Publications by authors named "Catherine Pennington"

31 Publications

Differentiating Functional Cognitive Disorder from Early Neurodegeneration: A Clinic-Based Study.

Brain Sci 2021 Jun 17;11(6). Epub 2021 Jun 17.

Department of Neurology, NHS Forth Valley, Stirling FK5 4WR, UK.

Functional cognitive disorder (FCD) is a relatively common cause of cognitive symptoms, characterised by inconsistency between symptoms and observed or self-reported cognitive functioning. We aimed to improve the clinical characterisation of FCD, in particular its differentiation from early neurodegeneration. Two patient cohorts were recruited from a UK-based tertiary cognitive clinic, diagnosed following clinical assessment, investigation and expert multidisciplinary team review: FCD, ( = 21), and neurodegenerative Mild Cognitive Impairment (nMCI, = 17). We separately recruited a healthy control group ( = 25). All participants completed an assessment battery including: Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test Part B (TMT-B); Depression Anxiety and Stress Scale (DASS) and Minnesota Multiphasic Personality Inventory (MMPI-2RF). In comparison to healthy controls, the FCD and nMCI groups were equally impaired on trail making, immediate recall, and recognition tasks; had equally elevated mood symptoms; showed similar aberration on a range of personality measures; and had similar difficulties on inbuilt performance validity tests. However, participants with FCD performed significantly better than nMCI on HVLT-R delayed free recall and retention (regression coefficient -10.34, = 0.01). Mood, personality and certain cognitive abilities were similarly altered across nMCI and FCD groups. However, those with FCD displayed spared delayed recall and retention, in comparison to impaired immediate recall and recognition. This pattern, which is distinct from that seen in prodromal neurodegeneration, is a marker of internal inconsistency. Differentiating FCD from nMCI is challenging, and the identification of positive neuropsychometric features of FCD is an important contribution to this emerging area of cognitive neurology.
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http://dx.doi.org/10.3390/brainsci11060800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234331PMC
June 2021

Altered awareness of cognitive and neuropsychiatric symptoms in Parkinson's disease and Dementia with Lewy Bodies: A systematic review.

Int J Geriatr Psychiatry 2021 01 14;36(1):15-30. Epub 2020 Sep 14.

Edinburgh Dementia Prevention, University of Edinburgh, Edinburgh, UK.

Objectives: Altered awareness of cognitive and neuropsychiatric symptoms is a common feature of neurodegeneration, which can significantly impact on quality of life, medication concordance and personal safety. Elucidating how awareness is affected by common alpha-synucleinopathies therefore has significant clinical relevance. We performed a systematic review of the literature on awareness of cognitive and neuropsychiatric symptoms in Parkinson's disease and Dementia with Lewy Bodies.

Methods: Searches of PubMed and Web of Science were carried out, using keywords and MeSH subheadings, limited to papers in English dealing with humans. The terms "Parkinson's" or "Lewy body" were used to denote the disease of interest, combined with either "agnosia", "anosognosia", "insight", "metacognition", or "neuropsychology" to denote the neuropsychological area of interest.

Results: 21 publications investigating awareness of cognitive symptoms, and 18 publications on awareness of neuropsychiatric symptoms were identified. The large majority focused on Parkinson's disease rather than Dementia with Lewy Bodies. Cognitively intact people with Parkinson's disease may over-report cognitive symptoms, whilst those with cognitive impairment under-report symptoms. Awareness of neuropsychiatric symptoms is likely to decline over time, particularly in those with progressive cognitive impairment.

Conclusions: Altered awareness of cognitive and neuropsychiatric symptoms is common in Parkinson's disease. Symptom awareness varies significantly between individuals, and appears to be influenced by mood and global cognitive functioning, with executive functioning specifically implicated. There are gaps in our understanding of how dopaminergic medications influence symptom awareness, and a need for longitudinal studies of how awareness changes over time in Parkinson's disease and Dementia with Lewy Bodies.
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http://dx.doi.org/10.1002/gps.5415DOI Listing
January 2021

Functional cognitive disorder: dementia's blind spot.

Brain 2020 10;143(10):2895-2903

Centre for Clinical Brain Sciences, The University of Edinburgh, EH16 4SB, UK.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.
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http://dx.doi.org/10.1093/brain/awaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586080PMC
October 2020

Fast Periodic Visual Stimulation indexes preserved semantic memory in healthy ageing.

Sci Rep 2020 08 4;10(1):13159. Epub 2020 Aug 4.

School of Psychological Science, University of Bristol, Bristol, BS8 1TU, UK.

Behavioural studies investigating the preservation of semantic memory in healthy ageing have reported mixed findings. One suggested reason for this discrepancy is that the processes underpinning lexical access to semantic knowledge may be sensitive to ageing. It is therefore necessary to assess semantic memory utilising tasks that are not explicitly linguistic. In this study, a fast periodic visual stimulation (FPVS) paradigm coupled with EEG was used to assess the ability of younger and older adults to automatically distinguish between images by their semantic category. Participants were presented with a 6 Hz stream of images drawn from one semantic category except every fifth image (occurring at a rate of 1.2 Hz) which was drawn from an alternate semantic category. For both younger and older adults, results demonstrate successful and comparable semantic categorisation. This was detectable at the individual level for 71% and 72% of older and younger adults, respectively. Given the rapid presentation rate and absence of explicit instruction to categorise images, the task is unlikely to utilise linguistic strategies and suggests the maintenance of semantic memory in healthy ageing. Moreover, this study utilised mobile EEG equipment and short presentation times that would be suitable for practical application outside a research setting.
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http://dx.doi.org/10.1038/s41598-020-69929-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403314PMC
August 2020

Altered awareness of motor symptoms in Parkinson's disease and Dementia with Lewy Bodies: A systematic review.

Int J Geriatr Psychiatry 2020 09 8;35(9):972-981. Epub 2020 Jul 8.

Edinburgh Dementia Prevention, University of Edinburgh, Edinburgh, UK.

Objectives: Altered awareness of motor symptoms is reported in people with Parkinson's disease and Dementia with Lewy Bodies, and may adversely affect quality of life and medication concordance. How symptom awareness is influenced by motor and cognitive disease severity, age and medication use is not fully understood. We carried out a systematic review of the literature on motor symptom awareness in Parkinson's disease and Dementia with Lewy Bodies.

Methods: Pubmed and Wed of Science were searched for relevant articles published in or prior to March 2019. Data regarding participant demographics, diagnosis, cognitive status, method of assessing awareness and study findings were extracted from relevant publications.

Results: Sixteen relevant publications were identified. Motor symptom awareness appears to decline over the course of Parkinson's disease. Imaging studies implicate the prefrontal cortex, with different mechanisms involved in hypokinesia and dyskinesia awareness. The hypothesis that people with right hemisphere based disease would have more severely reduced awareness is only weakly supported. Most studies focused on cognitively intact individuals, and on awareness of dyskinesia rather than hypokinesia.

Conclusions: Whilst reduced awareness of dyskinesia and to a lesser extent hypokinesia is common, there is a lack of longitudinal data on how awareness changes over time, and how it interacts with global cognitive changes. Motor symptom awareness in Dementia with Lewy Bodies is understudied. Future studies of symptom awareness should include robust assessment of overall cognitive functioning, and use a longitudinal design to elucidate how awareness changes over time. J Am Geriatr Soc 68:-, 2020.
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http://dx.doi.org/10.1002/gps.5362DOI Listing
September 2020

Mixed neuropathology in frontotemporal lobar degeneration.

Amyotroph Lateral Scler Frontotemporal Degener 2020 05 2;21(3-4):301-308. Epub 2020 Mar 2.

School of Clinical Sciences, University of Bristol, Bristol, UK.

: Frontotemporal lobar degeneration (FTLD) is a significant cause of dementia in mid-life and older adults. The extent of interactions between FTLD and other neurodegenerative pathologies is unclear. We reviewed the occurrences of mixed pathology in cases of neuropathologically diagnosed FTLD from the UK Brain Bank Network. : Clinicopathological details of cases of FTLD were extracted from the UK Brain Bank Network database. : Of 515 cases, 30.10% had mixed neuropathology. Concordance between clinical and neuropathological diagnosis was lower in these cases (38.71% vs. 59.17%). Alzheimer's spectrum pathology was the commonest additional finding. Age at death was higher in mixed neuropathology cases (mean 76.7 years vs. 72.59.0 years,  < 0.005), increasing in tandem with the number of neuropathologies present. : Mixed neuropathology is common in FTLD and associated with increased age at death. Our findings suggest that mixed neuropathology influences age at onset and clinical phenotype in FTLD and makes accurate antemortem diagnosis more difficult. Further investigation of interactions between neuropathologies and phenotype is warranted, particularly in view of the potential impact on clinical diagnosis and patient selection for clinical trials.Key pointsMixed neurodegenerative neuropathologies commonly occur with frontotemporal lobar degeneration.The likelihood of mixed neuropathology with FTLD increases with older age at death.Mixed neuropathology could influence the clinical phenotype of frontotemporal lobar degeneration.
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http://dx.doi.org/10.1080/21678421.2020.1733019DOI Listing
May 2020

Neural correlates of altered insight in frontotemporal dementia: a systematic review.

Neuroimage Clin 2019 5;24:102066. Epub 2019 Nov 5.

Research into Memory, Brain sciences and dementia Group (ReMemBr Group), Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, UK; Centre for Dementia Prevention, University of Edinburgh, UK.

Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.
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http://dx.doi.org/10.1016/j.nicl.2019.102066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889795PMC
September 2020

Pitting breastfeeding against formula is simplistic and unhelpful.

BMJ 2019 11 6;367:l6319. Epub 2019 Nov 6.

Royal Edinburgh Hospital, Edinburgh EH10 5HF, UK.

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http://dx.doi.org/10.1136/bmj.l6319DOI Listing
November 2019

Functional Cognitive Disorder: Diagnostic Challenges and Future Directions.

Diagnostics (Basel) 2019 Sep 28;9(4). Epub 2019 Sep 28.

ReMemBr Group, University of Bristol, Bristol Brain Centre, Southmead Hospital, Southmead Road, Bristol BS10 5NB, UK.

Functional cognitive disorder describes patients with persistent, troublesome subjective cognitive complaints that are inconsistent with a recognized disease process, and where significant discrepancies are found between subjective and objectively observed cognitive functioning. The etiology is heterogeneous and potentially related to underlying psychological factors. Making a diagnosis of functional cognitive disorder can be challenging and there is the potential for misdiagnosis of early-stage neurodegeneration. We compared neuropsychological findings in three groups: functional cognitive disorder (FCD), mild cognitive impairment (MCI), and healthy controls. Participants were recruited from the ReMemBr Group Clinic, North Bristol NHS Trust, and via Join Dementia Research. Both the FCD and MCI groups showed elevated prospective and retrospective memory symptom scores. Performance on the Montreal cognitive assessment was equivalent in the FCD and MCI groups, both being impaired compared with the controls. The FCD group was younger than those with MCI. We discuss challenges and controversies in the diagnosis of functional cognitive disorder, alongside illustrative cases and proposals for areas of research priority.
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http://dx.doi.org/10.3390/diagnostics9040131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963804PMC
September 2019

Diagnostic accuracy of frontotemporal dementia. An artificial intelligence-powered study of symptoms, imaging and clinical judgement.

Adv Med Sci 2019 Sep 2;64(2):292-302. Epub 2019 Apr 2.

Bristol Institute of Clinical Neurosciences, University of Bristol, Southmead Hospital, Bristol, UK.

Purpose: Frontotemporal dementia (FTD) is a neurodegenerative disorder associated with a poor prognosis and a substantial reduction in quality of life. The rate of misdiagnosis of FTD is very high, with patients often waiting for years without a firm diagnosis. This study investigates the current state of the misdiagnosis of FTD using a novel artificial intelligence-based algorithm.

Patients & Methods: An artificial intelligence algorithm has been developed to retrospectively analyse the patient journeys of 47 individuals diagnosed with FTD (age range 52-80). The algorithm analysed the efficiency of patient pathways by utilizing a reward signal of ‒1 to +1 to assess the symptoms, imaging techniques, and clinical judgement in both behavioural and language variants of the disease.

Results: On average, every patient was subjected to 4.93 investigations, of which 67.4% were radiological scans. From first presentation it took on average 939 days for a firm diagnosis. The mean time between appointments was 204 days, and the average patient had their diagnosis altered 7.37 times during their journey. The algorithm proposed improvements by evaluating the interventions that resulted in a decreased reward signal to both the individual and the population as a whole.

Conclusions: The study proves that the algorithm can efficiently guide clinical practice and improve the accuracy of the diagnosis of FTD whilst making the process of auditing faster and more economically viable.
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http://dx.doi.org/10.1016/j.advms.2019.03.002DOI Listing
September 2019

Visual rating assessment of cerebral atrophy and its relationship with cognitive function in chronic obstructive pulmonary disease.

BMJ Open Respir Res 2018 26;5(1):e000310. Epub 2018 Nov 26.

Academic Respiratory Unit, Clinical Sciences, University of Bristol, Bristol, UK.

Introduction: Widespread white matter damage and cognitive impairment have been demonstrated in chronic obstructive pulmonary disease (COPD). However, it remains unclear if brain atrophy is a global phenomenon or if specific subregions are differentially affected. The aims of this study are, first, to test a simple, validated visual analogue grading technique. Second, we hypothesised that frontal regions of the brains of patients with COPD will show greater signs of atrophy compared with control subjects. Third, any localised regions of atrophy would correlate with components of cognitive performance. Finally, the severity of cerebral atrophy would be associated with measures of respiratory disease severity.

Methods: We used a simple, validated visual analogue grading technique to assess the degree of regional atrophy in multiple brain regions from cerebral MR images in patients with stable non-hypoxaemic COPD (n=25) and age-matched control subjects (n=25). We also explored correlations between regional brain atrophy with demographics, cognitive performance measures and disease severity. Measures of cognitive performance focused on executive function, working memory, verbal memory, overall memory and processing speed. Measures of disease severity include lung function, gas exchange, health status and breathlessness questionnaires.

Results: The visual grading scale found that patients with COPD had significantly greater frontal atrophy than control subjects (p=0.02), independent of smoking history, comorbid depression or anxiety. Cognitive function was significantly worse in the COPD group for executive function (p<0.001), working memory (p=0.02), verbal memory (p=0.03) and processing speed (p=0.001). Group differences in atrophy did not appear to account for differences in cognitive function. We were unable to identify meaningful correlations between regional atrophy and disease severity or cognitive function.

Conclusion: Further work is needed to identify causative mechanisms behind unexplained structural brain changes in COPD.
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http://dx.doi.org/10.1136/bmjresp-2018-000310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267327PMC
November 2018

Tools for testing decision-making capacity in dementia.

Age Ageing 2018 11;47(6):778-784

Memory Research Group, School of Clinical Sciences, University of Bristol, Level 1 Learning & Research, Southmead Hospital, Bristol, UK.

Background: dementia is a common cause of altered decision-making capacity. Determining whether an individual has the ability to make a specific decision can be very challenging for both clinicians and researchers. The UK legislation requires that we both promote residual capacity where possible, and protect vulnerable adults who cannot make independent decisions. We evaluated published instruments designed to aid in the assessment of capacity, focussing on those meeting the UK legal requirements. We also consider further disease and culture-specific factors which may influence decision making.

Methods: a search of electronic databases was made for articles published between 2000 and 2017 detailing structured tools for the assessment of mental capacity. These were evaluated against the UK legal requirements.

Results: nine tools were identified which fulfilled the UK legal requirements. Their design and structure varied, as did the level of reliability and validity data available. Some instruments can be tailored for a specific decisional scenario, whilst others are designed for use by particular patient groups.

Discussion: a wide range of mental capacity assessment instruments is available, but not all fulfil the UK legal requirements. Healthcare professionals and researchers should be mindful of personal, cultural and disease-specific factors when assessing capacity. No gold standard for capacity assessment exists, which hampers the evaluation of different approaches. A combination of the opinion of a healthcare professional or researcher trained in capacity evaluation, plus the use of a structured assessment tool is the most robust approach.
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http://dx.doi.org/10.1093/ageing/afy096DOI Listing
November 2018

Challenges with Intestine and Multivisceral Re-Transplantation: Importance of Timing of Re-Transplantation and Optimal Immunosuppression.

Ann Transplant 2018 Feb 6;23:98-104. Epub 2018 Feb 6.

Transplant Division, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

BACKGROUND Patients undergoing re-transplantation often receive high doses of immunosuppression, which may lead to an immunocompromised status of the recipient. This study investigates the outcomes after intestine/multivisceral re-transplantation. MATERIAL AND METHODS Clinical outcomes of 23 patients undergoing 24 re-transplantations at a single intestine transplant center were reviewed. Bone marrow suppression was used as a surrogate marker of immunocompromised status, and was defined as platelet count <50 k/mm3 and absolute lymphocyte count <200/mm³. RESULTS All re-transplants except one were liver inclusive. Fifteen of 23 patients died at a median time of 12 months (range 0.2-75) after re-transplantation. Of the 15 deaths, nine (60%) resulted from complications associated with a compromised host immune status: graft versus host disease (GVHD) affecting bone marrow (three cases), persistent viral infection (three cases), post-transplant lymphoproliferative disorder (PTLD (one case), metastatic cancer (one case), multi-drug resistant polymicrobial sepsis (one case). Four deaths (27%) resulted from severe rejection. Non-survivors were more likely to have received alemtuzumab, and had higher incidence of bone marrow suppression. In addition to immunocompromised status and rejection, the use of alemtuzumab was associated with mortality after intestinal/multivisceral re-transplantation. CONCLUSIONS High mortality was associated with intestine/multivisceral re-transplantation. To improve clinical outcomes of intestine and multivisceral transplantation, it is important to allow reconstitution of host immunity. Longer interval between the two transplantations, and strategies such as allograft specific immunosuppression, may spare the host from the devastating effects of potent immunosuppression currently used.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248276PMC
http://dx.doi.org/10.12659/aot.908052DOI Listing
February 2018

The impact of ageing reveals distinct roles for human dentate gyrus and CA3 in pattern separation and object recognition memory.

Sci Rep 2017 10 25;7(1):14069. Epub 2017 Oct 25.

Bristol Institute of Clinical Neuroscience, North Bristol NHS Trust, Southmead Hospital, Bristol, BS10 5NB, UK.

Both recognition of familiar objects and pattern separation, a process that orthogonalises overlapping events, are critical for effective memory. Evidence is emerging that human pattern separation requires dentate gyrus. Dentate gyrus is intimately connected to CA3 where, in animals, an autoassociative network enables recall of complete memories to underpin object/event recognition. Despite huge motivation to treat age-related human memory disorders, interaction between human CA3 and dentate subfields is difficult to investigate due to small size and proximity. We tested the hypothesis that human dentate gyrus is critical for pattern separation, whereas, CA3 underpins identical object recognition. Using 3 T MR hippocampal subfield volumetry combined with a behavioural pattern separation task, we demonstrate that dentate gyrus volume predicts accuracy and response time during behavioural pattern separation whereas CA3 predicts performance in object recognition memory. Critically, human dentate gyrus volume decreases with age whereas CA3 volume is age-independent. Further, decreased dentate gyrus volume, and no other subfield volume, mediates adverse effects of aging on memory. Thus, we demonstrate distinct roles for CA3 and dentate gyrus in human memory and uncover the variegated effects of human ageing across hippocampal regions. Accurate pinpointing of focal memory-related deficits will allow future targeted treatment for memory loss.
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http://dx.doi.org/10.1038/s41598-017-13853-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656671PMC
October 2017

Functional Cognitive Disorder: A Common Cause of Subjective Cognitive Symptoms.

J Alzheimers Dis 2015 Sep;48 Suppl 1:S19-24

ReMemBr Group, University of Bristol, Bristol, UK.

Patients frequently present to the memory clinic with self-reported cognitive symptoms that cannot be attributed to structural, toxic, or metabolic causes, and are out of keeping with their performance on neuropsychological assessment. This can be considered to be Functional (psychosomatic) Cognitive Disorder, which results in significant patient distress and often has a major impact on social functioning and employment. We performed a retrospective analysis of the Bristol ReMemBr group cognitive clinic database to ascertain the prevalence of Functional Cognitive Disorder, review the patient characteristics, and develop new guidelines for diagnosis and management. 196 patients were screened of whom 23 were diagnosed with Functional Cognitive Disorder; the oldest patient with this diagnosis was aged 60 years at symptom onset. When considering only those presenting below the age of 60 years (total no. held on database = 69), a third were diagnosed with Functional Cognitive Disorder. On neuropsychological testing, 47% had an atypical (invalid) pattern of results, or failed tests of performance validity. Of those with valid neuropsychological results, 80% scored in the normal range. Depression and anxiety were common but did not appear to be the primary cause of cognitive symptoms. Particular characteristics seen were excessively low self-rating of memory ability, and discrepancies between perceived and actual cognitive performance. The rate of unemployment was high, often due to the cognitive symptomatology. This is an important disorder to address, being common in working adults, and carrying a risk of misdiagnosis as early neurodegeneration, with subsequent inappropriate treatment and inclusion in clinical trials.
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http://dx.doi.org/10.3233/JAD-150182DOI Listing
September 2015

Functional cognitive disorder: what is it and what to do about it?

Pract Neurol 2015 Dec 13;15(6):436-44. Epub 2015 Aug 13.

ReMemBr Group, School of Clinical Sciences, University of Bristol, Bristol, UK North Bristol NHS Trust, Institute of Neurosciences, Bristol, UK.

To err is human, and it is normal to make minor cognitive errors from time to time. Some people experience persistent subjective cognitive difficulties that cause distress and functional impairment, with no underlying structural, neurodegenerative, toxic or metabolic cause. This is considered a form of functional disorder. In this article, we review functional cognitive disorder and outline its core clinical features. Patients with this are typically of working age and have a source of psychological distress, such as chronic pain, work stress or family difficulties. Its distinction from incipient dementia is difficult and usually requires interval follow-up. Pointers towards possible dementia include abnormal neuroimaging or loss of insight. Many patients accept a functional cognitive disorder diagnosis and willingly engage with psychological therapies but there is no defined optimal treatment. Functional cognitive disorder is common but under-studied; future research priorities include the development of clear diagnostic criteria and robust trials of therapeutic strategies.
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http://dx.doi.org/10.1136/practneurol-2015-001127DOI Listing
December 2015

Evaluation of a Weight-based Rabbit Anti-thymocyte Globulin Induction Dosing Regimen for Kidney Transplant Recipients.

Pharmacotherapy 2015 Aug 3;35(8):748-54. Epub 2015 Aug 3.

Department of Pharmacy Services, University of Michigan Hospitals and Health Centers, Ann Arbor, Michigan.

Study Objective: Although rabbit anti-thymocyte globulin (rATG) is commonly used as induction therapy for kidney transplantation, dosing is not standardized. Recently available findings suggest that even subtle differences in the cumulative dose of rATG induction may have an impact on acute rejection rates for patients receiving steroid-minimization maintenance immunosuppression. This investigation evaluated the potential consequences of rounding and capping rATG doses in patients receiving steroid-containing maintenance immunosuppression when calculating the dose based on actual body weight.

Design: Single-center retrospective cohort study.

Setting: A large academic medical center.

Patients: A total of 261 adult kidney transplant recipients between July 1, 2010, and December 31, 2012, who received rATG induction and were maintained on tacrolimus, mycophenolate, and prednisone.

Methods And Measurements: Incidences of biopsy-confirmed acute rejection, opportunistic infections and hematologic effects within 12 months posttransplant were assessed for patients receiving a cumulative rATG dose of 5 mg/kg or higher (5.2 ± 0.2 mg/kg, n=138) compared with those who received a cumulative rATG dose lower than  5 mg/kg (4.5 ± 0.6 mg/kg, n=123). The groups had similar baseline characteristics, immunologic risk, and indications for rATG induction. The incidence of clinically relevant biopsy-confirmed acute rejection was low and similar between the groups (8.7% for rATG of 5 mg/kg or higher vs 8.9% for rATG lower than  5 mg/kg, p=0.944). Patient survival, all-cause graft survival, and graft function did not differ between the groups. Incidences of cytomegalovirus and BK virus infection as well as the extent and duration of lymphopenia were also similar between the groups.

Conclusions: In combination with triple maintenance immunosuppression consisting of tacrolimus, mycophenolate, and prednisone, modest differences in the cumulative rATG dose were not associated with increased risk of acute rejection. Measures to optimize rATG utilization present opportunities for cost-saving without sacrificing efficacy in this patient population.
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http://dx.doi.org/10.1002/phar.1624DOI Listing
August 2015

Sublingual tacrolimus as an alternative to oral administration for solid organ transplant recipients.

Am J Health Syst Pharm 2015 Feb;72(4):277-84

Catherine A. Pennington, M.S., Pharm.D., BCPS, is Clinical Hospital Pharmacist, Jackson Memorial Hospital, Miami, FL. Jeong M. Park, M.S., Pharm.D., BCPS, is Clinical Pharmacist Specialist, University of Michigan Hospitals and Health Centers, Ann Arbor, and Clinical Associate Professor, College of Pharmacy, University of Michigan, Ann Arbor.

Purpose: Available data regarding sublingual tacrolimus were analyzed to provide recommendations for solid organ transplant recipients.

Summary: Tacrolimus is an immunosuppressive agent with a narrow therapeutic range that is commonly used in solid organ transplantation. Achieving and maintaining appropriate tacrolimus exposure are critical for preventing rejection and minimizing toxicity. A variety of clinical situations requiring nonoral medication delivery arise, presenting the need for reliable alternative routes of tacrolimus administration. A review of the currently available literature revealed nine reports of sublingual tacrolimus use in human subjects. Seven reported that sublingual administration could achieve comparable tacrolimus trough concentrations to oral administration, but none investigated the correlation between tacrolimus trough concentration and exposure. One study of lung transplant recipients found that approximately 50% of the oral dose was needed to obtain therapeutic trough concentrations when converted to sublingual administration. Another study of patients with end-stage renal disease identified a similar sublingual:oral dosing ratio of 1:2. When converted from oral tacrolimus in combination with clotrimazole to sublingual administration, the sublingual:oral dosing ratio was 1:1.

Conclusion: In addition to enteral tube and i.v. tacrolimus dosing, sublingual administration may be considered for short-term use in patients who are unable to receive medications orally. Based on the available data, it is reasonable to initiate sublingual tacrolimus at 50% of the current or anticipated oral dose in the absence of interacting medications. Dosing must be individualized, taking into consideration concomitant interacting medications, and adjusted to target levels based on therapeutic drug monitoring.
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http://dx.doi.org/10.2146/ajhp140322DOI Listing
February 2015

18F-FDG PET-CT in the evaluation of paraneoplastic syndromes: experience at a regional oncology centre.

Nucl Med Commun 2012 Aug;33(8):872-80

West of Scotland PET Centre, Gartnavel Hospital, Glasgow, UK.

Objectives: Paraneoplastic syndromes (PNS) are remote manifestations of malignancy unrelated to tumour invasion or metastases. They pose a diagnostic challenge because of diverse presentations. (18)F-Fluorodeoxyglucose ((18)F-FDG) PET-CT is an emerging technique for the detection of malignancy; however, there is a paucity of data with regard to its role in the evaluation of PNS and its relation to pretest clinical risk.

Methods: A retrospective review of the database at the West of Scotland PET centre from 2007 to 2010 was conducted. Data extracted included demographics, clinical and pathological diagnosis, presence of classical syndromes, cross-sectional imaging, PET-CT imaging and management changes. A clinical scoring system was constructed to evaluate the pretest likelihood of having PNS, and the impact of a subsequent positive PET-CT scan was evaluated.

Results: A total of 68 consecutive patients with a median age (range) of 58 (23-82) years, of whom 44 (65%) were female, were included. Symptoms were neurological in 55 (81%), musculoskeletal in five (7%), endocrine in three (4%) and constitutional in five (7%) patients. Forty-three (62%) patients had a classical paraneoplastic syndrome and 34 (50%) had positive biomarkers. Eighteen (26%) patients had a positive PET-CT result. PET-CT was concordant with the clinical scoring in 49 (72%) patients; it upgraded the score in eight (12%) patients, and downgraded the score in 11 (16%) patients. Eight (12%) patients had confirmed malignancy. PET-CT was estimated to have 100% sensitivity, 82% specificity, 42% positive predictive value and 100% negative predictive value.

Conclusion: PET-CT is a highly sensitive and specific imaging technique in the evaluation of PNS and adds confidence to clinical likelihood.
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http://dx.doi.org/10.1097/MNM.0b013e3283550237DOI Listing
August 2012

N-methyl D-aspartate receptor antibody encephalitis associated with myelitis.

J Neurol Sci 2012 Jun 27;317(1-2):151-3. Epub 2012 Mar 27.

Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF, Scotland.

Encephalitis associated with antibodies to the N-methyl D-aspartate receptor (NMDA-R) was first described in young women with ovarian teratoma. It has subsequently been described in men, children and in those without an underlying tumour. Characteristic clinical features include neuropsychiatric symptoms, seizures, movement disorders, hypoventilation and autonomic instability. Spinal cord disease in association with other typical clinical features has been described in only one patient previously. We report a patient presenting with myelitis, with typical features of NMDA-R associated encephalitis manifesting 3 months later.
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http://dx.doi.org/10.1016/j.jns.2012.02.034DOI Listing
June 2012

Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.

Brain 2011 Jun;134(Pt 6):1829-38

National Prion Clinic, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.

Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations.
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http://dx.doi.org/10.1093/brain/awr079DOI Listing
June 2011

Neural correlates of episodic memory in behavioral variant frontotemporal dementia.

J Alzheimers Dis 2011 ;24(2):261-8

Neuroscience Research Australia, Sydney, NSW, Australia.

Impaired episodic memory is currently an exclusion criterion for behavioral variant frontotemporal dementia (bv-FTD), although prior studies have shown that neuropsychological memory performance varies from very impaired to intact in such patients. Our study investigated i) whether this variability might be due to the admixture of true bv-FTD and phenocopy syndrome patients and ii) the neural correlates of episodic memory deficits in bvFTD. Groups of patients with true bvFTD (n = 14), phenocopy syndrome (n = 6), Alzheimer's disease (AD) (n = 14), and healthy controls (n = 15) underwent memory testing and had MRI scanning with ratings of regional brain atrophy. Phenocopy patients did not differ to controls on memory scores or atrophy ratings. By contrast, bvFTD and AD patients were impaired on both measures in comparison to controls and more importantly, bvFTD and AD did not differ on memory scores. Atrophy patterns differed, with AD showing typical medial temporal lobe atrophy, while bvFTD patients had predominantly prefrontal cortex atrophy. In bvFTD neuropsychological memory performance correlated with frontal atrophy ratings while in AD significant correlations were found between memory and both medial temporal lobe and frontal atrophy ratings. Taken together, out data shows that bvFTD patients can show a similar degree of episodic memory impairment on neuropsychological tests to AD patients, however, the neural correlates differ. The previously variable reported memory performance in bvFTD is likely due to the inclusion of phenocopy patients, who are mostly undistinguishable from controls. These findings have implications for the diagnosis of bvFTD.
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http://dx.doi.org/10.3233/JAD-2011-101668DOI Listing
August 2011

PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism.

BMC Med Genet 2009 Dec 26;10:146. Epub 2009 Dec 26.

National CJD Surveillance Unit, University of Edinburgh, Bryan Matthews Building, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.

Background: Genetic analysis of the human prion protein gene (PRNP) in suspect cases of Creutzfeldt-Jakob disease (CJD) is necessary for accurate diagnosis and case classification. Previous publications on the genetic variation at the PRNP locus have highlighted the presence of numerous polymorphisms, in addition to the well recognised one at codon 129, with significant variability between geographically distinct populations. It is therefore of interest to consider their influence on susceptibility or the clinico-pathological disease phenotype. This study aimed to characterise the frequency and effect of PRNP open reading frame polymorphisms other than codon 129 in both disease and control samples sourced from the United Kingdom population.

Methods: DNA was extracted from blood samples and genetic data obtained by full sequence analysis of the prion protein gene or by restriction fragment length polymorphism analysis using restriction enzymes specific to the gene polymorphism under investigation.

Results: 147 of 166 confirmed cases of variant CJD (vCJD) in the UK have had PRNP codon 129 genotyping and all are methionine homozygous at codon 129; 118 have had full PRNP gene sequencing. Of the latter, 5 cases have shown other polymorphic loci: at codon 219 (2, 1.69%), at codon 202 (2, 1.69%), and a 24 bp deletion in the octapeptide repeat region (1, 0.85%). E219K and D202D were not found in sporadic CJD (sCJD) cases and therefore may represent genetic risk factors for vCJD.Genetic analysis of 309 confirmed UK sCJD patients showed codon 129 genotype frequencies of MM: 59.5% (n = 184), MV: 21.4% (n = 66), and VV: 19.1% (n = 59). Thirteen (4.2%) had the A117A polymorphism, one of which also had the P68P polymorphism, four (1.3%) had a 24 bp deletion, and a single patient had a novel missense variation at codon 167. As the phenotype of this latter case is similar to sCJD and in the absence of a family history of CJD, it is unknown whether this is a form of genetic CJD, or simply a neutral polymorphism.

Conclusions: This analysis of PRNP genetic variation in UK CJD patients is the first to show a comprehensive comparison with healthy individuals (n = 970) from the same population, who were genotyped for the three most common variations (codon 129, codon 117, and 24 bp deletion). These latter two genetic variations were equally frequent in UK sCJD or vCJD cases and a normal (healthy blood donor) UK population.
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http://dx.doi.org/10.1186/1471-2350-10-146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806268PMC
December 2009

The role of cerebrospinal fluid proteins as early diagnostic markers for sporadic Creutzfeldt-Jakob disease.

Neurosci Lett 2009 May 5;455(1):56-9. Epub 2009 Mar 5.

The National CJD Surveillance Unit, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, United Kingdom.

The utility of cerebrospinal fluid (CSF) proteins such as 14-3-3, tau protein and S-100b as diagnostic markers in the early stages of sporadic Creutzfeldt-Jakob disease (sCJD) is unclear. We examined the diagnostic value of these CSF proteins in the early stages of sCJD (within 6 weeks of onset of symptoms). Four groups of patients were compared: patients with probable or neuropathologically confirmed sCJD with CSF taken within 6 weeks of onset ('sCJD<6-week group', n=47); patients with CSF taken within 6 weeks of disease onset but with a diagnosis other than CJD ('non-sCJD<6-week group', n=21); patients with neuropathologically proven sCJD where CSF was taken later than 6 weeks after onset ('sCJD>6-week group', n=206); patients with CSF taken later than 6 weeks after onset of symptoms but with a diagnosis other than CJD ('non-sCJD>6-week group', n=166). The sensitivity and specificity of different combinations of neuronal proteins were ascertained. The sensitivities of all three markers were similar and ranged from 96% to 98%. The sensitivity of these markers was greater in the 'sCJD<6-week group' than in the 'sCJD>6-week group'. This may be due to differences in the PRNP codon 129 and PrP isotype distribution between these groups. CSF tau protein had the greatest specificity (82%). We found all three CSF protein markers to be highly sensitive in the early stages of sCJD, with CSF tau protein having the greatest specificity and efficiency. Our findings indicate that CSF protein markers are effective tests in the early stages of sCJD.
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http://dx.doi.org/10.1016/j.neulet.2009.02.067DOI Listing
May 2009

Occurrence and expression of gene transfer agent genes in marine bacterioplankton.

Appl Environ Microbiol 2008 May 21;74(10):2933-9. Epub 2008 Mar 21.

Department of Marine Sciences, University of Georgia, Athens, GA 30602, USA.

Genes with homology to the transduction-like gene transfer agent (GTA) were observed in genome sequences of three cultured members of the marine Roseobacter clade. A broader search for homologs for this host-controlled virus-like gene transfer system identified likely GTA systems in cultured Alphaproteobacteria, and particularly in marine bacterioplankton representatives. Expression of GTA genes and extracellular release of GTA particles ( approximately 50 to 70 nm) was demonstrated experimentally for the Roseobacter clade member Silicibacter pomeroyi DSS-3, and intraspecific gene transfer was documented. GTA homologs are surprisingly infrequent in marine metagenomic sequence data, however, and the role of this lateral gene transfer mechanism in ocean bacterioplankton communities remains unclear.
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http://dx.doi.org/10.1128/AEM.02129-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394915PMC
May 2008

Injections of leptin into rat ventromedial hypothalamus increase adipocyte apoptosis in peripheral fat and in bone marrow.

Cell Tissue Res 2007 Jan 22;327(1):133-41. Epub 2006 Sep 22.

Department of Cellular Biology and Anatomy, Medical College of Georgia, Laney Walker Blvd. CB2915, Augusta, GA 30912, USA.

The accumulation of fat cells (adipocytes) in bone marrow is now thought to be a factor contributing to age-related bone loss. Women with osteoporosis have higher numbers of marrow adipocytes than women with healthy bone, and bone formation rate is inversely correlated with adipocyte number in bone tissue biopsies from both men and women. Adipogenic differentiation of bone marrow stromal cells increases with age, but the factors regulating populations of mature adipocytes are not well understood. Leptin is thought to regulate adipose tissue mass via its receptors in the ventromedial hypothalamus (VMH). We have therefore tested the hypothesis that stimulation of leptin receptors in the VMH regulates adipocyte number in bone marrow. Results indicate that unilateral twice-daily injections of leptin into the rat VMH for only 4 or 5 days cause a significant reduction in the number of adipocytes in peripheral fat pads and bone marrow and indeed eliminate adipocytes almost entirely from bone marrow of the proximal tibia. Osteoblast surface is not affected with leptin treatment. Apoptosis assays performed on bone marrow samples from control and treated rats have revealed a significant increase in protein concentration of the apoptosis marker caspase-3 with leptin treatment. We conclude that stimulation of leptin receptors in the VMH significantly decreases the adipocyte population in bone marrow, primarily through apoptosis of marrow adipocytes. Elimination of marrow adipocytes via this central pathway may represent a useful strategy for the treatment and prevention of osteoporosis.
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http://dx.doi.org/10.1007/s00441-006-0312-3DOI Listing
January 2007

Age-related loss of muscle mass and bone strength in mice is associated with a decline in physical activity and serum leptin.

Bone 2006 Oct 5;39(4):845-53. Epub 2006 Jun 5.

Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, USA.

The mechanisms underlying age-related loss of muscle and bone tissue are poorly understood but are thought to involve changes in sex hormone status, physical activity, and circulating levels of inflammatory cytokines. This study attempts to develop an animal model useful for evaluating these mechanisms in vivo. Male C57BL/6 mice were included for study at 3, 6, 12, 18, 24, and 29 months of age. Endocortical mineralizing surface, serum leptin, body weight, and percentage of body fat all increased between 6 and 12 months of age as activity level declined. Serum levels of the inflammatory marker IL-6 increased significantly after 12 months of age, following the observed increase in body weight and percent body fat. Hindlimb muscle mass declined significantly between 18 and 24 months of age, both absolutely and relative to total body mass, with a further decline ( approximately 15%) between 24 and 29 months. Loss of muscle mass after 18 months of age was accompanied by a significant increase in bone resorption, as indicated by serum pyridinoline cross-links, and a significant decrease in fat mass, serum leptin, bone strength, bone mineral density, and vertical cage activity. No significant changes in serum testosterone with aging were detected in the mice, as levels were essentially constant between 6 and 29 months. Our data show that mice lose a significant amount of muscle and bone tissue with age, and this loss of musculoskeletal tissue is accompanied by a drop in serum leptin and preceded by a significant decrease in physical activity.
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http://dx.doi.org/10.1016/j.bone.2006.04.011DOI Listing
October 2006

Increased muscle mass with myostatin deficiency improves gains in bone strength with exercise.

J Bone Miner Res 2006 Mar 5;21(3):477-83. Epub 2005 Dec 5.

Department of Cellular Biology and Anatomy Medical College of Georgia, Augusta, Georgia 30912, USA.

Unlabelled: We tested the hypothesis that increased muscle mass augments increases in bone strength normally observed with exercise. Myostatin-deficient mice, which show increased muscle mass, were exercised along with wildtype mice. Results indicate that increases in bone strength with exercise are greater in myostatin-deficient mice than in wildtype mice, suggesting that the combination of increased muscle mass and physical activity has a greater effect on bone strength than either increased muscle mass or intense exercise alone.

Introduction: Muscle (lean) mass is known to be a significant predictor of peak BMD in young people, and exercise is also found to increase bone mass in growing humans and laboratory animals. We sought to determine if increased muscle mass resulting from myostatin deficiency would enhance gains in bone strength that usually accompany exercise.

Materials And Methods: Male mice lacking myostatin (GDF-8) were used as an animal model showing increased muscle mass. Wildtype and myostatin-deficient mice (n = 10-12 per genotype) were exercised on a treadmill for 30 minutes/day, 5 days/week, for 4 weeks starting at 12 weeks of age. Caged wildtype and myostatin-deficient mice (n = 10-12 per genotype) were included as sedentary controls. Structural and biomechanical parameters were measured from the radius.

Results: Ultimate force (F(u)), displacement (D(u)), toughness (energy-to-fracture; U), and ultimate strain (epsilon(u)) increased significantly with exercise in myostatin-deficient mice but not in normal mice. When F(u) is normalized by body mass, exercised myostatin-deficient mice show an increase in relative bone strength of 30% compared with caged controls, whereas exercised wildtype mice do not show a significant increase in ultimate force relative to caged controls. Relative to body weight, the radii of exercised myostatin-deficient mice are >25% stronger than those of exercised normal mice.

Conclusions: Increased muscle mass resulting from inhibition of myostatin function improves the positive effects of exercise on bone strength.
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http://dx.doi.org/10.1359/JBMR.051203DOI Listing
March 2006

Muscle-bone interactions in dystrophin-deficient and myostatin-deficient mice.

Anat Rec A Discov Mol Cell Evol Biol 2005 Sep;286(1):814-22

Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912, USA.

We have investigated muscle-bone interactions using two mouse mutants that are known to differ from normal mice in skeletal muscle growth and development: mice lacking myostatin (GDF8) and mice lacking dystrophin (mdx). Myostatin-deficient mice show increased muscle size and strength compared to normal mice, whereas the mdx mouse is a well-established animal model for Duchenne muscular dystrophy. The mdx mice have significantly larger hindlimb muscles than controls, and histological sections of the quadriceps muscles show dystrophic changes with extensive fibrosis. Femoral bone mineral density (BMD) and fracture strength (Fu) are significantly greater in mdx mice than controls, and these variables are more strongly correlated with quadriceps muscle mass than with body mass. In contrast, mdx mice do not shower high bone mineral density in the spine relative to controls, whereas myostatin-deficient mice have significantly increased BMD in the lumbar spine compared to normal mice. Both mdx mice and myostatin-deficient mice have expanded femoral trochanters for attachment of large hindlimb muscles, and both mutant strains show increased cross-sectional area moments of inertia mediolaterally (Iyy) but not anteroposteriorly (Ixx) compared to normal mice. These data suggest that lean (muscle) mass is a significant determinant of bone mineral density and strength in the limb skeleton, even when accompanied by a dystrophic phenotype. Likewise, increased muscle mass produces a marked increase in the external dimensions of muscle attachment sites, even when increased muscle size is accompanied by extensive fibrosis and muscle weakness.
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http://dx.doi.org/10.1002/ar.a.20224DOI Listing
September 2005

Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice.

J Bone Miner Res 2005 Jun 18;20(6):994-1001. Epub 2005 Jan 18.

Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912, USA.

Unlabelled: Normal mice and leptin-deficient ob/ob mice were treated with leptin to study effects on osteogenesis and adipogenesis in bone marrow. Leptin treatment significantly decreased bone marrow adipocyte size and number in ob/ob mice while increasing bone formation, BMC, and BMD. The results suggest that, in leptin-sensitive animals, the reduction in marrow adipocytes has positive effects on bone formation.

Introduction: Adipocytes, osteoblasts, and osteoclasts have leptin receptors, and leptin can also affect bone metabolism indirectly through its receptors in the hypothalamus. We examined the effects of leptin treatment on bone formation, BMD, and marrow adipocyte population in normal mice and leptin-deficient ob/ob mice.

Materials And Methods: At the age of 15 weeks, mice were implanted with Alzet osmotic pumps for subcutaneous delivery of treatment solutions (saline, 2.5 microg leptin/day, or 10 microg leptin/day) for 14 days at a delivery rate of 0.25 microl/h. Bone formation was assessed using fluorochrome labels, cell populations were quantified using histomorphometry, and bone densitometry was measured using DXA. We also used a Luminex Beadlyte assay system to quantify cell survival markers in bone marrow samples.

Results And Conclusions: Results indicate that both doses of leptin decreased the number of marrow adipocytes in ob/ob mice by >20% (p < 0.05) compared with PBS-treated ob/ob mice. The decrease in adipocyte number with leptin treatment is accompanied by an increase in concentration of the apoptosis marker caspase-3 in bone marrow adipocytes and hematopoietic cells. Both leptin doses also significantly (p < 0.05) increased the percentage of fluorochrome-labeled tibial endosteal surface by >30% compared with PBS-treated ob/ob mice. Leptin treatment increased whole body BMC by >30% in the ob/ob mice receiving the highest leptin dose. Leptin treatment provided no increase in bone formation, BMC, or BMD in normal, leptin-replete mice.
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http://dx.doi.org/10.1359/JBMR.050103DOI Listing
June 2005
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