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.

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.

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.

Parathyroid adenoma with coexistent sarcoid granulomas. A hypercalcemic patient.

A 56-year-old woman had hypercalcemia. Clinical symptoms and chest roentgenograms were suggestive of sarcoidosis. Results of laboratory studies, however, were compatible with primary hyperparathyroidism. At surgical exploration of the neck, a parathyroid adenoma was found. Microscopically, sarcoid-like granulomas were present within the adenoma. The association between hypercalcemic sarcoidosis and primary hyperparathyroidism is reviewed, and the importance of this finding is discussed.

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.

Medial calcinosis of Mönckeberg. A review of the problem and a description of a patient with involvement of peripheral, visceral and coronary arteries.

Massive medial calcific deposits (Mönckeberg's calcinosis) are described in the peripheral and visceral arteries, and similar but small-sized deposits in the coronary arteries of a 41 year old woman with diabetes mellitus. Although observed by roentgenogram fairly commonly during life in the muscular arteries of the legs in middle-aged men, medial calcinosis infrequently involves the visceral arteries and has never, to our knowledge, been documented in the coronary arteries. Although it may be associated with intimal atherosclerosis, medial calcinosis, per se, does not obstruct the lumens of the arteries and, therefore, does not lead to symptoms or signs of limb or organ ischemia. The cause of medial calcinosis remains a mystery, but it appears to affect people with diabetes more frequently than those without.

Hemochromatosis heart disease: an unemphasized cause of potentially reversible restrictive cardiomyopathy.

Cardiac involvement in hemochromatosis typically results in congestive cardiomyopathy; a restrictive cardiomyopathy due to hemochromatosis is distinctly rare. A restrictive cardiomyopathy, which developed in the patient described in this report, was due to hemochromatosis which mimicked constrictive pericarditis clinically, echocardiographically and hemodynamically, and resulted in a thoracotomy for attempted surgical therapy. The fact that hemochromatosis represents the only cause of a restrictive cardiomyopathy that is potentially reversible by medical therapy makes early recognition of hemochromatosis heart disease important.

Pulmonary venoocclusive disease in pregnancy.

A 23-year-old woman in her 27th week of gestation presented with clinical findings of progressive pulmonary hypertension. After cardiac catheterization she went into labor and was delivered by cesarean section. She died shortly thereafter from right heart failure. Pulmonary venoocclusive disease was found at autopsy. Hemodynamic changes during pregnancy, labor, delivery, and the postpartum period may have contributed to her deterioration and death. This is the first description of pulmonary venoocclusive disease in pregnancy.

Member characteristics, participation, and interests: Public Health Nutrition Practice Group.

A survey was developed to assess the level of participation and the membership interests of the Public Health Nutrition Practice Group (PHNPG). Forty-six percent (500 members) returned a completed survey. More than 80% of members believe PHNPG to be their main professional practice area "home" within the Council on Practice structure. Members overwhelmingly viewed practice group contributions as a responsibility, with personal career benefits being of secondary importance. Reading the practice group's newsletter and voting in elections were major areas of involvement. However, willingness to contribute time was a positive finding. Areas of interest and issues of greatest concern were identified. Results of the survey can be used to prepare long-range plans for PHNPG. Membership involvement in practice group activities is the key to an increase in re-enrollments and in new memberships.

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.

Accuracy assessment and control point configuration when using the DLT for photogrammetry.

The direct linear transformation (DLT) is a common technique used to calibrate cameras and subsequently reconstruct points filmed with two or more cameras in a three-dimensional object space. The assessment of the accuracy of this technique, and of the influence of the distribution of control points on accuracy were examined. It was concluded that to obtain a true estimation of reconstruction accuracy, an independent assessment criterion is required, and that the use of control points distributed around the outside, rather than within the space to be calibrated, is preferred.

An analytical examination of muscle force estimations using optimization techniques.

Muscle forces are often estimated during human movement using optimization procedures. The optimization procedures involve the minimization of an objective function relating to the muscle forces. In this study 15 different objective functions were evaluated by examining the analytical solutions to the objective functions and by comparing their force predictions with the forces estimated using a validated muscle model. The muscle forces estimated by the objective functions were shown to give poor correspondence with the muscle model predicted muscle forces. The objective function estimates were criticized for not taking sufficient account of the physiological properties of the muscles. As a consequence of the analysis of the objective functions an alternative, simpler function was presented with which to estimate muscle forces in vivo. This function required that to satisfy a given joint moment, the force exerted by each of the muscles divided by the maximum force possible by the muscle was constant for all muscles. For this function the maximum muscle force was determined using a muscle model assuming maximal activation.

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-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.