scholarly journals Mild cognitive impairment and donepezil impact mitochondrial respiratory capacity in skeletal muscle

Function ◽  
2021 ◽  
Author(s):  
Jill K Morris ◽  
Colin S McCoin ◽  
Kelly N Fuller ◽  
Casey S John ◽  
Heather M Wilkins ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Vastus Lateralis ◽  
Healthy Older Adults ◽  
Muscle Genes ◽  
Direct Measures ◽  
Mitochondrial Respiratory

Abstract Alzheimer's Disease (ad) associates with insulin resistance and low aerobic capacity suggestive of impaired skeletal muscle mitochondrial function. However, direct measures of muscle mitochondrial function have not been performed in ad. This study (n = 50) compared skeletal muscle mitochondrial respiratory function and gene expression profiling in cognitively healthy older adults (CH; n = 24) to 26 individuals in the earliest phase of ad-related cognitive decline, mild cognitive impairment (MCI; n = 11) or MCI taking an ad medication, donepezil (MCI + med; n = 15). Mitochondrial respiratory kinetics were measured in permeabilized muscle fibers from skeletal muscle biopsies of the vastus lateralis. Untreated MCI subjects exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH (P = 0.043) and MCI + med (P = 0.007) groups. MCI also exhibited poorer mitochondrial coupling control compared to CH (P = 0.014). RNA sequencing of skeletal muscle revealed unique differences in mitochondrial function and metabolism genes based on both MCI status (CH vs. MCI) and medication treatment (MCI vs. MCI + med). MCI + med modified over 600 skeletal muscle genes compared to MCI suggesting donepezeil powerfully impacts the transcriptional profile of skeletal muscle. Overall, skeletal muscle mitochondrial respiration is altered in untreated MCI but normalized in donepezil-treated MCI participants while mitochondrial leak control is impaired regardless of medication status. These results provide further evidence that skeletal muscle mitochondrial changes occur in the very early stages of ad, but is likely influenced by a common ad medicine. Further study of mitochondrial bioenergetics and the influence of transcriptional regulation in early ad is warranted.

scholarly journals Mild cognitive impairment is associated with skeletal muscle mitochondrial deficits

2020 ◽  
Author(s):  
Jill K Morris ◽  
Colin S. McCoin ◽  
Kelly N. Fuller ◽  
Casey S. John ◽  
Heather M. Wilkins ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Vastus Lateralis ◽  
Mitochondrial Uncoupling ◽  
Healthy Older Adults ◽  
Skeletal Muscle Biopsy

Alzheimer's Disease (AD) is associated with insulin resistance and low cardiorespiratory fitness, suggestive of impaired skeletal muscle mitochondrial function. We examined if individuals with Mild Cognitive Impairment (MCI), the earliest phase of AD-related cognitive decline, exhibit reduced skeletal muscle mitochondrial function, and if AD medication impacted outcomes. We present data from 50 individuals, including cognitively healthy older adults (CH; n=24) 60+ years of age and clinically diagnosed MCI subjects (n=26). MCI subjects were sub-divided into two groups; no AD medication (MCI; n=11), or AD medication treated (MCI+med; n=15). A skeletal muscle biopsy (vastus lateralis) was obtained and mitochondrial respiratory kinetics was measured in permeabilized muscle fibers. MCI subjects exhibited lower lipid-stimulated skeletal muscle mitochondrial respiration (State 3, ADP-stimulated) than both CH individuals (p=0.043) and medication-treated MCI subjects (p=0.006). MCI also exhibited poorer mitochondrial coupling control compared to CH subjects (p=0.014), while MCI+med and CH subjects did not differ. Compared to CH individuals, skeletal muscle mitochondrial leak control ratio was lower for the MCI+med group (p=0.008) and trended lower for non-medicated MCI (p=0.06), which suggests greater mitochondrial uncoupling in MCI. Skeletal muscle mitochondrial respiration is impaired in untreated MCI but normalized in medication-treated MCI participants while mitochondrial leak control is impaired regardless of medication status. These results provide further evidence that systemic mitochondrial deficits occur in the very early stages of AD, and that mitochondrial function is partially influenced by AD medication. Further analysis for a role of muscle mitochondria in the progression of early AD is warranted.

scholarly journals High Incomplete Skeletal Muscle Fatty Acid Oxidation Explains Low Muscle Insulin Sensitivity in Poorly Controlled T2D

2017 ◽  
Vol 103 (3) ◽  
pp. 882-889 ◽  
Author(s):  
Timothy P Gavin ◽  
Jacob M Ernst ◽  
Hyo-Bum Kwak ◽  
Sarah E Caudill ◽  
Melissa A Reed ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Fatty Acid Oxidation ◽  
Mitochondrial Respiration ◽  
Vastus Lateralis ◽  
Acid Oxidation ◽  
Vastus Lateralis Muscle ◽  
Intravenous Glucose ◽  
Mitochondrial Respiratory

Abstract Context Almost 50% of type 2 diabetic (T2D) patients are poorly controlled [glycated hemoglobin (HbA1c) ≥ 7%]; however, the mechanisms responsible for progressively worsening glycemic control are poorly understood. Lower skeletal muscle mitochondrial respiratory capacity is associated with low insulin sensitivity and the development of T2D. Objective We investigated if skeletal muscle insulin sensitivity (SI) was different between well-controlled T2D (WCD) and poorly controlled T2D (PCD) and if the difference was associated with differences resulting from mitochondrial respiratory function. Design Vastus lateralis muscle mitochondrial respiration, mitochondrial content, mitochondrial enzyme activity, and fatty acid oxidation (FAO) were measured. SI and the acute response to glucose (AIRg) were calculated by MINMOD analysis from glucose and insulin obtained during a modified, frequently sampled, intravenous glucose tolerance test. Results SI and AIRg were lower in PCD than WCD. Muscle incomplete FAO was greater in PCD than WCD and greater incomplete FAO was associated with lower SI and higher HbA1c. Hydroxyacyl-coenzyme A dehydrogenase expression and activity were greater in PCD than WCD. There was no difference in maximal mitochondrial respiration or content between WCD and PCD. Conclusion The current results suggest that greater skeletal muscle incomplete FAO in poorly controlled T2D is due to elevated β oxidation and is associated with worsening muscle SI.

scholarly journals Repetition Priming in Individuals with Amnestic Mild Cognitive Impairment and Alzheimer’s Dementia: a Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Liselotte De Wit ◽  
Vitoria Piai ◽  
Pilar Thangwaritorn ◽  
Brynn Johnson ◽  
Deirdre O’Shea ◽  
...  
Keyword(s):  
Systematic Review ◽  
Older Adults ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Repetition Priming ◽  
Meta Analysis ◽  
Healthy Older Adults ◽  
Amnestic Mci ◽  
Standard Mean Difference ◽  
Priming Paradigm

AbstractThe literature on repetition priming in Alzheimer’s disease (AD) is inconsistent, with some findings supporting spared priming while others do not. Several factors may explain these inconsistencies, including AD severity (e.g., dementia vs. Mild Cognitive Impairment; MCI) and priming paradigm-related characteristics. This systematic review and meta-analysis provides a quantitative summary of repetition priming in AD. We examined the between-group standard mean difference comparing repetition priming in AD dementia or amnestic MCI (aMCI; presumably due to AD) to controls. Thirty-two studies were selected, including 590 individuals with AD dementia, 267 individuals with amnestic MCI, and 703 controls. Our results indicated that both individuals with aMCI and AD dementia perform worse on repetition priming tasks than cognitively older adults. Paradigm-related moderators suggested that the effect size between studies comparing the combined aMCI or AD dementia group to cognitively healthy older adults was the highest for paradigms that required participants to produce, rather than identify, primes during the test phase. Our results further suggested that priming in AD is impaired for both conceptual and perceptual priming tasks. Lastly, while our results suggested that priming in AD is impaired for priming tasks that require deep processing, we were unable to draw firm conclusions about whether priming is less impaired in aMCI or AD dementia for paradigms that require shallow processing.

scholarly journals Five-Year Change in Body Mass Index Predicts Conversion to Mild Cognitive Impairment or Dementia Only in APOE ɛ4 Allele Carriers

2021 ◽  
pp. 1-11
Author(s):  
Kylie R. Kadey ◽  
John L. Woodard ◽  
Allison C. Moll ◽  
Kristy A. Nielson ◽  
J. Carson Smith ◽  
...  
Keyword(s):  
Older Adults ◽  
Body Mass Index ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Body Mass ◽  
Carrier Status ◽  
Healthy Older Adults ◽  
E4 Allele ◽  
Lifestyle Risk

Background: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ɛ4 (APOE ɛ4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia. Objective: The aim of this study was to investigate the interaction between APOE ɛ4 status and baseline (bBMI) and five-year BMI change (ΔBMI) on conversion to MCI or dementia in initially cognitively healthy older adults. Methods: The associations between bBMI, ΔBMI, APOE ɛ4 status, and conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer’s Coordinating Center (NACC) database. Results: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p <  0.001, OR = 2.06. Neither bBMI (OR = 0.99, 95%CI = 0.96–1.02) nor the bBMI by APOE interaction (OR = 1.02, 95%CI = 0.96–1.08) predicted conversion. Although ΔBMI also did not significantly predict conversion (OR = 0.90, 95%CI = 0.78–1.04), the interaction between ΔBMI and carrier status was significant (OR = 0.72, 95%CI = 0.53–0.98). For carriers only, each one-unit decline in BMI over five years was associated with a 27%increase in the odds of conversion (OR = 0.73, 95%CI = 0.57–0.94). Conclusion: A decline in BMI over five years, but not bBMI, was strongly associated with conversion to MCI or dementia only for APOE ɛ4 carriers. Interventions and behaviors aimed at maintaining body mass may be important for long term cognitive health in older adults at genetic risk for AD.

scholarly journals Atorvastatin impairs liver mitochondrial function in obese Göttingen Minipigs but heart and skeletal muscle are not affected

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liselotte Bruun Christiansen ◽  
Tine Lovsø Dohlmann ◽  
Trine Pagh Ludvigsen ◽  
Ewa Parfieniuk ◽  
Michal Ciborowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Citrate Synthase ◽  
Obese Group ◽  
Control Group ◽  
Dependent Manner ◽  
Respiratory Capacity ◽  
Protein Carbonyl Content ◽  
Functional Changes ◽  
Mitochondrial Respiratory

AbstractStatins lower the risk of cardiovascular events but have been associated with mitochondrial functional changes in a tissue-dependent manner. We investigated tissue-specific modifications of mitochondrial function in liver, heart and skeletal muscle mediated by chronic statin therapy in a Göttingen Minipig model. We hypothesized that statins enhance the mitochondrial function in heart but impair skeletal muscle and liver mitochondria. Mitochondrial respiratory capacities, citrate synthase activity, coenzyme Q10 concentrations and protein carbonyl content (PCC) were analyzed in samples of liver, heart and skeletal muscle from three groups of Göttingen Minipigs: a lean control group (CON, n = 6), an obese group (HFD, n = 7) and an obese group treated with atorvastatin for 28 weeks (HFD + ATO, n = 7). Atorvastatin concentrations were analyzed in each of the three tissues and in plasma from the Göttingen Minipigs. In treated minipigs, atorvastatin was detected in the liver and in plasma. A significant reduction in complex I + II-supported mitochondrial respiratory capacity was seen in liver of HFD + ATO compared to HFD (P = 0.022). Opposite directed but insignificant modifications of mitochondrial respiratory capacity were seen in heart versus skeletal muscle in HFD + ATO compared to the HFD group. In heart muscle, the HFD + ATO had significantly higher PCC compared to the HFD group (P = 0.0323). In the HFD group relative to CON, liver mitochondrial respiration decreased whereas in skeletal muscle, respiration increased but these changes were insignificant when normalizing for mitochondrial content. Oral atorvastatin treatment in Göttingen Minipigs is associated with a reduced mitochondrial respiratory capacity in the liver that may be linked to increased content of atorvastatin in this organ.

Individuals With Mild Cognitive Impairment and Alzheimer's Disease Benefit From Audiovisual Speech Cues and Supportive Sentence Context

2021 ◽  
pp. 1-10
Author(s):  
Alexandre Chauvin ◽  
Shari Baum ◽  
Natalie A. Phillips
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Speech Perception ◽  
Sentence Context ◽  
Speech Perception In Noise ◽  
Healthy Older Adults ◽  
Speech Cues

Purpose Speech perception in noise becomes difficult with age but can be facilitated by audiovisual (AV) speech cues and sentence context in healthy older adults. However, individuals with Alzheimer's disease (AD) may present with deficits in AV integration, potentially limiting the extent to which they can benefit from AV cues. This study investigated the benefit of these cues in individuals with mild cognitive impairment (MCI), individuals with AD, and healthy older adult controls. Method This study compared auditory-only and AV speech perception of sentences presented in noise. These sentences had one of two levels of context: high (e.g., “Stir your coffee with a spoon”) and low (e.g., “Bob didn't think about the spoon”). Fourteen older controls ( M age = 72.71 years, SD = 9.39), 13 individuals with MCI ( M age = 79.92 years, SD = 5.52), and nine individuals with probable Alzheimer's-type dementia ( M age = 79.38 years, SD = 3.40) completed the speech perception task and were asked to repeat the terminal word of each sentence. Results All three groups benefited (i.e., identified more terminal words) from AV and sentence context. Individuals with MCI showed a smaller AV benefit compared to controls in low-context conditions, suggesting difficulties with AV integration. Individuals with AD showed a smaller benefit in high-context conditions compared to controls, indicating difficulties with AV integration and context use in AD. Conclusions Individuals with MCI and individuals with AD do benefit from AV speech and semantic context during speech perception in noise (albeit to a lower extent than healthy older adults). This suggests that engaging in face-to-face communication and providing ample context will likely foster more effective communication between patients and caregivers, professionals, and loved ones.

scholarly journals Magnetic Resonance Hippocampal Subfield Volumetric Analysis for Differentiating among Healthy Older Adults and Older Adults with Mild Cognitive Impairment or Major Depressive Disorder

2021 ◽  
Vol 73 (12) ◽  
pp. 786-792
Author(s):  
Doonyaporn Wongsawaeng ◽  
Orasa Chawalparit ◽  
Siriwan Piyapittayanan ◽  
Tanyaluck Thientunyakit ◽  
Weerasak Muangpaisan ◽  
...  
Keyword(s):  
Older Adults ◽  
Major Depressive Disorder ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Depressive Disorder ◽  
Subgroup Analysis ◽  
Amyloid Pet ◽  
Major Depressive ◽  
Healthy Older Adults ◽  
Valuable Adjunct

Objective: Depression among older adults is frequently an early symptom of cognitive decline, and is believed to be a risk factor for Alzheimer’s disease (AD). Hippocampal subfield volume loss is found in both mild cognitive impairment (MCI) and major depressive disorder (MDD). We aimed to investigate the potential of MR hippocampal subfield volumetry for discriminating among healthy older adults (HOA) and older adults with MCI or MDD. Materials and Methods: Seventy age-matched subjects (29 non-depressed MCI, 12 MDD, and 29 HOA) underwent 3-Tesla MR imaging (MRI) with high-resolution 3D-T1W-TFE whole brain. Hippocampal subfield volumetric measurements were performed using FreeSurfer software to distinguish among MCI, MDD, and HOA. Subgroup analysis with amyloid PET result was also performed.Results: Significantly smaller bilateral hippocampal tail volume was observed in MCI compared to HOA (p=0.004 and p=0.04 on the left and right side, respectively). The same comparative finding was observed at left HATA (hippocampus-amygdala-transition-area) of MCI (p=0.046). Other regions showed non-significantly smaller size in MCI than in HOA [left molecular layer HP (p=0.06), left whole hippocampus (p=0.06), and left CA1 (p=0.07)]. There was a non-significant trend toward smaller size in almost all 13 subfield hippocampal regions of MCI compared to MDD, even in subgroup analysis with amyloid PET result.Conclusion: MR hippocampal subfield volumetry may have value in routine clinical practice for screening individuals with MCI, and may be a valuable adjunct to amyloid PET study for very early-stage diagnosis of AD.

Tissue-specific control of mitochondrial respiration in obesity-related insulin resistance and diabetes

2012 ◽  
Vol 302 (6) ◽  
pp. E731-E739 ◽  
Author(s):  
Maria H. Holmström ◽  
Eduardo Iglesias-Gutierrez ◽  
Juleen R. Zierath ◽  
Pablo M. Garcia-Roves
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Respiratory Capacity ◽  
Tissue Specific ◽  
Mitochondrial Respiratory

The tissue-specific role of mitochondrial respiratory capacity in the development of insulin resistance and type 2 diabetes is unclear. We determined mitochondrial function in glycolytic and oxidative skeletal muscle and liver from lean (+/ ?) and obese diabetic ( db/db) mice. In lean mice, the mitochondrial respiration pattern differed between tissues. Tissue-specific mitochondrial profiles were then compared between lean and db/db mice. In liver, mitochondrial respiratory capacity and protein expression, including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), was decreased in db/db mice, consistent with increased mitochondrial fission. In glycolytic muscle, mitochondrial respiration, as well as protein and mRNA expression of mitochondrial markers, was increased in db/db mice, suggesting increased mitochondrial content and fatty acid oxidation capacity. In oxidative muscle, mitochondrial complex I function and PGC-1α and mitochondrial transcription factor A (TFAM) protein levels were decreased in db/db mice, along with increased level of proteins related to mitochondrial dynamics. In conclusion, mitochondrial respiratory performance is under the control of tissue-specific mechanisms and is not uniformly altered in response to obesity. Furthermore, insulin resistance in glycolytic skeletal muscle can be maintained by a mechanism independent of mitochondrial dysfunction. Conversely, insulin resistance in liver and oxidative skeletal muscle from db/db mice is coincident with mitochondrial dysfunction.

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