How can dementia and disability be prevented in older adults: where are we today and where are we going?

Ageing of the population, together with population growth, has brought along an ample increase in the number of older individuals living with dementia and disabilities. Dementia is the main cause of disability in old age, and promoting healthy brain ageing is considered as a key element in diminishing the burden of age-related disabilities. The World Health Organization recently launched the first risk reduction guidelines for cognitive impairment and dementia. According to recent estimates, approximately 40% of dementia cases worldwide could be attributable to 12 modifiable risk factors: low education; midlife hypertension and obesity; diabetes, smoking, excessive alcohol use, physical inactivity, depression, low social contact, hearing loss, traumatic brain injury and air pollution indicating clear prevention potential. Dementia and physical disability are closely linked with shared risk factors and possible shared underlying mechanisms supporting the possibility of integrated preventive interventions. FINGER trial was the first large randomized controlled trial indicating that multidomain lifestyle-based intervention can prevent cognitive and functional decline amongst at-risk older adults from the general population. Within the World-Wide FINGERS network, the multidomain FINGER concept is now tested and adapted worldwide proving evidence and tools for effective and easily implementable preventive strategies. Close collaboration between researchers, policymakers and healthcare practitioners, involvement of older adults and utilization of new technologies to support self-management is needed to facilitate the implementation of the research findings. In this scoping review, we present the current scientific evidence in the field of dementia and disability prevention and discuss future directions in the field.

Midlife improvements in financial situation are associated with a reduced dementia risk later in life: the CAIDE 30-year study.

OBJECTIVES: Perceived financial strain is associated with various health conditions, but it is unknown whether it is associated with an increased risk for dementia. The goal is to examine the associations between midlife perceptions of financial situation and dementia risk later in life. METHODS: Participants were derived from the Cardiovascular Risk Factors, Aging, and Dementia population-based cohort study (n = 2000) (between 1972 and 1987, baseline mean age 50 years) in Finland. Participants returned for two re-examinations in late life (in 1998 and 2005-2008, mean age 71 and 78 years). In this study, 1442 subjects that participated in at least one re-examination (mean total follow-up 25 years) were included in analyses. Financial strain was measured using two questions in midlife on perceptions of financial situation and perceptions of changes in financial situation. For each question, participants were categorized into three groups reporting improvement, worsening, or stability, with the latter set as the reference group. Analyses were adjusted for potential confounding factors. RESULTS: The group reporting better financial situation had a reduced risk for dementia (fully adjusted model: odds ratio (OR): 0.53, 95% confidence interval (CI): 0.33-0.86). In contrast, the group reporting worse financial situation did not have an increased risk for dementia (OR: 1.04, 95% CI: 0.53-2.02). Analyses on perceptions of current financial situation showed that the groups reporting satisfaction or dissatisfaction with financial situation did not differ in risk for dementia. CONCLUSION: This study is the first to show that midlife improvements in financial situation are associated with a reduced dementia risk later in life. Potential pathways related to stress reduction, improved lifestyle, and potential biological mechanisms are discussed.

Self-rated physical fitness and estimated maximal oxygen uptake in relation to all-cause and cause-specific mortality.

This study investigated the longitudinal associations of self-rated physical fitness and estimated maximal oxygen uptake (VO2max) with all-cause and cause-specific mortality. A total of 59 741 participants in the Finnish National FINRISK Study Cohort had data on self-rated physical fitness and covariates. A subsample of 4823 participants had estimated VO2max data. Follow-up ranged from 3 to 38 years. Associations of self-rated physical fitness and VO2max with mortality were analyzed using multivariate Cox proportional hazard models. The study showed that poor self-rated physical fitness was related to all-cause mortality (hazard ratio [HR] 1.9; 95% confidence interval [CI] 1.8-2.0) and mortality due to cardiovascular (HR 2.0, 95% CI 1.9-2.2), cerebrovascular (HR 1.9, 95% CI 1.6-2.2) and respiratory diseases (HR 2.1, 95% CI 1.9-2.4), trauma (HR 1.7, 95% CI 1.3-2.0), infections (HR 1.8, 95% CI 1.3-2.7), dementia (HR 1.9, 95% CI 1.6-2.3), and cancer (HR 1.7, 95% CI 1.5-1.9). Coexisting higher age, physical inactivity, male gender, and severe chronic conditions further increased the risk. In men, higher VO2max was associated with a lower risk of lung cancer mortality (HR 0.8, 95% CI 0.7-0.96). Based on the results, self-rated physical fitness reflects a combination of unfavorable biological and lifestyle-related factors, which increase mortality risk. A simple question about perceived physical fitness may reveal at-risk individuals who would benefit from more intensive treatment of chronic conditions and other interventions aiming to promote better fitness and well-being.

Whole body frontal plane mechanics across walking, running, and sprinting in young and older adults.

This study investigated the whole body frontal plane mechanics among young (26 ± 6 years), early old (61 ± 5 years), and old (78 ± 4 years) adults during walking, running, and sprinting. The age-groups had similar walking (1.6 m/s) and running (4.0 m/s) speeds, but different maximal sprinting speed (young 9.3 m/s, early old 7.9 m/s, and old 6.6 m/s). Surprisingly, although the old group exerted much lower vertical ground reaction force during running and sprinting, the hip frontal plane moment did not differ between the age-groups. Kinematic analysis demonstrated increased hip adduction and pelvis drop, as well as reduced trunk lateral flexion among old adults, especially during sprinting. These alterations in the hip and pelvis motions may reflect insufficient force production of hip abductors to stabilize the pelvis during single-limb support, while limited trunk lateral flexion may enhance control of the mediolateral balance. On the other hand, larger trunk side-to-side movement among the young and early old adults may provide a mechanism to prevent the increase of the hip frontal moment despite greater vertical ground reaction force. This, in turn, can assist hip abductors to maintain stability of the pelvis during sprinting while allowing powerful force generation by a large adductor muscle group.

Importance of Patella, Quadriceps Forces, and Depthwise Cartilage Structure on Knee Joint Motion and Cartilage Response During Gait.

In finite-element (FE) models of the knee joint, patella is often omitted. We investigated the importance of patella and quadriceps forces on the knee joint motion by creating an FE model of the subject's knee. In addition, depthwise strains and stresses in patellar cartilage with different tissue properties were determined. An FE model was created from subject's magnetic resonance images. Knee rotations, moments, and translational forces during gait were recorded in a motion laboratory and used as an input for the model. Three material models were implemented into the patellar cartilage: (1) homogeneous model, (2) inhomogeneous (arcadelike fibrils), and (3) random fibrils at the superficial zone, mimicking early stages of osteoarthritis (OA). Implementation of patella and quadriceps forces into the model substantially reduced the internal-external femoral rotations (versus without patella). The simulated rotations in the model with the patella matched the measured rotations at its best. In the inhomogeneous model, maximum principal stresses increased substantially in the middle zone of the cartilage. The early OA model showed increased compressive strains in the superficial and middle zones of the cartilage and decreased stresses and fibril strains especially in the middle zone. The results suggest that patella and quadriceps forces should be included in moment- and force-driven FE knee joint models. The results indicate that the middle zone has a major role in resisting shear forces in the patellar cartilage. Also, early degenerative changes in the collagen network substantially affect the cartilage depthwise response in the patella during walking.

Knee Control and Jump-Landing Technique in Young Basketball and Floorball Players.

Poor knee alignment is associated with increased loading of the joints, ligaments and tendons, and may increase the risk of injury. The study purpose was to compare differences in knee kinematics between basketball and floorball players during a vertical drop jump (VDJ) task. We wanted to investigate whether basketball players, whose sport includes frequent jump-landings, exhibited better knee control compared with floorball players, whose sport involves less jumping. Complete data was obtained from 173 basketball and 141 floorball players. Peak knee valgus and flexion angles during the VDJ were analyzed by 3D motion analysis.Larger knee valgus angles were observed among basketball players (- 3.2°, 95%CI -4.5 to - 2.0) compared with floorball players (- 0.9°, 95%CI -2.3 to 0.6) (P=0.022). Basketball players landed with a decreased peak knee flexion angle (83.1°, 95%CI 81.4 to 84.8) compared with floorball players (86.5°, 95%CI 84.6 to 88.4) (P=0.016). There were no significant differences in height, weight or BMI between basketball and floorball players. Female athletes exhibited significantly greater valgus angles than males. This study revealed that proper knee control during jump-landing does not seem to develop in young athletes simply by playing the sport, despite the fact that jump-landings occur frequently in practice and games.

Association between mid- to late life physical fitness and dementia: evidence from the CAIDE study.

OBJECTIVES: This study investigated the association between perceived physical fitness at midlife, changes in perceived fitness during the three decades from mid- to late life and dementia risk. DESIGN: Prospective cohort study. SETTING: Cardiovascular risk factors, ageing and incidence of dementia (CAIDE) study. SUBJECTS: Subjects were selected from four independent, random samples of population-based cardiovascular surveys and were first examined in 1972, 1977, 1982 or 1987, when they were on average 50 years old. The CAIDE target population included 3559 individuals. A random sample of 2000 individuals still alive in 1997 was drawn for re-examinations (performed in 1998 and 2005-2008) that consisted of cognitive assessments, with 1511 subjects participating in at least one re-examination. Dementia diagnoses were also confirmed from national registers for the entire target population. MAIN OUTCOME MEASURE: All-cause dementia. RESULTS: Poor physical fitness at midlife was associated with increased dementia risk in the entire target population [hazard ratio (HR), 1.5; 95% confidence interval (CI), 1.1-2.0]. In participants, odds ratio (OR) was 2.0 (95% CI, 0.9-4.0). This association was significant in apolipoprotein E ε4 allele (APOEε4) noncarriers (OR, 4.3; 95% CI, 1.4-13.3), men (HR, 1.8; 95% CI, 1.1-3.0) and people with chronic conditions (HR, 2.9; 95% CI, 1.3-6.6). A decline in fitness after midlife was also associated with dementia (OR, 3.0; 95% CI, 1.7-5.1), which was significant amongst both men and women and more pronounced in APOEε4 carriers (OR, 4.4; 95% CI, 2.1-9.1). CONCLUSIONS: Perceived poor physical fitness reflects a combination of biological and lifestyle-related factors that can increase dementia risk. A simple question about perceived physical fitness may reveal at-risk individuals who could benefit from preventive interventions.

Relationship between fundamental motor skills and physical activity in 4-year-old preschool children.

This study evaluated the relationships between objectively measured physical activity and fundamental motor skills in 4-year-old children. Physical activity was monitored in 20 girls and 17 boys over 5 consecutive days (3 days at preschool and 2 days at home) and their fundamental motor skills measured. Multiple linear regressions controlled for sex, age, and body mass index indicated that the total skill score was significantly associated with physical activity, explaining 13%, 16%, and 16% of the variance in total, moderate-to-vigorous, and light-to-vigorous physical activity, respectively. Sliding and galloping were significantly associated with moderate-to-vigorous physical activity, and throwing and catching combination was significantly associated with total, moderate-to-vigorous, and light-to-vigorous physical activity. The findings warrant future investigations with larger samples to examine the relationship between locomotor, manipulative skills, and physical activity behaviors.

Radiation response of vulvar squamous cell carcinoma (UM-SCV-1A, UM-SCV-1B, UM-SCV-2, and A-431) cells in vitro.

Standard therapy for squamous cell carcinoma (SCC) of the vulva consists of radical surgery and inguinal node dissection. Radiation therapy has been used for preoperative treatment in advanced cases to reduce the size of the tumor, and also as the only treatment in inoperable or recurrent disease. To study the inherent radiation sensitivity of vulvar carcinoma, we tested three new vulvar carcinoma cell lines and the long-established cell line A-431 by using a 96-well plate clonogenic assay, earlier shown by us to be suitable for survival studies of SCC. SCC and adenocarcinoma cell lines derived from other sites were used as a reference. Cells were irradiated with a 4-MeV linear accelerator at a dose rate of 2.0 Gy/min. The vulvar cell lines were found to be highly resistant to radiation with the average mean inactivation dose of 3.44 +/- 0.34 Gy as calculated from the area under the curve. The results were consistent in repeated experiments and for all cell lines. The average value for area under the curve was 1.79 +/- 0.30 for the other SCC lines tested. The values for area under the curve differed significantly (P less than 0.0001) between the vulvar lines and reference SCC lines. These results indicate that vulvar SCC cells in vitro express exceptional inherent radioresistance, and thus development of other forms of additional treatment would be more advantageous in advanced cases.

Effects of paclitaxel with or without cremophor EL on cellular clonogenic survival and apoptosis.

Paclitaxel is currently formulated in a vehicle of 50% ethanol and 50% polyethoxylated surfactant cremophor EL. Cremophor EL has been reported to reverse P-glycoprotein-mediated multidrug resistance (MDR) at doses which are clinically achievable. It has also been reported to have a cytotoxic effect per se. In this study we used two different methods to evaluate the survival of cells exposed to paclitaxel with or without cremophor EL and the vehicle alone. Two laryngeal SCC cell lines (UT-SCC-19A and UT-SCC-29) and two ovarian adenocarcinoma cell lines (UT-OC-3 and UT-OC-5) established in our laboratory were investigated. Northern hybridisation was used to study the mdr-1 mRNA expression of the cell lines. With sensitive Northern analyses, these four lines yielded mdr-1 mRNA signals of the expected 4.5 kb size and of variable intensity, generally at higher levels than those in the positive control cell line KB. The 96-well plate clonogenic assay was used to obtain the fraction survival data and apoptosis was recorded by time-lapse video microscopy. Both methods indicate that cremophor EL alone has no effect on cellular survival. Consequently, paclitaxel without cremophor EL is as active as paclitaxel with cremophor EL in vitro.

Radiotherapy treatment planning and long-term follow-up with [(11)C]methionine PET in patients with low-grade astrocytoma.

PURPOSE: To evaluate the feasibility of [(11)C]-methionine positron emission tomography (MET PET) in radiotherapy (RT) treatment planning and long-term follow-up in patients with low-grade glioma. PATIENTS: Thirteen patients with low-grade astrocytoma and 1 with anaplastic astrocytoma underwent sequential MET PET and magnetic resonance imaging (MRI) before and 3, 6, 12, and 21-39 months after RT, respectively. Ten patients were studied after initial debulking surgery or biopsy and 4 in the recurrence phase. METHODS: A total of 58 PET scans were performed. After transmission scanning, a median dose of 425 MBq of MET was injected intravenously and emission data was acquired 20 min after injection for 20 min. The uptake of MET in tumor area was measured as standardized uptake value (SUV) and tumor-to-contralateral brain SUV ratios were generated to assess irradiation effects on tumor metabolism. Functional imaging with PET was compared with concurrent MRI in designing the RT planning volumes and in assessment of response to RT during a median follow-up time of 33 months. RESULTS: In 12 patients (86%), tumor area was clearly discernible in the baseline PET study. In the remaining 2 patients with a suspected residual tumor in MRI, PET showed only a diffuse uptake of MET interpreted as negative in the original tumor area. In the dose planning of RT, MET PET was helpful in outlining the gross tumor volume in 3 of 11 cases (27%), whereas PET findings either coincided with MRI (46%) or were less distinctive (27%) in other cases. In quantitative evaluation, patients with a low tumor SUV initially had significantly better prognosis than those with a high SUV. Tumor-to-contralateral brain uptake ratios of MET discriminated well patients remaining clinically stable from those who have since relapsed or died of disease. CONCLUSION: Quantitative MET PET has prognostic value at the time of initial treatment planning of low-grade glioma. Some patients may benefit of RT volume definition with MET PET, which seems to disclose residual tumor better than MRI in selected cases. Stable or decreasing uptake of MET in tumor area after RT during follow-up seems to be a favorable sign.

Intercomparison of radiotherapy treatment planning systems for external photon and electron beam dose calculations.

Dose distributions calculated by six different treatment planning systems (TPSs), used by the hospitals in Finland or in Russia, were compared with measured dose distributions. Five typical cases of irradiation were selected: regular fields, oblique incidence, irregular field, wedge field and inhomogeneity in a water equivalent phantom. The beam data for each TPS where those pertaining to the beam where the comparative relative measurements were performed. The results indicate that the dose distributions produced by different TPSs can differ from each other as well as from the measured dose distributions up to a level which is not acceptable in terms of the ICRU recommendations. Greatest differences seem to be related to the omission or undue consideration of the scatter components of the beam.

Allogeneic bone marrow transplantation in multiple myeloma: a report of four cases.

Allogeneic bone marrow transplantation offers a new and promising form for treatment of multiple myeloma incurable with chemotherapy. We present four cases of advanced multiple myeloma given bone marrow transplantation from HLA-identical and MLC-negative sibling donors. One patient had a recurrent plasmacytoma 8 months later and one died 12 days after the transplantation whereas the other two are in good clinical remission 15 and 19 months post-transplantation.

The intrinsic radiosensitivity and sublethal damage repair capacity of five cervical carcinoma cell lines tested with the 96-well-plate assay.

We have tested the intrinsic radiosensitivity and capacity for sublethal damage repair (SLDR) in split-dose experiments with the 96-well plate clonogenic assay. Four out of five cell lines were squamous-cell carcinoma (SCC) lines (CaSki, ME-180, HX151c, HX156c) and one cell line was established from glassy-cell carcinoma (UM-GCC-1). Comparison of radiosensitivities was by with D value, the mean inactivation dose. D for these cell lines varied from 1.7 Gy to 2.5 Gy. As a group, cervical carcinoma cell lines were more radioresistant than endometrial adenocarcinoma cell lines tested with the same assay, but more radiosensitive than vulvar SCC lines. Three cell lines showed clear SLDR, but two cell lines were unable to carry out this function. Furthermore, cell lines capable of SLDR also showed significant increase in survival when D values were compared after the radiation dose was split into three instead of two fractions. These results indicate the importance of adding another radiobiological parameter to the intrinsic radiosensitivity when predictive tests are planned.

Comparison of cellular radiosensitivity between different localizations of head and neck squamous-cell carcinoma.

The prognosis of carcinomas arising from various sites in the head and neck varies even when the stage of the disease is taken into consideration, e.g. laryngeal carcinoma has a more favourable prognosis compared to oral-cavity malignancies. The purpose of this study was to evaluate intrinsic cellular radiosensitivity as one possible explanation for the observed differences in the survival rates of different anatomical groups. The radiation survival curves were determined for well characterized cell lines derived from laryngeal carcinoma (n = 14), pharyngeal carcinoma (n = 6), carcinoma of the oral cavity (n = 14) and the skin of the face (n = 3). The intrinsic radiosensitivity was expressed as area under the survival curve (AUC) values, and this cellular parameter was compared with clinical data and survival of the patients. The intrinsic radiosensitivity in the whole group varied between 1.0 Gy and 2.8 Gy with an average of 1.9 Gy. The mean AUC values for the laryngeal cell lines were 2.0 Gy +/- 0.2, for the oral cavity 1.8 +/- 0.3 Gy, for the pharynx 1.8 +/- 0.2 Gy and for cutaneous carcinoma 2.1 +/- 0.1 Gy. There was a slight difference between the groups of glottic and supraglottic cell lines (mean 1.8 +/- 0.2 Gy and 2.1 +/- 0.3 Gy, respectively), which is consistent with the differences in clinical curability of these cancers. Otherwise, the differences in cellular radiosensitivity of the carcinoma groups studied did not reach statistical significance. These results indicate that the intrinsic radiosensitivity of squamous-cell carcinoma (SCC) of the larynx does not significantly differ from that of SCC of other sites of the head and neck. Variations in the intrinsic radiosensitivity do not as such seem to explain the observed differences in radiocurability of SCC variously localized in the head and neck.

Sublethal damage repair after fractionated irradiation in endometrial cancer cell lines tested with the 96-well plate clonogenic assay.

Two long-established and seven newly established endometrial adenocarcinoma cell lines were tested for their capacity to repair sublethal damage after fractionated irradiation. Cell survival was determined with the 96-well plate clonogenic assay based on limiting dilutions. Total radiation doses of 0.75 Gy, 1.25 Gy, 2.50 Gy, 5.00 Gy and 7.50 Gy were used either as a single dose or divided into two or three equal fractions with a 24 h interval. Survival data were fitted to the linear quadratic model, and the area under the survival curve (AUC), equivalent to the mean inactivation dose, was obtained with numerical integration. The amount of sublethal damage repair (SLDR) was expressed as an area-under-the-curve (AUC) ratio comparing survivals from fractionated-dose with those from single-dose experiments. SLDR capacity of the cell lines expressed as an AUC ratio varied between 1.00 and 1.59, and the mean was 1.17. Two highly radiosensitive cell lines were found to be SLDR-deficient, but most of the cell lines studied had some SLDR capacity. We have earlier shown that endometrial cancer cell lines as a group are more radiosensitive than squamous-cell carcinoma (SCC) lines. Data obtained in this study suggest that the capacity for SLDR in these cell lines is rather limited compared with the majority of SCC lines tested. This finding underlines further the high radioresponsiveness of endometrial cancer.

Effects of radiation fractionation on four squamous cell carcinoma lines with dissimilar inherent radiation sensitivity.

The effect of radiation fractionation was investigated using a new 96-well-plate clonogenic assay in four squamous cell carcinoma lines. Earlier experiments had shown that two of the cell lines (UT-SCC-1A and UM-SCC-14A) were inherently relatively sensitive to irradiation, and two (UM-SCC-1 and UM-SCV-1A) relatively resistant. All of the four carcinomas from which the cell lines were established had poor clinical outcome. The radiation doses were given as a single exposure, or split into two or three equal fractions with a 24-h interval. The two inherently sensitive cell lines showed enhanced survival after radiation fractionation as compared with a single dose, whereas the resistant cell lines did not. The result suggests that both the inherent resistance of cancer cells to irradiation and the repair of sublethal radiation damage may lead to treatment failure, and that shortening of the total irradiation time may overcome cancer cell recovery between fractions in some, but not in all carcinomas.

Radiosensitivity of dermal and tumor fibroblasts derived from the same patient.

The in vitro radiosensitivity of dermal fibroblasts has been found to vary between individuals, and a number of studies have also shown that this parameter correlates with radiation-induced late injuries in clinical radiotherapy. In addition, certain genetic disorders are known to effect radiosensitivity, e.g. normal tissues of patients homozygous or heterozygous for the ataxia teleangiectasia gene show unusual sensitivity to radiation both in vivo and in vitro. Thus, it has been assumed that there is a genetically determined component resulting in a certain intrinsic cellular radiation response in an individual. To study this possible relationship between different cells of a specific patient, we established eight pairs of dermal and tumor fibroblast cultures. The donor patients had either adenocarcinoma of the uterus or squamous cell carcinoma (SCC) of the head and neck. The radiosensitivity of these strains was determined by a 96-well plate clonogenic assay, previously used by us for radiosensitivity testing of cancer cells. From a paired comparison, the values for the cell fraction surviving 2.0 Gy (SF2), of both fibroblast strains, were found to be on the same level in five out of eight cases. In patient 6, the SF2 of tumor fibroblasts was significantly higher than that of dermal fibroblasts (P=0.0014). In two additional cases the tendency was the same, but not statistically significant. As groups, the two types of fibroblasts did not differ from each other, mean SF2 values of 0.24+/-0.07 and 0.21+/-0.05, respectively. The SF2 of tumor fibroblasts from SCC patients proved to be significantly higher than that of the adenocarcinoma patients (P=0.030). These preliminary results indicate that the in vitro radiosensitivity of tumor fibroblasts correlates with normal cell sensitivity in many cases, but not in all. The radiosensitivity of tumor fibroblasts also seems to follow the level of in vitro radiosensitivity determined for the corresponding histological type of tumor cells. Further studies are needed to determine more closely the relationship between the radiosensitivities of tumor cells and tumor fibroblasts, thus evaluating the possibility of testing radiosensitivity from tumor fibroblasts in order to estimate tumor response.

Genome size variation in Hordeum spontaneum populations

Populations of wild barley, Hordeum spontaneum (C. Koch), originating from 10 ecologically and geographically different sites in Israel, were assessed for genome size. Measurements were obtained by flow cytometry using propidium iodide staining. Genome sizes ranged from 9.35 to 9.81 pg. Variance analysis indicated a significant difference between populations. Genome sizes were positively correlated with mean January temperature. Our results corroborate previous findings of intraspecific variation in genome size from different plant species. The positive correlations between climate and genome size suggest that the latter is adaptive and determined by natural selection.