Baseline bone turnover marker levels can predict change in bone mineral density during antiresorptive treatment in osteoporotic patients: the Copenhagen bone turnover marker study.

Anti-resorptive osteoporosis treatment might be more effective in patients with high bone turnover. In this registry study including clinical data, high pre-treatment bone turnover measured with biochemical markers was correlated with higher bone mineral density increases. Bone turnover markers may be useful tools to identify patients benefitting most from anti-resorptive treatment. INTRODUCTION: In randomized, controlled trials of bisphosphonates, high pre-treatment levels of bone turnover markers (BTM) were associated with a larger increase in bone mineral density (BMD). The purpose of this study was to examine this correlation in a real-world setting. METHODS: In this registry-based cohort study of osteoporosis patients (n = 158) receiving antiresorptive therapy, the association between pre-treatment levels of plasma C-telopeptide of type I Collagen (CTX) and/or N-terminal propeptide of type I procollagen (PINP) and change in bone mineral density (BMD) at lumbar spine, total hip, and femoral neck upon treatment was examined. Patients were grouped according to their pre-treatment BTM levels, defined as values above and below the geometric mean for premenopausal women. RESULTS: Pre-treatment CTX correlated with annual increase in total hip BMD, where patients with CTX above the geometric mean experienced a larger annual increase in BMD (p = 0.008) than patients with CTX below the geometric mean. The numerical pre-treatment level of CTX showed a similar correlation at all three skeletal sites (total hip (p = 0.03), femoral neck (p = 0.04), and lumbar spine (p = 0.0003)). A similar association was found for PINP where pre-treatment levels of PINP above the geometric mean correlated with a larger annual increase in BMD for total hip (p = 0.02) and lumbar spine (p = 0.006). CONCLUSION: Measurement of pre-treatment BTM levels predicts osteoporosis patients' response to antiresorptive treatment. Patients with high pre-treatment levels of CTX and/or PINP benefit more from antiresorptive treatment with larger increases in BMD than patients with lower pre-treatment levels.

Spinal cord injuries without radiologic abnormality in children: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: The objective of this study is to systematically review the literature for pediatric cases of spinal cord injuries without radiologic abnormality (SCIWORA) to investigate any possible relationship between initial neurologic impairment and eventual neurologic status. SETTING: A university department of orthopedics. METHODS: Following the preferred reporting items for systemic reviews and meta-analysis (PRISMA) guidelines for systematic review, the databases of PubMed and OvidSP were electronically searched for articles that use individuals under 18 years old, have trauma resulting in spinal cord injury and have no fractures or dislocations on radiographs. When available, the patients' age, sex, mechanism of injury and spinal cord level were recorded. Individuals with cervical injury, who had specific information on cervical level and mechanism of injury, were recorded as well. Patients who reported specific magnetic resonance imaging findings and the time from the injury were also reported. When possible, the American Spinal Injury Association Impairment Scale (AIS) was determined initially after the injury and then at last follow-up. RESULTS: A total of 433 pediatric patients were identified with SCIWORA. The most prevalent mechanism of injury was sports-related injury cases (39.83%) followed by fall (24.18%) and motor vehicle-related (23.18%) injuries. The mean improvement recorded for all patients was 0.89 AIS grades. CONCLUSION: The most common mechanism of injury was sports-related and cervical injury, which occurred more frequently than other levels. Initial AIS grade A showed poorer outcomes in the pediatric population compared with the adult population. Initial presentation of D showed the highest likelihood of no permanent neurologic impairment (AIS of E).

Genotype-phenotype studies of VCP-associated inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia.

Valosin containing protein (VCP) disease associated with inclusion body myopathy, Paget disease of the bone and frontotemporal dementia is a progressive autosomal dominant disorder caused by mutations in Valosin containing protein gene. To establish genotype-phenotype correlations we analyzed clinical and biochemical markers from a database of 190 members in 27 families harboring 10 missense mutations. Individuals were grouped into three categories: symptomatic, presymptomatic carriers and noncarriers. The symptomatic families were further divided into ten groups based on their VCP mutations. There was marked intra and inter-familial variation; and significant genotype-phenotype correlations were difficult to establish because of small numbers. Nevertheless when comparing the two most common mutations, R155C mutation was found to be more severe, with an earlier onset of myopathy and Paget (p = 0.03). Survival analysis of all subjects revealed an average life span after diagnosis of myopathy and Paget of 18 and 19 years respectively, and after dementia only 6 years. R155C had a reduced survival compared to the R155H mutation (p = 0.03).We identified amyotrophic lateral sclerosis (ALS) was diagnosed in 13 individuals (8.9%) and Parkinson's disease in five individuals (3%); however, there was no genotypic correlation. This study represents the largest dataset of patients with VCP disease and expands our understanding of the natural history and provides genotype-phenotype correlations in this unique disease.

The frequency of and associations with hospitalization secondary to lupus flares from the 1000 Faces of Lupus Canadian cohort.

OBJECTIVES: Hospitalization is a major factor in health care costs and a surrogate for worse outcomes in chronic disease. The aim of this study was to determine the frequency of hospitalization secondary to lupus flare, the causes of hospitalization, and to determine risk factors for hospitalization in patients with systemic lupus erythematosus (SLE). METHODS: Data were collected as part of the 1000 Canadian Faces of Lupus, a prospective cohort study, where annual major lupus flares including hospitalizations were recorded over a 3-year period. RESULTS: Of 665 patients with available hospitalization histories, 68 reported hospitalization related to a SLE flare over 3 years of follow-up. The average annual hospitalization rate was 7.6% (range 6.6-8.9%). The most common reasons for hospitalization were: hematologic (22.1%), serositis (20.6%), musculoskeletal (MSK) (16.2%), and renal (14.7%). Univariate risk factors for lupus hospitalization included (OR [95% CI]; p < 0.05): juvenile-onset lupus (2.2 [1.1-4.7]), number of ACR SLE criteria (1.4 [1.1-1.7], baseline body mass index (BMI) (1.1 [1.0-1.1]), psychosis (3.4 [1.2-9.9]), aboriginal race (3.2 [1.5-6.7]), anti-Smith (2.6 [1.2-5.4]), erythrocyte sedimentation rate >25 mm/hr (1.9 [1.1-3.4]), proteinuria >0.5 g/d (4.2 [1.9-9.3], and SLAM-2 score (1.1 [1.0-1.2]). After multivariate regression only BMI, number of ACR criteria, and psychosis were associated with hospitalization for lupus flare. CONCLUSIONS: The mean annual rate of hospitalization attributed to lupus was lower than expected. Hematologic, serositis, MSK and renal were the most common reasons. In a regression model elevated BMI, more ACR criteria and psychosis were associated with hospitalization.

Suprascapular nerve blockage for painful shoulder pathology - a systematic review and meta-analysis of treatment techniques.

BACKGROUND: Suprascapular nerve blockade (SSNB) through injection (SSNBi) and/or pulsed radiofrequency (PRF) provide options for the management of painful shoulder pathology. Multiple techniques for delivery of SSNB are described but no consensus on optimal symptom control is available. This systematic review and meta-analysis aims to assess patient-focussed outcomes in SSNB and explore the impact of variation in the technical application of this treatment modality. METHODS: MEDLINE, Embase and CINAHL were searched for case series, cohort studies and randomised control trials published from database inception until 28 January 2021. Articles reporting use of SSNBi or PRF for treatment of shoulder pain with a minimum 3 months follow-up were included. Patient-reported outcome measures (PROMs) were extracted and the pooled standardised mean difference (SMD), weighted by study size, was reported. Quality of methodology was assessed using Wylde's nonsummative four-point system. FINDINGS: Of 758 references, 18 studies were included, totalling 704 SSNB. Average pain improvement at 3 months was 52.3%, with meta-analysis demonstrating a SMD of 2.37. Whereas SSNBi combined with PRF shows the greatest SMD of 2.75, this did not differ significantly from SSNBi or PRF when used as monotherapy. Location of treatment and the guidance technique used did not influence outcome. CONCLUSION: SSNBi and PRF provide safe and effective treatment for shoulder pain, as judged by PROMs. This may be of particular value in aging or comorbid patients and with surgical restrictions during the COVID-19 pandemic. Regardless of technique, patients experience a marked improvement in pain that is maintained beyond 3 months.

Differential reports of pain and depression differentiate mild cognitive impairment from cognitively intact elderly participants.

BACKGROUND: Positive associations between pain and depression in the general population have been well characterized; however, the interplay between pain, depression, and early cognitive decline, characterized as mild cognitive impairment (MCI), is poorly understood. METHODS: The current study examined the association of self-reported pain complaints (measured by the 36-item Short Form Health Survey) and self-reported depressive symptoms (measured by the 30-item Geriatric Depression Scale) in cognitively intact participants (n = 492) and participants with a clinical diagnosis of MCI (n = 83). RESULTS: Depressive symptoms and subjective reports of pain were significantly associated in the entire sample (r = .29; P < .0001). Multiple logistic regression modeling (adjusted for age, education, and APOE4 status as covariates) demonstrated that while depressive symptoms were positively associated with the diagnosis of MCI (P < .001), subjective pain reports were negatively associated with MCI (P < .002). CONCLUSION: While the negative association of subjective pain complaints with MCI might arguably be explained by the development of anosognosia, self-reports of depressive symptoms were actually increased in these participants, suggesting preserved insight into cognitive decline-associated symptoms. It is possible that preferential involvement of limbic circuitry in MCI could explain these findings. Future studies are needed to elucidate the reasons for the dissociation of pain and depressive symptoms in MCI described in the present article.

A targeted association study in systemic lupus erythematosus identifies multiple susceptibility alleles.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Multiple genetic and environmental factors contribute to the pathogenesis of this disease. Recent genome-wide association studies have added substantially to the number of genes associated with SLE. To replicate some of these susceptibility loci, single-nucleotide polymorphisms reported to be associated to SLE were evaluated in a cohort of 245 well-phenotyped Canadian SLE trios. Our results replicate previously reported associations to alleles of interferon regulatory factor 5 (IRF5), major histocompatibility complex (MHC), tumor necrosis factor (ligand) superfamily member 4 (TNFSF4), Kell blood group complex subunit-related family member 6 (XKR6), B-cell scaffold protein with ankyrin repeats 1 (BANK1), protein tyrosine phosphatase non-receptor type 22 (PTPN22), ubiquitin-conjugating enzyme E2L 3 (UBE2L3) and islet cell autoantigen 1 (ICA1). We also identify putative associations to cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a gene associated with several autoimmune disorders, and ERBB3, a locus on 12q13 that was previously reported to be associated with type 1 diabetes. This study confirms the existence of multiple genetic risk factors for SLE, and supports the notion that some risk factors for SLE are shared with other inflammatory disorders.

Measurements of dynamic surface changes by digital holography for in situ plasma erosion applications.

There are currently few viable diagnostic techniques for in situ measurement of plasma facing component erosion. Digital holography is intended to fill this gap. Progress on the development of single and dual CO2 laser digital holography diagnostics for in situ plasma facing component erosion is discussed. The dual laser mode's synthetic wavelength allows the measurable range to be expanded by a factor of ∼400 compared to single laser digital holography. This allows the diagnostic to measure surface height changes of up to 4.5 µm in single laser mode and up to 2 mm in dual laser mode. Results include ex situ measurements of plasma eroded targets and also dynamic measurements of nm and µm scale motion of a target mounted on a precision translation stage. Dynamic measurements have successfully been made with the system operating in both single and dual laser modes, from ∼50 nm to ∼4 µm in single laser mode and up to ∼400 µm in dual laser mode (limited only by the stage speed and camera acquisition duration). These results demonstrate the feasibility of using digital holography to characterize plasma facing component erosion dynamically, i.e., during plasma exposure. Results of proof-of-principle in situ digital holographic measurements of targets exposed to an electrothermal arc plasma source are presented.

A digital holography ex situ measurement characterization of plasma-exposed surface erosion from an electrothermal arc source.

Digital holography has been proposed to fulfill a need for an imaging diagnostic capable of in situ monitoring of surface erosion caused by plasma-material interaction in nuclear fusion devices. A digital holography diagnostic for 3D surface erosion measurement has been developed at Oak Ridge National Laboratory with the goal of deployment on a plasma device. A proof-of-concept in situ demonstration is planned which would involve measurement of plasma erosion on targets exposed to an electrothermal arc source. This work presents the results of an ex situ characterization of the capability and limitations of holographic imaging of targets exposed to the arc source. Targets were designed to provide a fiducial for comparison of deformed and unaffected areas. The results indicated that the average net erosion was ∼150 nm/plasma exposure, which is expected to be within the diagnostic's measurement capacity. Surface roughness averages determined by holographic image analysis showed good agreement with measurements taken with a profilometer. The limit of the holography diagnostic's x-y spatial resolution was characterized by comparison with scanning electron microscope imaging.

Synchronous auditory nerve activity in the carboplatin-chinchilla model of auditory neuropathy.

Two hallmark features of auditory neuropathy (AN) are normal outer hair cell function in the presence of an absent/abnormal auditory brainstem response (ABR). Studies of human AN patients are unable to determine whether disruption of the ABR is the result of a reduction of neural input, a loss of auditory nerve fiber (ANF) synchrony, or both. Neurophysiological data from the carboplatin model of AN reveal intact neural synchrony in the auditory nerve and inferior colliculus, despite significant reductions in neural input. These data suggest that (1), intact neural synchrony is available to support an ABR following carboplatin treatment and, (2), impaired spike timing intrinsic to neurons is required for the disruption of the ABR observed in human AN.

Reports of abnormal cervical cancer screening tests in systemic sclerosis.

OBJECTIVE: To assess the prevalence of abnormal cervical cancer screening (Pap tests) reported by women with SSc onset before the age of 50 yrs. METHODS: Female members of a Canadian multi-centre SSc cohort completed standardized assessments and were questioned regarding a history of an abnormal Pap test. Potential correlates examined included demographics, reproductive history, smoking, diffuse vs limited SSc type, immunosuppressant exposure and SSc duration. RESULTS: In the 320 women with SSc onset before the age of 50 yrs, the life-time prevalence of an abnormal Pap test (according to self-report) was 25.4% (95% CI CI 20.9, 30.4%). By comparison, self-reported prevalence of abnormal Pap tests among general population Canadian females was recently reported at 13.8% (95% CI 11.6, 16.4%). Women with diffuse SSc (n = 142), tended to have a higher prevalence of self-reported cervical dysplasia (31.7%) compared with those with limited disease (20.7%), but the CIs overlapped. A multivariate logistic regression found a significant positive association between self-reported abnormal Pap test and diffuse disease [odds ratio (OR) 1.87; 95% CI 1.01, 3.47]. An independent association of an abnormal Pap test with smoking (OR 2.43; 95% CI 1.23, 4.78) and with younger age at disease onset was also noted. CONCLUSIONS: We noted a high prevalence of abnormal Pap tests self-reported in our sample. Increased risk was seen among those with diffuse SSc, and also among smokers and those with a younger age at disease onset. Thus, it seems prudent to ensure that adequate attention is paid to cervical cancer screening for women with SSc.

Uncapping and deregulation of telomeres lead to detrimental cellular consequences in yeast.

Telomeres are the protein-nucleic acid structures at the ends of eukaryote chromosomes. Tandem repeats of telomeric DNA are templated by the RNA component (TER1) of the ribonucleoprotein telomerase. These repeats are bound by telomere binding proteins, which are thought to interact with other factors to create a higher-order cap complex that stabilizes the chromosome end. In the budding yeast Kluyveromyces lactis, the incorporation of certain mutant DNA sequences into telomeres leads to uncapping of telomeres, manifested by dramatic telomere elongation and increased length heterogeneity (telomere deregulation). Here we show that telomere deregulation leads to enlarged, misshapen "monster" cells with increased DNA content and apparent defects in cell division. However, such deregulated telomeres became stabilized at their elongated lengths upon addition of only a few functionally wild-type telomeric repeats to their ends, after which the frequency of monster cells decreased to wild-type levels. These results provide evidence for the importance of the most terminal repeats at the telomere in maintaining the cap complex essential for normal telomere function. Analysis of uncapped and capped telomeres also show that it is the deregulation resulting from telomere uncapping, rather than excessive telomere length per se, that is associated with DNA aberrations and morphological defects.

Receptor-coupled activation of phosphoinositide-specific phospholipase C by an N protein.

Cleavage of phosphatidylinositol 4,5-bisphosphate by phospholipase C results in the production of two important second messengers: inositol-1,4,5-trisphosphate and 1,2-diacylglycerol. Although several receptors promote this cleavage, the molecular details of phospholipase C activation have remained unresolved. In this study, occupancy of a Ca2+-mobilizing receptor, the oligopeptide chemoattractant receptor on human polymorphonuclear leukocyte plasma membranes, was found to lead to the activation of a guanine nucleotide regulatory (N) protein by guanosine 5'-triphosphate. The activated N protein then stimulated a polyphosphoinositide-specific phospholipase C by reducing the Ca2+ requirement for expression of this activity from superphysiological to normal intracellular concentrations. Therefore, the N protein-mediated activation of phospholipase C may be a key step in the pathway of cellular activation by chemoattractants and certain other hormones.

Protein crystal growth in microgravity.

The crystals of most proteins or other biological macromolecules are poorly ordered and diffract to lower resolutions than those observed for most crystals of simple organic and inorganic compounds. Crystallization in the microgravity environment of space may improve crystal quality by eliminating convection effects near growing crystal surfaces. A series of 11 different protein crystal growth experiments was performed on U.S. space shuttle flight STS-26 in September 1988. The microgravity-grown crystals of gamma-interferon D1, porcine elastase, and isocitrate lyase are larger, display more uniform morphologies, and yield diffraction data to significantly higher resolutions than the best crystals of these proteins grown on Earth.

A biomechanical basis for tears of the human acetabular labrum.

OBJECTIVE: Acetabular labral tears predominantly affect young patients and are a source of hip pain in the athlete. Four causes of the initiation of labral tears have been proposed; trauma, hypolaxity of the anterior capsule, dysplasia and bony impingement. A further cause could be reduced biomechanical properties in the area most susceptible to tears. However, no work has defined these properties. DESIGN: 32 compressive and 32 tensile test samples were harvested from fresh-frozen cadaveric acetabula. The labrum was divided into eight areas to allow comparison around its circumference. Semiconfined compressive testing and tensile testing were performed at a displacement rate of 10 mm/min in a controlled environment of 100% humidity at 37 (SD 1) degrees C. SETTING: Cadaveric study. RESULTS: The mean compressive stiffness was 31.75 (SD 16.7) MPa, and the mean tensile elastic modulus was 24.7 (SD 10.8) MPa. The anterosuperior region had a significantly lower compressive elastic modulus than either of the posterior quadrants (p<0.05) and a significantly lower tensile modulus to the anterioinferior area (p<0.05). CONCLUSIONS: The biomechanical properties in the anterosuperior region may be a contributing factor to the initiation of labral tears.

Delayed administration of a potent cyclin dependent kinase and glycogen synthase kinase 3 beta inhibitor produces long-term neuroprotection in a hypoxia-ischemia model of brain injury.

We compared the neuroprotective efficacy of a potent and CNS-penetrant cyclin dependent kinase (CDK) and glycogen synthase kinase 3 beta (GSK3beta) inhibitor (Compound 1) in juvenile (postnatal day 21; P21) and adult C57Bl/6 mice (postnatal day 60; P60) using a model of hypoxic-ischemic brain injury (HI). Neuronal cell counts and density measures from brain sections stained with Cresyl Violet revealed that exposure of P21 mice to 60 min of HI resulted in extensive damage to the ipsilateral cornu ammonis 1 (CA1) region of the hippocampus (40% cell loss) and striatum (30% cell loss) 7 days later. Exposure of P60 mice to 40 min of HI produced a similar pattern of cell loss. Intraperitoneal administration of Compound 1 (3 mg/kg) 1, 5 and 9 h after 60 min of HI did not reduce brain injury in P21 mice relative to vehicle controls. By contrast, in P60 mice, this treatment significantly decreased cell loss in the ipsilateral hippocampus (10% cell loss) and striatum (15% loss) relative to vehicle controls. Terminal uridine deoxynucleotidyl transferase (TUNNEL) positive cell counts and infarct volume were also substantially reduced in P60 mice treated with Compound 1. A motor coordination test performed twice weekly until 5 weeks post-HI confirmed that Compound 1 produced long lasting functional recovery. Our results indicate that Compound 1 produced long lasting neuroprotective effects in adult but not juvenile mice suggesting that inhibition of the CDKs and GSK3beta plays a distinct neuroprotective role in the juvenile and adult brain.

Tensile properties of the human glenoid labrum.

Human fresh-frozen cadaveric glenoid labrae from 16 donors were harvested and ten of these had no gross degeneration. These ten were divided into eight equal circumferential sections. Each section was cut to produce test-samples from the core layer with a cross-section of 1 x 1 mm. Tensile testing was performed within a controlled environment unit at 37 +/- 1 degrees C and 100% relative humidity. Each test-sample was precycled to a quasi-static state to alleviate the effects of deep-freezing, prior to final testing. The tangent modulus was calculated for each test-sample before and after a 5-min period of stress relaxation and at yield. The mean elastic modulus and yield stress of the glenoid labrum were 22.8 +/- 11.4 and 2.5 +/- 2.1 MPa, respectively. The anterosuperior portion had a lower elastic modulus and lower yield stress than the inferior portion (both P < 0.02). The pre-stress relaxation tangent modulus was significantly lower than the post-stress relaxation tangent modulus for all portions of the labrum. The glenoid labrum has similar tensile material properties to articular cartilage. Its elastic modulus varies around its circumference. This suggests that the labrum may encounter different forces at different positions.

Collagenous microstructure of the glenoid labrum and biceps anchor.

The glenoid labrum is a significant passive stabilizer of the shoulder joint. However, its microstructural form remains largely unappreciated, particularly in the context of its variety of functions. The focus of labral microscopy has often been histology and, as such, there is very little appreciation of collagen composition and arrangement of the labrum, and hence the micromechanics of the structure. On transmission electron microscopy, significant differences in diameter, area and perimeter were noted in the two gross histological groups of collagen fibril visualized; this suggests a heterogeneous collagenous composition with potentially distinct mechanical function. Scanning electron microscopy demonstrated three distinct zones of interest: a superficial mesh, a dense circumferential braided core potentially able to accommodate hoop stresses, and a loosely packed peri-core zone. Confocal microscopy revealed an articular surface fine fibrillar mesh potentially able to reduce surface friction, bundles of circumferential encapsulated fibres in the bulk of the tissue, and bone anchoring fibres at the osseous interface. Varying microstructure throughout the depth of the labrum suggests a role in accommodating different types of loading. An understanding of the labral microstructure can lead to development of hypotheses based upon an appreciation of this component of material property. This may aid an educated approach to surgical timing and repair.

Clinical features of mild cognitive impairment differ in the research and tertiary clinic settings.

OBJECTIVE: Comparative analysis of subjects with mild cognitive impairment (MCI) diagnosed in a primary research setting and those seen in a tertiary care memory disorders clinic. METHODS: Subjects who received a diagnosis of MCI between July 1, 2005, and December 31, 2006, in a longitudinal research study of normal cognition (n = 48) and patients diagnosed in a tertiary care referral clinic (n = 34) were evaluated using similar methodologies. Comparative analyses of detailed medical, neurological and neuropsychological data are presented. RESULTS: The diagnosis of MCI was not accepted by 13 of 48 subjects (27%) classified as MCI in the primary research setting. Nondegenerative, potentially treatable causes of cognitive decline were found in 3 of 34 subjects (9%) seen in the tertiary referral clinic and in 11 of 35 subjects (31%) identified as MCI in the primary research setting (p = 0.02, Fisher's exact test). MCI subjects identified in the primary research setting were older than those referred to the memory clinic (mean +/- SD, 79.7 +/- 7.0 vs. 71.5 +/- 9.0 years, p < 0.0001, t test) and had more years of education (16.0 +/- 3.2 vs. 13.6 +/- 4.2 years, p < 0.01, t test). MCI subjects in the primary research setting appeared to be in a milder stage of disease, characterized by higher Mini-Mental State Examination scores (28.2 +/- 1.8 vs. 25.7 +/- 1.8, p < 0.0001), and a tendency towards single domain involvement, predominantly memory (mean number of domains involved, 1.0 vs. 2.5, p < 0.0001). More advanced stages of MCI, seen in the tertiary referral population, had additional involvement of attention (p < 0.0001, Fisher's exact test) and visuospatial domains (p < 0.0002, Fisher's exact test). Semiquantitative grading of hippocampal and medial temporal lobe atrophy did not differ between groups (p = 0.81, Mann-Whitney U test). CONCLUSIONS: The diagnosis of MCI may be unwelcome in naïve persons. Remedial causes of MCI should be actively investigated. Demographic and clinical characteristics of MCI differ between research subjects and patients referred to a tertiary care clinic.

Improved predictive model for pre-symptomatic mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: Delineation of gray matter (GM) structures on brain MRI scans is termed segmentation. Accuracy of segmentation is a key factor in the valid comparison of GM density and volume between individuals and groups. Previously, it was demonstrated that a group of normal subjects who later developed mild cognitive impairment (MCI) had decreased GM volume in the medial temporal lobe compared to other normal subjects who remained normal an average 5.4 years after the scan. The objective of this study was to show whether accuracy of this predictive model was increased using an advanced segmentation technique. METHODS: Structural MRI was performed on 74 longitudinally examined normal aged subjects. All subjects were cognitively normal at the time of their scan, but 18 later developed MCI, and six of these 18 went on from MCI to an AD diagnosis. We independently delineated GM using both a standard segmentation technique and a local Gaussian active contour (LGAC) technique. We compared the contribution of extracted volumes from each technique to a model predicting subjects who will eventually develop MCI. RESULTS: Accuracy of the standard technique to distinguish pre-MCI from normal using imaging alone was 79% (sensitivity 78% and specificity 73%). Using LGAC, accuracy rose to 84% (sensitivity 78% and specificity 84%). DISCUSSION: Structural brain changes precede MCI in longitudinally followed normal subjects. The LGAC technique improves the accuracy of a predictive model incorporating these structural changes by improving GM segmentation and the specificity of the model.