Multi-Domain Interventions for Dementia Prevention - A Systematic Review.

OBJECTIVES: There is a growing incidence of cognitive decline and dementia associated with the ageing population. Lifestyle factors such as diet, physical activity, and cognitive activities may individually or collectively be undertaken to increase one's odds of preventing cognitive decline and future dementia. This study will examine whether clinical trials using multidomain lifestyle intervention can significantly decrease the risk of cognitive decline and therefore dementia. DESIGN, SETTING AND PARTICIPANTS: This systematic literature review of multidomain lifestyle interventions for the prevention of cognitive decline and dementia followed the PRISMA guidelines. Clinical trials involving multidomain intervention (i.e., diet and physical activity, or without cognitive training) in older adults (≥ 49 years old) at higher risk of dementia were identified through 5 electronic databases (EMBASE, MEDLINE, CINAHL, Cochrane, and Scopus). A comprehensive search was performed to identify and retrieve publications until 15 November 2022. Trials were published in English. RESULTS: The included studies (n=15) assessed change in cognition in response to a multidomain lifestyle intervention. However, the cognitive outcome measures used in these studies were heterogeneous. Despite this heterogeneity, two thirds of the studies showed improvement in cognition following a multidomain intervention (n=10 with a total of 9,439 participants). However, five studies reported no improvement in cognition following the multidomain intervention. The most common form of dietary intervention included higher amount of fruit and vegetable intake; whole-grain cereal products instead of refined; low fat options in milk and meat products; and limiting sucrose intake to less than 50 g/day. Most clinical trial studies were powered to examining the effects of multidomain interventions in cognition but were not designed to test the contribution of individual domains (i.e., dietary changes, increased physical activity, or increased cognitive stimulation alone). CONCLUSION: This systematic review aimed to determine the effect of multimodal lifestyle interventions on cognitive outcomes in older adults at risk of dementia. We found that participants with conditions that may increase the risk of dementia, (e.g., hypertension, cardiovascular fragility) do benefit from multi-modal lifestyle changes including diet, physical activity, and cognitive training. Two thirds of studies using multidomain lifestyle interventions showed improvements in cognitive function. Trials with a focus on cognitive training, dietary improvement, and physical activity may prevent or delay cognitive decline in older adults including those at risk of developing dementia. Future studies should consider longer follow-up periods and adequate power to be able to examine the effects of each lifestyle component in the context of multimodal interventions.

Physical activity and amyloid-ß plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing.

Previous studies suggest physical activity improves cognition and lowers Alzheimer's disease (AD) risk. However, key AD pathogenic factors that are thought to be influenced by physical activity, particularly plasma amyloid-ß (Aß) and Aß brain load, have yet to be thoroughly investigated. The objective of this study was to determine if plasma Aß and amyloid brain deposition are associated with physical activity levels, and whether these associations differed between carriers and non-carriers of the apolipoprotein E (APOE) ε4 allele. Five-hundred and forty six cognitively intact participants (aged 60-95 years) from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) were included in these analyses. Habitual physical activity levels were measured using the International Physical Activity Questionnaire (IPAQ). Serum insulin, glucose, cholesterol and plasma Aß levels were measured in fasting blood samples. A subgroup (n=116) underwent (11)C-Pittsburgh compound B (PiB) positron emission tomography (PET) scanning to quantify brain amyloid load. Higher levels of physical activity were associated with higher high density lipoprotein (HDL) (P=0.037), and lower insulin (P<0.001), triglycerides (P=0.019) and Aß1-42/1-40 ratio (P=0.001). After stratification of the cohort based on APOE ε4 allele carriage, it was evident that only non-carriers received the benefit of reduced plasma Aß from physical activity. Conversely, lower levels of PiB SUVR (standardised uptake value ratio) were observed in higher exercising APOE ε4 carriers. Lower plasma Aß1-42/1-40 and brain amyloid was observed in those reporting higher levels of physical activity, consistent with the hypothesis that physical activity may be involved in the modulation of pathogenic changes associated with AD.

Multiple effects of physical activity on molecular and cognitive signs of brain aging: can exercise slow neurodegeneration and delay Alzheimer's disease?

Western countries are experiencing aging populations and increased longevity; thus, the incidence of dementia and Alzheimer's disease (AD) in these countries is projected to soar. In the absence of a therapeutic drug, non-pharmacological preventative approaches are being investigated. One of these approaches is regular participation in physical activity or exercise. This paper reviews studies that have explored the relationship between physical activity and cognitive function, cognitive decline, AD/dementia risk and AD-associated biomarkers and processes. There is now strong evidence that links regular physical activity or exercise to higher cognitive function, decreased cognitive decline and reduced risk of AD or dementia. Nevertheless, these associations require further investigation, more specifically with interventional studies that include long follow-up periods. In particular, relatively little is known about the underlying mechanism(s) of the associations between physical activity and AD neuropathology; clearly this is an area in need of further research, particularly in human populations. Although benefits of physical activity or exercise are clearly recognised, there is a need to clarify how much physical activity provides the greatest benefit and also whether people of different genotypes require tailored exercise regimes.

Intense physical activity is associated with cognitive performance in the elderly.

Numerous studies have reported positive impacts of physical activity on cognitive function. However, the majority of these studies have utilised physical activity questionnaires or surveys, thus results may have been influenced by reporting biases. Through the objective measurement of routine levels of physical activity via actigraphy, we report a significant association between intensity, but not volume, of physical activity and cognitive functioning. A cohort of 217 participants (aged 60-89 years) wore an actigraphy unit for 7 consecutive days and underwent comprehensive neuropsychological assessment. The cohort was stratified into tertiles based on physical activity intensity. Compared with individuals in the lowest tertile of physical activity intensity, those in the highest tertile scored 9%, 9%, 6% and 21% higher on the digit span, digit symbol, Rey Complex Figure Test (RCFT) copy and Rey Figure Test 30-min recall test, respectively. Statistically, participants in the highest tertile of physical activity intensity performed significantly better on the following cognitive tasks: digit symbol, RCFT copy and verbal fluency test (all P<0.05). The results indicate that intensity rather than quantity of physical activity may be more important in the association between physical activity and cognitive function.

Induced smoothing for rank regression with censored survival times.

Adaptions of weighted rank regression to the accelerated failure time model for censored survival data have been successful in yielding asymptotically normal estimates and flexible weighting schemes to increase statistical efficiencies. However, for only one simple weighting scheme, Gehan or Wilcoxon weights, are estimating equations guaranteed to be monotone in parameter components, and even in this case are step functions, requiring the equivalent of linear programming for computation. The lack of smoothness makes standard error or covariance matrix estimation even more difficult. An induced smoothing technique overcame these difficulties in various problems involving monotone but pure jump estimating equations, including conventional rank regression. The present paper applies induced smoothing to the Gehan-Wilcoxon weighted rank regression for the accelerated failure time model, for the more difficult case of survival time data subject to censoring, where the inapplicability of permutation arguments necessitates a new method of estimating null variance of estimating functions. Smooth monotone parameter estimation and rapid, reliable standard error or covariance matrix estimation is obtained.

MR angiography and surgery for unruptured familial intracranial aneurysms in persons with a family history of cerebral aneurysms.

OBJECTIVE: We used MR angiography to determine prevalence of unruptured familial intracranial aneurysms in a prepaid medical care program. We compared surgical outcomes and the cost of treating unruptured versus ruptured aneurysms. We compared the cost of MR angiography with the cost of screening mammography and with the cost of surgically treating a ruptured aneurysm. SUBJECTS AND METHODS: During a 30-month period, we performed MR angiography to show cerebral aneurysms in 63 surgical candidates who had one or more first-degree relatives with an aneurysm. Unruptured aneurysms seen on MR angiography were evaluated by digital subtraction angiography (DSA) and treated surgically. RESULTS: MR angiography showed nine unruptured aneurysms in six patients. Eight aneurysms were seen on MR angiography and nine were seen on DSA. Seven unruptured aneurysms were treated surgically. The mean treatment cost was 50% lower for an unruptured aneurysm than that for a ruptured aneurysm. No patient surgically treated for an unruptured aneurysm required rehabilitation, unlike 25% of patients with ruptured aneurysms. The annual total cost of MR angiography was equivalent to 2.9% of the annual cost of screening mammography. The annual cost of MR angiography equaled half the cost of treating one patient after aneurysm rupture. CONCLUSION: MR angiography showed a 9.5% prevalence of unruptured aneurysms among persons who had one or more first-degree relatives with a cerebral aneurysm. DSA confirmed 88% of aneurysms found on MR angiography. Persons with unruptured aneurysms had better treatment outcomes at lower cost than did patients treated for aneurysm rupture. The annual MR angiography cost was low compared with the cost of screening mammography and with the cost of treating one patient with aneurysm rupture.

Tolerance of Arc repressor to multiple-alanine substitutions.

Arc repressor mutants containing from three to 15 multiple-alanine substitutions have spectral properties expected for native Arc proteins, form heterodimers with wild-type Arc, denature cooperatively with Tms equal to or greater than wild type, and, in some cases, fold as much as 30-fold faster and unfold as much as 50-fold slower than wild type. Two of the mutants, containing a total of 14 different substitutions, also footprint operator DNA in vitro. The stability of some of the proteins with multiple-alanine mutations is significantly greater than that predicted from the sum of the single substitutions, suggesting that a subset of the wild-type residues in Arc may interact in an unfavorable fashion. Overall, these results show that almost half of the residues in Arc can be replaced by alanine en masse without compromising the ability of this small, homodimeric protein to fold into a stable, native-like structure.

The gastric bypass operation reduces the progression and mortality of non-insulin-dependent diabetes mellitus.

Of 232 morbidly obese patients with non-insulin-dependent diabetes mellitus referred to East Carolina University between March 5, 1979, and January 1, 1994, 154 had a Roux-en-Y gastric bypass operation and 78 did not undergo surgery because of personal preference or their insurance company"s refusal to pay for the procedure. The surgical and the nonoperative (control) groups were comparable in terms of age, weight, body mass index, sex, and percentage with hypertension. The two groups were compared retrospectively to determine differences in survival and the need for medical management of their diabetes. Mean length of follow-up was 9 years in the surgical group and 6.2 years in the control group. The mean glucose levels in the surgical group fell from 187 mg/dl preoperatively and remained less than 140 mg/dl for up to 10 years of follow-up. The percentage of control subjects being treated with oral hypoglycemics or insulin increased from 56.4% at initial contact to 87.5% at last contact (P = 0.0003), whereas the percentage of surgical patients requiring medical management fell from 31.8% preoperatively to 8.6% at last contact (P = 0.0001). The mortality rate in the control group was 28% compared to 9% in the surgical group (including perioperative deaths). For every year of follow-up, patients in the control group had a 4.5% chance of dying vs. a 1.0% chance for those in the surgical group. The improvement in the mortality rate in the surgical group was primarily due to a decrease in the number of cardiovascular deaths.

The workup for bariatric surgery does not require a routine upper gastrointestinal series.

BACKGROUND: Morbid obesity is a serious disease that afflicts over five million Americans, threatening their health with such co-morbidities as diabetes, arthritis, pulmonary failure and stroke. Surgery is the only effective therapy, providing long-term control of weight, diabetes, pulmonary failure, and hypertension for as long as 14 years. Because the operation presents a major expense, this study examined whether X-ray examination of the gut could be omitted safely as a cost-saving measure. METHODS: The records of 814 consecutive morbidly obese patients who underwent gastric bypass were reviewed to determine: (1) whether these individuals had undergone an upper gastro-intestinal (GI) series, and (2) if these studies influenced therapy or caused cancellation or postponement of surgery. RESULTS: Of the 814 patients, 657 (80.7%) underwent a preoperative GI radiography. Of these examinations, 393 (59.8%) were normal, with the following abnormalities in the remaining 264: hiatal hernia, 164; esophageal reflux, 39; Schatzki's ring, 18; small bowel diverticula, four; renal stones, four; malrotation, three; gall stones, two; pyloric ulcer, one; possible pelvic mass, one; calcified leiomyoma, one; and dysphagial lusoria, one. None of these findings resulted in cancellation or a delay in surgery. CONCLUSIONS: The upper GI series can be safely omitted from the routine preoperative evaluation of patients undergoing gastric bypass. At a cost of $741.00 per examination, this change represents significant potential savings. Similar evaluations of other routine preoperative tests may well provide a better basis for the evaluation of these complex patients.

Sequence determinants of folding and stability for the P22 Arc repressor dimer.

The Arc repressor is a small, homodimeric protein. Studies of mutant proteins show that the side chains that form the hydrophobic core are the most important determinants of structure. A variety of hydrogen bonds and salt bridges also contribute to stabilization of the native structure, but these can often be replaced by hydrophobic interactions. The transition state for folding/unfolding is dimeric and contains a large amount of buried hydrophobic surface, but the beta-sheet of native Arc is not formed. Moreover, relatively little side chain information appears to be used in the transition state, suggesting that tight packing of the hydrophobic core and optimization of hydrogen-bond geometry are events that occur later in folding.

P22 Arc repressor: transition state properties inferred from mutational effects on the rates of protein unfolding and refolding.

The kinetics of unfolding and refolding have been measured for a set of Arc repressor mutants bearing single amino acid substitutions at 44 of the 53 residue positions. Roughly half of the mutations cause significant changes in the unfolding and/or refolding rate constants. These substitutions alter the hydrophobic core, tertiary hydrogen bonds and salt bridges, and glycines with restricted backbone conformations. Overall, the mutations cause larger changes in the unfolding rates than the refolding rates, indicating that significantly less side-chain information is used between the denatured state and transition state than between the transition state and native state. The set of mutants displays reasonable Brønsted behavior, suggesting that many native interactions are partially formed in the transition state. Taken together, these observations suggest that the overall structure of most of the protein must be somewhat native-like in the transition state but without close, complementary packing of the hydrophobic core or good hydrogen bond geometry. Such a transition state is inconsistent with a model in which monomers fold to their correct conformations and then dock to form the dimer but supports a model in which folding and dimerization are concurrent processes.

Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus.

OBJECTIVE: This report documents that the gastric bypass operation provides long-term control for obesity and diabetes. SUMMARY BACKGROUND DATA: Obesity and diabetes, both notoriously resistant to medical therapy, continue to be two of our most common and serious diseases. METHODS: Over the last 14 years, 608 morbidly obese patients underwent gastric bypass, an operation that restricts caloric intake by (1) reducing the functional stomach to approximately 30 mL, (2) delaying gastric emptying with a c. 0.8 to 1.0 cm gastric outlet, and (3) excluding foregut with a 40 to 60 cm Roux-en-Y gastrojejunostomy. Even though many of the patients were seriously ill, the operation was performed with a perioperative mortality and complication rate of 1.5% and 8.5%, respectively. Seventeen of the 608 patients (< 3%) were lost to follow-up. RESULTS: Gastric bypass provides durable weight control. Weights fell from a preoperative mean of 304.4 lb (range, 198 to 615 lb) to 192.2 lb (range, 104 to 466) by 1 year and were maintained at 205.4 lb (range, 107 to 512 lb) at 5 years, 206.5 lb (130 to 388 lb) at 10 years, and 204.7 lb (158 to 270 lb) at 14 years. The operation provides long-term control of non-insulin-dependent diabetes mellitus (NIDDM). In those patients with adequate follow-up, 121 of 146 patients (82.9%) with NIDDM and 150 of 152 patients (98.7%) with glucose impairment maintained normal levels of plasma glucose, glycosylated hemoglobin, and insulin. These antidiabetic effects appear to be due primarily to a reduction in caloric intake, suggesting that insulin resistance is a secondary protective effect rather than the initial lesion. In addition to the control of weight and NIDDM, gastric bypass also corrected or alleviated a number of other comorbidities of obesity, including hypertension, sleep apnea, cardiopulmonary failure, arthritis, and infertility. Gastric bypass is now established as an effective and safe therapy for morbid obesity and its associated morbidities. No other therapy has produced such durable and complete control of diabetes mellitus.

Protein stability effects of a complete set of alanine substitutions in Arc repressor.

The equilibrium stabilities of a complete set of single alanine-substitution mutants of the Arc repressor of bacteriophage P22 have been determined by thermal and urea denaturation experiments. Only half the alanine substitutions cause significant changes in stability, with the most deleterious mutations affecting side chains in the hydrophobic core or in salt bridges and hydrogen bonds which are protected from solvent. The five mutations that are most destabilizing affect a cluster of core residues that seem to form a structural foundation for Arc.

Scanning mutagenesis of the Arc repressor as a functional probe of operator recognition.

Protein-DNA and protein-protein interactions are central to most biological regulation, and yet our understanding of these macromolecular recognition events is still incomplete. Both types of interactions are critical for the function of the Arc repressor. The functional importance of residues in or near its operator DNA-binding surface and dimer-dimer interaction surface has been probed by alanine-scanning mutagenesis. Mutations in three categories cause large binding defects: beta-sheet side chains that directly interact with DNA bases; side chains that link different DNA-binding regions of Arc, and side chains required to maintain the active DNA-binding conformation.

P22 Arc repressor: enhanced expression of unstable mutants by addition of polar C-terminal sequences.

Many mutant variants of the P22 Arc repressor are subject to intracellular proteolysis in Escherichia coli, which precludes their expression at levels sufficient for purification and subsequent biochemical characterization. Here we examine the effects of several different C-terminal extension sequences on the expression and activity of a set of Arc mutants. We show that two tail sequences, KNQHE (st5) and H6KNQHE (st11), increase the expression levels of most mutants from 10- to 20-fold and, in some cases, result in restoration of biological activity in the cell. A third tail sequence, HHHHHH (st6), was not as effective in increasing mutant expression levels. All three tail sequences are functionally and structurally silent, as judged by their lack of effects on the DNA binding activity and stability of otherwise wild-type Arc. The properties of the st11 tail sequence make it an efficient system for the expression and purification of mutant Arc proteins, both because mutant expression levels are increased and because the proteins can be rapidly purified using nickel-chelate affinity chromatography. Arc mutants containing the EA28, RL31, and SA32 mutations were purified in the st11 background. The thermodynamic stability of the EA28 mutant (delta delta Gu approximately -0.4 kcal/mol) is reduced modestly compared to the st11 parent, whereas the RL31 mutant (delta delta Gu approximately -3.0 kcal/mol) and SA32 mutant (delta delta Gu approximately -3.3 kcal/mol) are substantially less stable.

Arterial thrombosis: putative role of lipoprotein(a).

Lipoprotein(a) has been associated with several arterial thrombotic disorders. This article presents evolving concepts of Lp(a) and its potential role in coagulation. An overview of lipoprotein structure and function provides background information for further understanding of the pathophysiologic role of Lp(a) in atherosclerosis and thrombosis. Further research is needed to clarify the function of Lp(a) in humans and its role in arterial thrombosis.

Innovative nuclear pharmacy service. A comprehensive management plan for clinical investigations.

OBJECTIVE: To provide an overview of the investigational nuclear pharmacy service at the Medical University of South Carolina. DATA SOURCES: References were selected from published bibliographies of nuclear pharmacy and hospital pharmacy articles and from specific-topic searches of the MEDLINE computerized database (all languages, through 1992). STUDY SELECTION: Studies of clinical pharmacy functions that were considered relevant to the specialty practice of nuclear pharmacy were chosen. DATA EXTRACTION: Studies were reviewed for internal consistency and appropriateness. DATA SYNTHESIS: Data on the clinical impact of nuclear pharmacy services do not exist. CONCLUSIONS: Based on our experience in establishing an investigational drug service, we conclude that nuclear pharmacists should take an active role in clinical investigations. The outcomes of this kind of involvement are very rewarding.

Assembly of the Arc repressor-operator complex: cooperative interactions between DNA-bound dimers.

Arc repressor, a member of the beta-ribbon family of DNA binding proteins, binds to its 21-base-pair operator as a tetramer. Here, the Arc dimer is shown to bind specifically to DNA fragments containing operator half-sites, and the equilibrium and kinetic constants for these reactions are determined. DNA-bound dimers are also shown to be transient intermediates in association experiments, indicating that assembly of the Arc tetramer-operator complex occurs by sequential addition of dimers to operator half-sites. When the left or right operator half-site is occupied by an Arc dimer, cooperative interactions increase the affinity of the second dimer by approximately 5900-fold [delta delta G = -5.1 (+/- 0.5) kcal/mol]. This increase in affinity is largely caused by an increase in the half-life of the complex; "non-cooperatively" bound dimers dissociate with a half-life of a few seconds while "cooperatively" bound dimers have half-lives of more than 1 h.

Single-plane transesophageal echocardiography for assessing function of mechanical or bioprosthetic valves in the aortic valve position.

To assess the value and limitations of single-plane transesophageal echocardiography in the evaluation of prosthetic aortic valve function, 89 patients (69 mechanical and 20 bioprosthetic aortic valves) were studied by combined transthoracic and transesophageal 2-dimensional and color flow Doppler echocardiography. In the assessment of aortic regurgitation, the transthoracic and transesophageal echocardiographic findings were concordant in 71 of 89 patients (80%). In 8 patients, the degree of aortic regurgitation was underestimated by the transthoracic approach; in each case the quality of the transthoracic echocardiogram was poor. In 10 patients, transesophageal echocardiography failed to detect trivial aortic regurgitation due to acoustic shadowing of the left ventricular outflow tract from a mechanical valve in the mitral valve position. Transesophageal echocardiography was superior to transthoracic echocardiography in diagnosing perivalvular abscess, subaortic perforation, valvular dehiscence, torn or thickened bioprosthetic aortic valve cusps, and in clearly distinguishing perivalvular from valvular aortic regurgitation. Transesophageal echocardiography correctly diagnosed bioprosthetic valve obstruction in 1 patient, but failed to diagnose mechanical valve obstruction in another. In conclusion, transesophageal echocardiography offers no advantage over the transthoracic approach in the detection and quantification of prosthetic aortic regurgitation unless the transthoracic image quality is poor. Transesophageal echocardiography is limited in detecting mechanical valve obstruction and in detecting aortic regurgitation in the presence of a mechanical prosthesis in the mitral valve position. However, it is superior to transthoracic echocardiography in identifying perivalvular pathology, differentiating perivalvular from valvular regurgitation and in defining the anatomic abnormality responsible for the prosthetic valve dysfunction. Combined transthoracic and transesophageal examination provides complete anatomic and hemodynamic assessment of prosthetic aortic valve function.