Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Active lifestyles moderate clinical outcomes in autosomal dominant frontotemporal degeneration.

INTRODUCTION: Leisure activities impact brain aging and may be prevention targets. We characterized how physical and cognitive activities relate to brain health for the first time in autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: A total of 105 mutation carriers (C9orf72/MAPT/GRN) and 69 non-carriers reported current physical and cognitive activities at baseline, and completed longitudinal neurobehavioral assessments and brain magnetic resonance imaging (MRI) scans. RESULTS: Greater physical and cognitive activities were each associated with an estimated >55% slower clinical decline per year among dominant gene carriers. There was also an interaction between leisure activities and frontotemporal atrophy on cognition in mutation carriers. High-activity carriers with frontotemporal atrophy (-1 standard deviation/year) demonstrated >two-fold better cognitive performances per year compared to their less active peers with comparable atrophy rates. DISCUSSION: Active lifestyles were associated with less functional decline and moderated brain-to-behavior relationships longitudinally. More active carriers "outperformed" brain volume, commensurate with a cognitive reserve hypothesis. Lifestyle may confer clinical resilience, even in autosomal dominant FTLD.

Cognitive Performance Does not Limit Physical Activity Participation in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).

OBJECTIVES: We examined whether multiple domains of baseline cognitive performance were associated with prospective physical activity (PA) adherence in the Lifestyle Interventions and Independence for Elders Pilot study (LIFE-P). DESIGN, SETTING, PARTICIPANTS: The LIFE-P study was a single-blind, multicenter, randomized controlled trial of a PA intervention compared to a successful aging educational intervention in sedentary, mobility-limited older adults. INTERVENTION: A 12-month structured, moderate-intensity, multi-modal PA program that included walking, resistance training, and flexibility exercises. For the first 2 months (adoption), 3 center-based exercise sessions (40-60 min) / week were conducted. During the next 4 months (transition), center-based sessions were conducted 2 times / week. The subsequent maintenance phase consisted of optional once-to-twice-per-week center-based sessions and home-based PA. MEASUREMENTS: Tests of executive and global cognitive functioning, working memory and psychomotor speed were administered at baseline. Median test scores were used to dichotomize participants into low or high cognitive performance groups. RESULTS: 52 mobility-limited older adults (age: 76.9 ±5 yrs) were randomized to the PA arm of LIFE-P. Compared to participants with high cognitive performance, participants with low performance had similar PA adherence rates (all P ≥ 0.34). Furthermore, weak and non-significant univariate relationships were elicited between all measures of cognition and overall PA adherence levels (r values ranged: -0.20 to 0.12, P ≥ 0.12). CONCLUSION: These data suggest that cognitive performance does not limit long-term PA adherence in mobility-limited older adults. Additional studies in larger cohorts are warranted to verify these findings.

Strength and performance asymmetry during maximal velocity sprint running.

The aim of this study was to empirically examine the interaction of athlete-specific kinematic kinetic and strength asymmetry in sprint running. Bilateral ground reaction force and kinematic data were collected during maximal velocity (mean = 9.05 m/s) sprinting for eight athletes. Bilateral ground reaction force data were also collected while the same athletes performed maximal effort squat jumps. Using novel composite asymmetry scores, interactions between kinematic and kinetic asymmetry were compared for the group of sprinters. Asymmetry was greater for kinematic variables than step characteristics, with largest respective values of 6.68% and 1.68%. Kinetic variables contained the largest asymmetry values, peaking at >90%. Asymmetry was present in all kinematic and kinetic variables analyzed during sprint trials. However, individual athlete asymmetry profiles were reported for sprint and jump trials. Athletes' sprint performance was not related to their overall asymmetry. Positive relationships were found between asymmetry in ankle work during sprint running and peak vertical force (r = 0.895) and power (r = 0.761) during jump trials, suggesting that the ankle joint may be key in regulating asymmetry in sprinting and highlighting the individual nature of asymmetry. The individual athlete asymmetry profiles and lack of relationship between asymmetry of limb strength and sprint performance suggest that athletes are not "limb dominant" and that strength imbalances are joint and task specific. Compensatory kinetic mechanisms may serve to reduce the effects of strength or biological asymmetry on the performance outcome of step velocity.

Gait asymmetry: composite scores for mechanical analyses of sprint running.

Gait asymmetry analyses are beneficial from clinical, coaching and technology perspectives. Quantifying overall athlete asymmetry would be useful in allowing comparisons between participants, or between asymmetry and other factors, such as sprint running performance. The aim of this study was to develop composite kinematic and kinetic asymmetry scores to quantify athlete asymmetry during maximal speed sprint running. Eight male sprint trained athletes (age 22±5 years, mass 74.0±8.7 kg and stature 1.79±0.07 m) participated in this study. Synchronised sagittal plane kinematic and kinetic data were collected via a CODA motion analysis system, synchronised to two Kistler force plates. Bilateral, lower limb data were collected during the maximal velocity phase of sprint running (velocity=9.05±0.37 ms(-1)). Kinematic and kinetic composite asymmetry scores were developed using the previously established symmetry angle for discrete variables associated with successful sprint performance and comparisons of continuous joint power data. Unlike previous studies quantifying gait asymmetry, the scores incorporated intra-limb variability by excluding variables from the composite scores that did not display significantly larger (p<0.05) asymmetry than intra-limb variability. The variables that contributed to the composite scores and the magnitude of asymmetry observed for each measure varied on an individual participant basis. The new composite scores indicated the inter-participant differences that exist in asymmetry during sprint running and may serve to allow comparisons between overall athlete asymmetry with other important factors such as performance.

Atmospheric chemistry of linear perfluorinated aldehydes: dissociation kinetics of CnF2n+1CO radicals.

Linear perfluorinated aldehydes (PFALs, CnF2n+1CHO) are important intermediate species in the atmospheric oxidation pathway of many polyfluorinated compounds. PFALs can be further oxidized in the gas phase to give perfluorinated carboxylic acids (PFCAs, CnF2n+1C(O)OH, n = 6, 12) which have been detected in animal tissues and at low parts per billion levels in human blood sera. In this paper, we report ab initio quantum chemistry calculations of the decarbonylation kinetics of CnF2n+1CO radicals. Our results show that CnF2n+1CO radicals have a strong tendency to decompose to give CnF2n+1 and CO under atmospheric conditions: the Arrhenius activation energies for decarbonylation of CF3CO, C2F5CO, and C3F7CO obtained using PMP4/6-311++G(2d,p) are 8.8, 6.6, and 5.8 kcal/mol, respectively, each of which is about 5 kcal/mol lower than the barrier for the corresponding nonfluorinated radicals. The lowering of the barrier for decarbonylation of CnF2n+1CO relative to that of CnH2n+1CO is well explained by electron withdrawal by F atoms that serve to weaken the critical C-CO bond. These results have important implications for the atmospheric fate of PFALs and the atmospheric pathways to PFCAs. The main effect of decarbonylation of CnF2n+1CO is to decrease the molar yield of CnF2n+1C(O)OH; if 100% of the CnF2n+1CO decompose, the yield of CnF2n+1C(O)OH must be zero. There is considerable scope for additional experimental and theoretical studies.

2,6-Bis[2-(4-pentylphenyl)vinyl]anthracene: a stable and high charge mobility organic semiconductor with densely packed crystal structure.

The development of new organic semiconductors with improved electrical performance and enhanced environmental stability is the focus of considerable research activity. This paper presents the design, synthesis, optical and electrochemical characterization, crystal packing, modeling and thin film morphology, and organic thin film field effect transistor (OTFT) device data analysis for a novel 2,6-bis[2-(4-pentylphenyl)vinyl]anthracene (DPPVAnt) organic semiconductor. We observed a hole mobility of up to 1.28 cm2/V.s and on/off current ratios greater than 107 for OTFTs fabricated using DPPVAnt as an active semiconductor layer. The mobility value is comparable to that of the current best p-type semiconductor pentacene-based device performance. In addition, we found a very interesting relationship between the charge mobility and molecule crystal packing in addition to the thin film orientation and morphology of the semiconductor as determined from single-crystal molecule packing study, thin film X-ray diffraction, and AFM measurements. The high performance of the semiconductor ranks among the best performing p-type organic semiconductors reported so far and will be a very good candidate for applications in organic electronic devices.

2-Phenylpyridine: To Twist or Not To Twist?

Density functional theory methods were used to investigate the structures associated with 2-phenylpyridine, ppy, and several of its electronic states. The structure of ppy has the aromatic rings twisted with respect to one another by ∼21°, which is about half the value found for biphenyl. In comparison with ppy, both the isoelectronic cation, ppyH(+), and anion, ppy(-), have larger twist angles. The extent of twisting is governed by the delicate balance between π conjugation and repulsive orbital/steric interactions, and the magnitudes of these interactions were investigated by examining the torsional energy barriers for all three molecular species. In contrast, every one of the investigated open-shell structures [Formula: see text] ppy(•)(+), ppy(•)(-), ppy*, ppyH(+)*, and ppy(-)* [Formula: see text] has coplanar aromatic rings, that is, no twist angle. Frontier molecular orbital analyses reveal that the π-type bonding between the bridging carbons becomes dominant over any repulsive orbital and steric interactions, thereby leading to coplanar rings. Also, the energetics associated with ppy and its various electronic states were investigated and reported.

Computational Characterization of Metal Binding Groups for Metalloenzyme Inhibitors.

The mode of action of many pest or disease control agents involves inhibition of some metalloenzyme that is essential for the survival of the target organism. These inhibitors typically consist of a functional group that is capable of a primary binding interaction with the metal and a scaffold that is capable of secondary interactions with the remainder of the enzyme. To characterize the binding ability of various metal binding groups (BGs), we have performed electronic structure calculations on ligand displacement reactions in a model system related to the metalloenzyme, peptide deformylase: E-M-R + BG → E-M-BG + R. Here E represents a model coordination environment for the metal M, and R is a reference ligand (e.g., water) that may be displaced by a metal binding group. Since the oxidation state of many of the metals considered allows for multiple spin states, we also studied the influence of spin state on the coordination environment. Qualitative considerations of electronic structure inspired by the calculations provide an understanding of binding energy trends across a variety of ligands for a given metal and across a variety of metals for a given ligand.

Strategies for maintaining a handstand in the anterior-posterior direction.

PURPOSE: The purpose of this analysis was to determine the contributions made by wrist, shoulder, and hip joint torques in maintaining a handstand. METHODS: Handstand balances (N = 6) executed on a force plate and recorded with two genlocked video cameras were subjected to inverse dynamics analysis to determine anterior-posterior joint torques at the wrists, shoulders, and hips. Multiple regression analyses were conducted to investigate which of the joint torques were influential in accounting for anterior-posterior whole-body mass center (CM) movement. RESULTS: Results demonstrated that, in general, all calculated joint torques contributed to CM movement. In a number of trials, wrist torque played a dominant role in accounting for CM variance. Ostensibly, superior handstand balances are characterized by important contributions from wrist torques and shoulder torques with little influence from hip torques. In contrast, hip torques were found to be increasingly influential in less successful balances. CONCLUSIONS: It is concluded that multiple joints are utilized in maintaining a handstand balance in the anterior-posterior direction, and there appears to be two joint involvement strategies, which supports similar findings from postural research on normal upright stance.

Prevalence and significance of unrecognized lower extremity peripheral arterial disease in general medicine practice*.

OBJECTIVE: To determine the prevalence of unrecognized lower extremity peripheral arterial disease (PAD) among men and women aged 55 years and older in a general internal medicine (GIM) practice and to identify characteristics and functional performance associated with unrecognized PAD. DESIGN: Cross-sectional. SETTING: Academic medical center. PARTICIPANTS: We identified 143 patients with known PAD from the noninvasive vascular laboratory, and 239 men and women aged 55 and older with no prior PAD history from a GIM practice. Group 1 consisted of patients with PAD consecutively identified from the noninvasive vascular laboratory (n = 143). Group 2 included GIM practice patients found to have an ankle brachial index less than 0.90, consistent with PAD (n = 34). Group 3 consisted of GIM practice patients without PAD (n = 205). MEASUREMENTS AND MAIN RESULTS: Leg functioning was assessed with the 6-minute walk, 4-meter walking velocity, and Walking Impairment Questionnaire (WIQ). Of GIM practice patients, 14% had unrecognized PAD. Only 44% of patients in Group 2 had exertional leg symptoms. Distances achieved in the 6-minute walk were 1,130, 1,362, and 1,539 feet for Groups 1, 2, and 3, respectively, adjusting for age, gender, and race (P <.001). The degree of difficulty walking due to leg symptoms as reported on the WIQ was comparable between Groups 2 and 3 and significantly greater in Group 1 than Group 2. In multiple logistic regression analysis including Groups 2 and 3, current cigarette smoking was associated independently with unrecognized PAD (odds ratio [OR], 6.82; 95% confidence interval [95% CI], 1.55 to 29.93). Aspirin therapy was nearly independently associated with absence of PAD (OR, 0.37; 95% CI, 0.12 to 1.12). CONCLUSION: Unrecognized PAD is common among men and women aged 55 years and older in GIM practice and is associated with impaired lower extremity functioning. Ankle brachial index screening may be necessary to diagnose unrecognized PAD in a GIM practice.

Race and sex influence clearance of nifedipine: results of a population study.

OBJECTIVE: To estimate oral clearance of nifedipine and to determine demographic and clinical covariates that affect nifedipine clearance in a clinical population. METHODS: Apparent oral clearance of nifedipine and protein binding were measured in 226 patients receiving sustained-release nifedipine formulations for hypertension and coronary artery disease (black men, n = 111; black women, n = 27; white men, n = 64; white women, n = 24). Mean age +/- SD was 71 +/- 11 years, and mean weight was 86 +/- 17 kg. Nifedipine concentrations were analyzed by HPLC, protein binding was measured by equilibrium dialysis, clearance and covariate effects were estimated by a nonlinear mixed effects population model, and statistical analyses were performed by a nonlinear mixed-effects model (clearance) and ANOVA (protein binding). RESULTS: Clearance was significantly slower in black subjects (8.9 +/- 0.7 mL/min/kg; mean +/- SE) compared with white subjects (11.6 +/- 0.8 mL/min/kg; P = .00004) and in men compared with women (9.3 +/- 0.6 versus 12.1 +/- 1.5 mL/min/kg; P = .0021). Reported alcohol use (alcohol, 8.6 +/- 1.1 versus no alcohol, 10.8 +/- 0.6 mL/min/kg; P = .0002) and smoking status (smoker, 8.8 +/- 2.0 versus nonsmoker, 10.2 +/- 0.6 mL/min/kg; P = .0362) also affected nifedipine clearance. Race and sex had no effect on protein binding of nifedipine (P = .29 and P = .44, respectively). No effects of age, stable coronary artery disease, or reported intake of beta-blockers on nifedipine clearance were detected in this primarily elderly population with hypertension. CONCLUSIONS: The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses.

A prescription survey of the use of atypical antipsychotics for hospital inpatients in the United Kingdom.

OBJECT: Available efficacy data for atypical antipsychotics relate almost entirely to the use of atypicals alone. Previous surveys have, however, shown that typical antipsychotics are often co-prescribed alongside atypical drugs. We sought to evaluate prescribing of atypical antipsychotics to inpatients during one week of June 1998. METHOD: Requests for information were sent out to 229 UK centres which employed psychiatric pharmacists. From these, 143 (62%) responses were received, providing information on 3685 patients prescribed atypical antipsychotics. Data on patients prescribed an atypical for longer than 6 weeks were used as the primary indicator of prescribing practice. RESULTS: For all atypicals examined, co-prescription of typical drugs was commonplace. The proportions of patients receiving an atypical as the sole antipsychotic were: clozapine 56.5%, risperidone 27.6%, sertindole 27.1%, olanzapine 18.9%, quetiapine 9.7% and amisulpride 7.1%. Patients prescribed regular typical antipsychotics alongside atypical drugs were significantly more likely to be prescribed regular anticholinergic medication, indicating higher rates of acute extrapyramidal effects in those receiving antipsychotic polypharmacy. Atypical antipsychotics were prescribed alone in a minority of patients. CONCLUSIONS: Whilst there is some support for antipsychotic polypharmacy in certain cases, judging by strict evidence-based criteria the prescribing of atypical antipsychotics in our survey was poor. (Int J Psych Clin Pract 2000; 4:41-46).

A two-segment simulation model of long horse vaulting.

The optimum pre-flight characteristics of the Hecht and handspring somersault vaults were determined using a two-segment simulation model. The model consisted of an arm segment and a body segment connected by a frictionless pin joint, simulating the vault from the Reuther board take-off through to landing. During horse contact, shoulder torque was set to zero in the model. Five independent pre-flight variables were varied over realistic ranges and an objective function was maximized to find the optimum pre-flight for each vault. The Hecht vault required a low trajectory of the mass centre during pre-flight, with a low vertical velocity of the mass centre and a low angular velocity of the body at horse contact. In contrast, the optimum handspring somersault required a high pre-flight trajectory, with a high angular velocity of the body and a high vertical velocity at horse contact. Despite the simplicity of the model, the optimum pre-flights were similar to those used in competitive performances.

Measuring running speed using photocells.

Photocell timing systems are used routinely to measure running speeds. In this study, the accuracy of such systems was evaluated using centre of mass speed estimates from three-dimensional video analysis as criteria. One subject ran at five nominal speeds (5-9 m x s(-1)) for each of five separations (1.6-2.4 m) between consecutive photocells. Running speeds were calculated from the photocell data using single beam and double beam systems. For single beam systems, the start of the first break of a beam and the start of the longest break of a beam were used as trigger criteria. For double beam systems, the first occurrence of both beams being broken and the start of the longest double break were used as trigger criteria. Root mean square speed errors were smaller for the double beam systems. The longest break criterion gave smaller root mean square errors than the first break criterion. In general, errors in speed were smaller for greater photocell separations. An error of 0.1 m x s(-1) was achieved using a single beam system set at hip height with a longest break criterion for photocell separations of around two stride lengths. The advantage of using a double beam system is that it achieves this accuracy without the need to adjust photocell separation for different stride lengths.

Quantification of the uncertainties in resultant joint moments computed in a dynamic activity.

Resultant joint moments are an important variable with which to examine human movement, but the uncertainty with which resultant joint moments are calculated is often ignored. This paper presents a procedure for examining the uncertainty with which resultant joint moments are calculated. The uncertainty was calculated by changing the parameters and variables required to compute the resultant joint moments, by amounts relating to their estimated uncertainties, and then quantifying the resulting change in the resultant joint moments. The procedure was applied to the elbow joint during loaded elbow flexion executed at maximum volitional speed. For this activity, the estimated moments were most sensitive to uncertainties in the derivatives of the position data. A number of other sources of error and uncertainty were identified which warrant further investigation. The protocols outlined in this study are applicable to other activities.

Hand placement techniques in long horse vaulting.

In this study, the effects of two different hand placement techniques used by gymnasts to perform Tsukahara and Kasamatsu long horse vaults were examined. Selected linear and angular flight descriptors were calculated to determine whether those gymnasts making initial hand contact on the end of the horse gained additional lift, range or rotation when compared to those gymnasts making the more traditional initial hand contact on top of the horse. Three-dimensional cine-film analysis using the Direct Linear Transformation (DLT) was used to obtain data on 17 elite gymnasts competing in the 1991 World Student Games at Sheffield, UK. The gymnasts were divided into two groups according to the techniques used: group E in which the first hand contact was made on the vertical surface of the near end and the second on the top of the horse, and group T in which both hands were placed on top of the horse. The vertical and horizontal motion of each gymnast's mass centre and the somersault rotation during pre-flight (board take-off to horse contact) and post-flight (horse take-off to ground landing) were determined. The projections of linear displacements of each gymnast's mass centre onto a vertical plane were determined from the three-dimensional mass centre co-ordinates, and somersault angles were calculated using the line joining the midpoints of each gymnast's shoulders and knees. Whole body mass centre linear velocity and somersault angular velocity were determined using quintic splines.(ABSTRACT TRUNCATED AT 250 WORDS)