evaluate deep learning models that integrate EHR data that is both structured and free-text to predict visual prognosis. METHODS: We identified 5547 patients with low vision (defined as best documented visual acuity (VA) less than 20/40) on ≥ 1 encounter from EHR from 2009 to 2018, with ≥ 1 year of follow-up from the earliest date of low vision, who did not improve to greater than 20/40 over 1 year. Ophthalmology notes on or prior to the index date were extracted. Structured data available from the EHR included demographics, billing and procedure codes, medications, and exam findings including VA, intraocular pressure, corneal thickness, and refraction. To predict whether low vision patients would still have low vision a year later, we developed and compared deep learning models that used structured inputs and free-text progress notes. We compared three different representations of progress notes, including 1) using previously developed ophthalmology domain-specific word embeddings, and representing medical concepts from notes as 2) named entities represented by one-hot vectors and 3) named entities represented as embeddings. Standard performance metrics including area under the receiver operating curve (AUROC) and F1 score were evaluated on a held-out test set. RESULTS: Among the 5547 low vision patients in our cohort, 40.7% (N = 2258) never improved to better than 20/40 over one year of follow-up. Our single-modality deep learning model based on structured inputs was able to predict low vision prognosis with AUROC of 80% and F1 score of 70%. Deep learning models utilizing named entity recognition achieved an AUROC of 79% and F1 score of 63%. Deep learning models further augmented with free-text inputs using domain-specific word embeddings, were able to achieve AUROC of 82% and F1 score of 69%, outperforming all single- and multiple-modality models representing text with biomedical concepts extracted through named entity recognition pipelines. DISCUSSION: Free text progress notes within the EHR provide valuable information relevant to predicting patients' visual prognosis. We observed that representing free-text using domain-specific word embeddings led to better performance than representing free-text using extracted named entities. The incorporation of domain-specific embeddings improved the performance over structured models, suggesting that domain-specific text representations may be especially important to the performance of predictive models in highly subspecialized fields such as ophthalmology.

Deep Learning Approaches for Predicting Glaucoma Progression Using Electronic Health Records and Natural Language Processing.

Purpose: Advances in artificial intelligence have produced a few predictive models in glaucoma, including a logistic regression model predicting glaucoma progression to surgery. However, uncertainty exists regarding how to integrate the wealth of information in free-text clinical notes. The purpose of this study was to predict glaucoma progression requiring surgery using deep learning (DL) approaches on data from electronic health records (EHRs), including features from structured clinical data and from natural language processing of clinical free-text notes. Design: Development of DL predictive model in an observational cohort. Participants: Adult patients with glaucoma at a single center treated from 2008 through 2020. Methods: Ophthalmology clinical notes of patients with glaucoma were identified from EHRs. Available structured data included patient demographic information, diagnosis codes, prior surgeries, and clinical information including intraocular pressure, visual acuity, and central corneal thickness. In addition, words from patients' first 120 days of notes were mapped to ophthalmology domain-specific neural word embeddings trained on PubMed ophthalmology abstracts. Word embeddings and structured clinical data were used as inputs to DL models to predict subsequent glaucoma surgery. Main Outcome Measures: Evaluation metrics included area under the receiver operating characteristic curve (AUC) and F1 score, the harmonic mean of positive predictive value, and sensitivity on a held-out test set. Results: Seven hundred forty-eight of 4512 patients with glaucoma underwent surgery. The model that incorporated both structured clinical features as well as input features from clinical notes achieved an AUC of 73% and F1 of 40%, compared with only structured clinical features, (AUC, 66%; F1, 34%) and only clinical free-text features (AUC, 70%; F1, 42%). All models outperformed predictions from a glaucoma specialist's review of clinical notes (F1, 29.5%). Conclusions: We can successfully predict which patients with glaucoma will need surgery using DL models on EHRs unstructured text. Models incorporating free-text data outperformed those using only structured inputs. Future predictive models using EHRs should make use of information from within clinical free-text notes to improve predictive performance. Additional research is needed to investigate optimal methods of incorporating imaging data into future predictive models as well.

Exercise and executive function in individuals with chronic stroke: a pilot study.

BACKGROUND AND PURPOSE: Emerging evidence suggests that exercise may improve cognitive function in older adults. The purpose of this pilot study was to describe changes in measures of cognition and executive function in individuals with chronic stroke following participation in aerobic and strengthening exercise. METHODS: A single-group, pretest-posttest design was used. Nine individuals with chronic stroke (mean age = 63.7 ± 9.1 years, mean time since stroke = 50.4 ± 37.9 months) completed a 12-week program of aerobic and strengthening exercise, 3 days per week. The primary outcome measures examined executive function (Digit Span Backwards and Flanker tests). Secondary measures examined various aspects of aerobic fitness (VO2peak and 6-minute walk distance) and function (Fugl-Meyer and 10-m walk speed). RESULTS: Following the intervention, significant improvements were found in the Digit Span Backwards test (mean change = 0.56 ± 0.9 digits; P = 0.05), Fugl-Meyer score (mean change = 3.6 ± 5.7; P = 0.05), and Stroke Impact Scale total score (mean change = 33.8 ± 38.5; P = 0.02). A significant correlation was found between improved aerobic capacity and improved performance on the Flanker test (r = 0.74; P = 0.02). DISCUSSION: The results of this study indicate that a 12-week aerobic and strengthening exercise program was associated with improvements in selected measures of executive function and functional capacity in people with stroke. Limitations of this study include the small sample size and lack of a comparison group. CONCLUSIONS: This pilot study contributes to the emerging evidence that exercise improves cognition in people with stroke. These benefits indicate the need for future study with a larger group to have sufficient power to further explore these relationships.

Development and evaluation of novel ophthalmology domain-specific neural word embeddings to predict visual prognosis.

OBJECTIVE: To develop and evaluate novel word embeddings (WEs) specific to ophthalmology, using text corpora from published literature and electronic health records (EHR). MATERIALS AND METHODS: We trained ophthalmology-specific WEs using 121,740 PubMed abstracts and 89,282 EHR notes using word2vec continuous bag-of-words architecture. PubMed and EHR WEs were compared to general domain GloVe WEs and general biomedical domain BioWordVec embeddings using a novel ophthalmology-domain-specific 200-question analogy test and prediction of prognosis in 5547 low vision patients using EHR notes as inputs to a deep learning model. RESULTS: We found that many words representing important ophthalmic concepts in the EHR were missing from the general domain GloVe vocabulary, but covered in the ophthalmology abstract corpus. On ophthalmology analogy testing, PubMed WEs scored 95.0 %, outperforming EHR (86.0 %) and GloVe (91.0 %) but less than BioWordVec (99.5 %). On predicting low vision prognosis, PubMed and EHR WEs resulted in similar AUROC (0.830; 0.826), outperforming GloVe (0.778) and BioWordVec (0.784). CONCLUSION: We found that using ophthalmology domain-specific WEs improved performance in ophthalmology-related clinical prediction compared to general WEs. Deep learning models using clinical notes as inputs can predict the prognosis of visually impaired patients. This work provides a framework to improve predictive models using domain-specific WEs.

One-Year Aerobic Exercise Reduced Carotid Arterial Stiffness and Increased Cerebral Blood Flow in Amnestic Mild Cognitive Impairment.

BACKGROUND: Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer's disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion. OBJECTIVE: To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD. METHODS: This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid ß-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak). RESULTS: Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. AET improved VO2peak, decreased carotid ß-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r = 0.388, p = 0.034) and negatively with carotid ß-stiffness index (r = -0.418, p = 0.007) and CBF pulsatility (r = -0.400, p = 0.014). Decreases in carotid ß-stiffness were associated with increases in cerebral perfusion (r = -0.494, p = 0.003). AET effects on cognitive performance were minimal compared with SAT. CONCLUSION: AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

Exertion fatigue and chronic fatigue are two distinct constructs in people post-stroke.

BACKGROUND AND PURPOSE: Post-stroke fatigue is a common and neglected issue despite the fact that it impacts daily functions, quality of life, and has been linked with a higher mortality rate because of its association with a sedentary lifestyle. The purpose of this study was to identify the contributing factors of exertion fatigue and chronic fatigue in people post-stroke. METHODS: Twenty-one post-stroke people (12 males, 9 females; 59.5 ± 10.3 years of age; time after stroke 4.1 ± 3.5 years) participated in the study. The response variables included exertion fatigue and chronic fatigue. Participants underwent a standardized fatigue-inducing exercise on a recumbent stepper. Exertion fatigue level was assessed at rest and immediately after exercise using the Visual Analog Fatigue Scale. Chronic fatigue was measured by the Fatigue Severity Scale. The explanatory variables included aerobic fitness, motor control, and depressive symptoms measured by peak oxygen uptake, Fugl-Meyer motor score, and the Geriatric Depression Scale, respectively. RESULTS: Using forward stepwise regression, we found that peak oxygen uptake was an independent predictor of exertion fatigue (P = 0.006), whereas depression was an independent predictor of chronic fatigue (P = 0.002). CONCLUSIONS: Exertion fatigue and chronic fatigue are 2 distinct fatigue constructs, as identified by 2 different contributing factors.

Brain Perfusion Change in Patients with Mild Cognitive Impairment After 12 Months of Aerobic Exercise Training.

Aerobic exercise (AE) has recently received increasing attention in the prevention of Alzheimer's disease (AD). There is some evidence that it can improve neurocognitive function in elderly individuals. However, the mechanism of these improvements is not completely understood. In this prospective clinical trial, thirty amnestic mild cognitive impairment participants were enrolled into two groups and underwent 12 months of intervention. One group (n = 15) performed AE training (8M/7F, age = 66.4 years), whereas the other (n = 15) performed stretch training (8M/7F, age = 66.1 years) as a control intervention. Both groups performed 25-30 minutes training, 3 times per week. Frequency and duration were gradually increased over time. Twelve-month AE training improved cardiorespiratory fitness (p = 0.04) and memory function (p = 0.004). Cerebral blood flow (CBF) was measured at pre- and post-training using pseudo-continuous-arterial-spin-labeling MRI. Relative to the stretch group, the AE group displayed a training-related increase in CBF in the anterior cingulate cortex (p = 0.016). Furthermore, across individuals, the extent of memory improvement was associated with CBF increases in anterior cingulate cortex and adjacent prefrontal cortex (voxel-wise p < 0.05). In contrast, AE resulted in a decrease in CBF of the posterior cingulate cortex, when compared to the stretch group (p = 0.01). These results suggest that salutary effects of AE in AD may be mediated by redistribution of blood flow and neural activity in AD-sensitive regions of brain.

Cerebral White Matter Integrity in Amnestic Mild Cognitive Impairment: A 1-Year Randomized Controlled Trial of Aerobic Exercise Training.

Cerebral white matter (WM) represents the structural substrate of neuronal communications which is damaged by Alzheimer's disease (AD). Aerobic exercise training (AET) may improve WM integrity in cognitively normal older adults, but its efficacy remains unknown in patients with amnestic mild cognitive impairment (MCI), a prodromal phase of AD dementia. Therefore, we conducted a proof-of-concept study that randomized 70 amnestic MCI patients to a 1-year program of AET or a non-aerobic stretching and toning (SAT), active control group. Thirty-six patients completed both baseline and follow-up MRI scans, and cerebral WM integrity was measured by WM lesion volume and diffusion characteristics using fluid-attenuated-inversion-recovery and diffusion tensor imaging respectively. Peak oxygen uptake (VO2peak) and neuropsychological function were also measured. At baseline and 1-year follow-up, WM lesion volume and diffusion characteristics were similar between the AET and SAT groups, although VO2peak significantly improved after AET. The AET group showed slight improvement in neuropsychological performance. When analyzing individual data, tract-based spatial statistics demonstrated that VO2peak improvements are associated with attenuated elevations in mean and axial diffusivities, particularly the anterior WM fiber tracts (e.g., genu of corpus callosum). In patients with amnestic MCI, we found that although AET intervention did not improve WM integrity at group level analysis, individual cardiorespiratory fitness gains were associated with improved WM tract integrity of the prefrontal cortex.

The relationship between fatigue, aerobic fitness, and motor control in people with chronic stroke: a pilot study.

BACKGROUND: Fatigue is a commonly neglected issue despite the high incidence rate reported in people post-stroke. OBJECTIVE: To explore the relationship between fatigue, aerobic fitness, and motor control in people with chronic stroke. METHODS: Nine people post-stroke participated in this cross-sectional study (7 females, mean age = 56.8 (11.8) years, range 47-73, time post-stroke = 47.6 (51.2) months, range 11-140). Participants performed a six-minute-walk exercise in order to induce fatigue, followed immediately by a Fatigue Index (FI) scale to report fatigue at the moment. The distance walked (6MWD) was documented. On a separate visit, aerobic fitness was characterized by VO(2Peak) using a cycle-ergometer. In addition, Fugl-Meyer (FM) test was administered to assess motor control of the hemiparetic side. Pearson Product Correlation Coefficient and multiple linear regression were used to analyze the relationships between FI, VO(2Peak) and FM. RESULTS: VO(2Peak) showed significant positive correlations with FM (r = .779, p = .013) and 6MWD (r = .726, p = .027). Fatigue index displayed significant negative correlations with VO(2Peak) (r = -.739, p = .023) and FM (r = -.873, p = .002), but not with 6MWD (r = -.620, p = .075). Using stepwise multiple regression, we found that that FM was an independent predictor of FI (p = .002) and explained 76.2% of variance in FI (R2 = .762). CONCLUSION: Our data suggests that motor control capability may be a good predictor of fatigue in people post-stroke. Fatigue is a complex phenomenon; a quantifiable measure that is sensitive to multiple components is needed in order to distinguish the nature of fatigue and its contributing factors.

Exercise Training in Amnestic Mild Cognitive Impairment: A One-Year Randomized Controlled Trial.

BACKGROUND: The current evidence is inconclusive to support the benefits of aerobic exercise training (AET) for preventing neurocognitive decline in patients with amnestic mild cognitive impairment (aMCI). OBJECTIVE: To examine the effect of a progressive, moderate-to-high intensity AET program on memory and executive function, brain volume, and cortical amyloid-ß (Aß) plaque deposition in aMCI patients. METHODS: This is a proof-of-concept trial that randomized 70 aMCI patients to 12 months of AET or stretching and toning (SAT, active control) interventions. Primary neuropsychological outcomes were assessed by using the California Verbal Learning Test-second edition (CVLT-II) and the Delis-Kaplan Executive Function System (D-KEFS). Secondary outcomes were the global and hippocampal brain volumes and the mean cortical and precuneus Aß deposition. RESULTS: Baseline cognitive scores were similar between the groups. Memory and executive function performance improved over time but did not differ between the AET and SAT groups. Brain volume decreased and precuneus Aß plaque deposition increased over time but did not differ between the groups. Cardiorespiratory fitness was significantly improved in the AET compared with SAT group. In amyloid positive patients, AET was associated with reduced hippocampal atrophy when compared with the SAT group. CONCLUSION: The AET and SAT groups both showed evidence of slightly improved neuropsychological scores in previously sedentary aMCI patients. However, these interventions did not prevent brain atrophy or increases in cortical Aß deposition over 12 months. In amyloid positive patients, AET reduced hippocampal atrophy when compared with the SAT group.

Diffusion tensor imaging in preclinical and presymptomatic carriers of familial Alzheimer's disease mutations.

Measures are needed that identify persons that will develop Alzheimer's disease in order to target them for preventative interventions. There is evidence from animal, pathological and imaging studies that disruption of white matter occurs in the course of Alzheimer's disease and may be an early event. Prior studies have suggested that late-myelinating regions or white matter connecting limbic structures are particularly susceptible to degradation. Persons destined to develop the disease by virtue of fully penetrant genetic alterations (familial Alzheimer's disease or FAD) provide a model in which early and even presymptomatic changes of the disease may be identified. In this study we performed diffusion tensor imaging (DTI) on 2 demented and 21 subjects at-risk for inheriting an FAD mutation. We compared global and localized fractional anisotropy (FA) measures in white matter between FAD mutation carriers and non-carriers in the preclinical (clinical dementia rating <1, n = 20) and presymptomatic (clinical dementia rating = 0, n = 15) stages of the disease. There were no significant differences between mutation carriers and non-carriers with regard to absolute age, age relative to the typical age of disease diagnosis in their family, gender or Mini-Mental Status Examination Score. Among preclinical FAD mutation carriers (n = 12), mean whole brain white-matter FA (P = 0.045), FA of the columns of the fornix (P = 0.012), area of the perforant pathways bilaterally (right side: P = 0.028, left side: P = 0.027) and left orbitofrontal lobe (P = 0.024) were decreased relative to that of non-carriers (n = 8). We also found that FA in the columns of the fornix (P = 0.008) and left orbitofrontal lobe white matter (P = 0.045) were decreased in the eight presymptomatic mutation carriers compared to seven non-carriers. Logistic regression demonstrated that FA of the columns of the fornix was a better predictor of mutation status than was cross-sectional area of the fornix, global mean white-matter FA and left frontal lobe white-matter FA. In a linear regression analysis, white-matter volume (P = 0.002), hippocampal volume (P = 0.023) and mutation status (P = 0.032) significantly predicted fornix FA. We conclude that FA is decreased in the white matter in preclinical and even presymptomatic FAD mutation carriers, particularly in the late-myelinating tracts connecting limbic structures. Decreased FA in of the columns of the fornix is particularly robust in early FAD and may provide a biomarker for early disease in sporadic Alzheimer's disease.

Cardiorespiratory Fitness and White Matter Neuronal Fiber Integrity in Mild Cognitive Impairment.

BACKGROUND: Mounting evidence showed the self-reported levels of physical activity are positively associated with white matter (WM) integrity and cognitive performance in normal adults and patients with mild cognitive impairment (MCI). However, the objective measure of cardiorespiratory fitness (CRF) was not used in these studies. OBJECTIVE: To determine the associations of CRF measured by maximal oxygen uptake (VO2max) with WM fiber integrity and neurocognitive performance in older adults with MCI. METHODS: Eighty-one participants (age = 65±7 years, 43 women), including 26 cognitively normal older adults and 55 amnestic MCI patients, underwent VO2max test to measure CRF, diffusion tensor imaging (DTI) to assess WM fiber integrity, and neurocognitive assessment focused on memory and executive function. DTI data were analyzed by the tract-based spatial statistics and region-of-interest approach. RESULTS: Cognitively normal older adults and MCI patients were not different in global WM fiber integrity and VO2max. VO2max was associated positively with DTI metrics of fractional anisotropy in ∼54% WM fiber tracts, and negatively with mean and radial diffusivities in ∼46% and ∼56% of the WM fiber tracts. The associations of VO2max with DTI metrics remained statistically significant after adjustment of age, sex, body mass index, WM lesion burden, and MCI status. The DTI metrics obtained from the area that correlated to VO2max were associated with executive function performance in MCI patients. CONCLUSIONS: Higher levels of CRF are associated with better WM fiber integrity, which in turn is correlated with better executive function performance in MCI patients.

Investigating post-stroke fatigue: An individual participant data meta-analysis.

OBJECTIVE: The prevalence of post-stroke fatigue differs widely across studies, and reasons for such divergence are unclear. We aimed to collate individual data on post-stroke fatigue from multiple studies to facilitate high-powered meta-analysis, thus increasing our understanding of this complex phenomenon. METHODS: We conducted an Individual Participant Data (IPD) meta-analysis on post-stroke fatigue and its associated factors. The starting point was our 2016 systematic review and meta-analysis of post-stroke fatigue prevalence, which included 24 studies that used the Fatigue Severity Scale (FSS). Study authors were asked to provide anonymised raw data on the following pre-identified variables: (i) FSS score, (ii) age, (iii) sex, (iv) time post-stroke, (v) depressive symptoms, (vi) stroke severity, (vii) disability, and (viii) stroke type. Linear regression analyses with FSS total score as the dependent variable, clustered by study, were conducted. RESULTS: We obtained data from 14 of the 24 studies, and 12 datasets were suitable for IPD meta-analysis (total n = 2102). Higher levels of fatigue were independently associated with female sex (coeff. = 2.13, 95% CI 0.44-3.82, p = 0.023), depressive symptoms (coeff. = 7.90, 95% CI 1.76-14.04, p = 0.021), longer time since stroke (coeff. = 10.38, 95% CI 4.35-16.41, p = 0.007) and greater disability (coeff. = 4.16, 95% CI 1.52-6.81, p = 0.010). While there was no linear association between fatigue and age, a cubic relationship was identified (p < 0.001), with fatigue peaks in mid-life and the oldest old. CONCLUSION: Use of IPD meta-analysis gave us the power to identify novel factors associated with fatigue, such as longer time since stroke, as well as a non-linear relationship with age.

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment represents an early stage of Alzheimer's disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O2/min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction ( p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% ( p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO2-inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.

Older adults with amnestic mild cognitive impairment exhibit exacerbated gait slowing under dual-task challenges.

BACKGROUND: With age, performance of motor tasks becomes more reliant on cognitive resources to compensate for the structural and functional declines in the motor control regions in the brain. We hypothesized that participants with amnestic mild cognitive impairment (aMCI) are more prone to motor dysfunctions than cognitively normal older adults under dual-task conditions where competitive demands challenge cognitive functions while performing a motor task simultaneously. METHODS: Sixteen aMCI participants (females=9, age=64±5yrs, clinical dementia rating score=0.5) and 10 age- and education-matched cognitively normal adults (females=5, age=62±6yrs) participated. Using a 10-meter-walk test (10MW), gait velocity was recorded at baseline and under 4 different dual-task (DT) conditions designed to challenge working memory, executive function, and episodic memory. Specifically, DT1: verbal fluency; DT2: 5-digit backward span; DT3: serial-7 subtraction; and DT4: 3-item delayed recall. Physical function was measured by Timed Up-and-Go (TUG), simple reaction time (RT) to a free-falling yardstick, and functional reach (FR). RESULTS: No difference was found in physical functions, aerobic fitness, and exercise cardiopulmonary responses between aMCI participants and controls. However, aMCI participants showed more pronounced gait slowing from baseline when compared to the controls (p<0.05; p=0.001; p<0.001; p<0.001, respectively). CONCLUSIONS: Our finding supports the theory of shared resource of motor and cognitive control. Participants with aMCI manifested more gait slowing than cognitively-normal older adults under DT conditions, with the largest differences during tests of working and episodic memory. The outcome of dual-task assessment shows promise as a potential marker for detection of aMCI and early Alzheimer disease.