Apathy/depression, but not subjective fatigue, is related with cognitive dysfunction in patients with multiple sclerosis

Background

Cognitive impairment could affect quality of life for patients with multiple sclerosis (MS), and cognitive function may be correlated with several factors such as depression and fatigue. This study aimed to evaluate cognitive function in Japanese patients with MS and the association between cognitive function and apathy, fatigue, and depression.

Methods

The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was performed in 184 Japanese patients with MS and 163 healthy controls matched for age, gender, and education. The Apathy Scale (AS), Fatigue Questionnaire (FQ), and Beck Depression Inventory Second Edition (BDI-II) were used to evaluate apathy, fatigue, and depression, respectively. Student’s t-test was used to compare MS patients and healthy controls. Correlations between two factors were assessed using the Pearson correlation test, and multiple regression analysis was used to evaluate how much each factor affected the BRB-N score.

Results

In all BRB-N tests, patients with MS scored significantly lower than controls, and the effect size of symbol digit modalities test was the highest among the 9 tests of the BRB-N. Patients with MS had higher AS (p?<?0.001), FQ (p?<?0.0001), and BDI-II (p?<?0.0001) scores than controls. In patients with MS, scores on most of the BRB-N tests correlated with scores on the AS and BDI-II; however, there was little correlation between scores on the BRB-N tests and those on the FQ.

Conclusions

Cognitive function was impaired, particularly information-processing speed, and decreased cognitive function was correlated with apathy and depression in Japanese patients with MS. Despite the association between cognitive variables and depression/apathy, cognitive function was impaired beyond the effect of depression and apathy. However, subjective fatigue is not related with cognitive impairment. Taken together, this suggests that different therapeutic approaches are needed to improve subjective fatigue and cognition, and thereby quality of life, in patients with MS.     

Association between microscopic brain damage as indicated by magnetization transfer imaging and anticardiolipin antibodies in neuropsychiatric lupus

The pathogenetic role of anticardiolipin antibodies (aCLs) in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) without cerebral infarcts remains elusive. Magnetization transfer imaging (MTI) has proved to be a sensitive tool for detecting diffuse microscopic brain damage in NPSLE patients. In this study we examined the correlation between grey and white matter magnetization transfer ratio (MTR) parameters and the presence of IgM and IgG aCLs and lupus anticoagulant in 18 patients with systemic lupus erythematosus and a history of NPSLE but without cerebral infarcts on conventional magnetic resonance imaging. Lower grey matter mean MTR (P < 0.05), white matter mean MTR (P < 0.05), white matter peak location (P < 0.05) and grey matter peak location (trend toward statistical significance) were observed in IgM aCL-positive patients than in IgM aCL-negative patients. No significant differences were found in MTR histogram parameters with respect to IgG aCL and lupus anticoagulant status, nor with respect to anti-dsDNA or anti-ENA (extractable nuclear antigen) status. This is the first report of an association between the presence of aCLs and cerebral damage in grey and white matter in NPSLE. Our findings suggest that aCLs are associated with diffuse brain involvement in NPSLE patients.     

Fatigue and Mood Correlates of Sleep Length in Three Age‐Social Groups: School Children,Students, and Employees

The aim of the study was to trace the consequences of insufficient sleep, in terms of chronic sleep reduction rather than acute sleep deprivation, on fatigue, mood, cognitive performance self‐estimations, and daytime sleepiness in different age‐social groups. The age group of the subjects reflects their social situation and their working time organization: adolescents (n=191) obeyed the strict school schedules with starting times often before 08:00 h; university students (n=115) had more flexible timetables; young employees (n=126) were engaged in regular morning schedules or irregular daytime hours or day and night shifts. A questionnaire study determined the declared need of sleep, self‐reported sleep length, chronic fatigue (using a scale comprised of eight fatigue symptoms and four mood and three cognitive items), and daytime sleepiness (Epworth Sleepiness Scale). The declared need for sleep decreased in subsequent age groups from 9 h 23 min in school children to 8 h 22 min in university students and to 7 h 37 min in young employees. Consequently, the discrepancy between preferred and real sleep length (sleep deficit) was the largest in adolescents: 106 min. Females showed a greater need of sleep than males (p=.025) and significantly more fatigue, mood, and cognitive problems; they also exhibited higher level of daytime sleepiness (p<.000). The sleep index (reported sleep length related to requirements) correlated significantly with all health issues in women (p<.000), while only with fatigue symptoms in men (p=.013). Actual sleep length was unrelated to mood and fatigue issues; the declared individual need of sleep and sleep index showed significant associations, especially in the group of adolescents. The most frequent complaints of adolescents included tiredness on awakening (46%), nervousness, and general weakness; university students reported excessive drowsiness (50%), tension, and nervousness; employees suffered mostly from negative moods, such as tension (49%), nervousness, and irritability. The findings of the study indicate that chronic sleep loss seems to affect females more severely than males. The associations of fatigue and mood with sleep need and sleep index were more pronounced in younger subjects. Surprisingly, fatigue symptoms in school children and university students were as frequent as in hard‐working adults. Because the problem of insufficient sleep is already present in youngsters, their work time organization needs more attention.     

Association between TNF promoter −308 G>A and LTA 252 A>G polymorphisms and systemic lupus erythematosus

Tumor necrosis factor (TNF) and lymphotoxin alpha (LTA) are pivotal cytokines in the pathogenesis of systemic lupus erythematosus (SLE). To investigate the possible association of the polymorphism of the TNF promoter gene ?308 and that of the LTA gene 252 with susceptibility to SLE and with phenotypic disease features in Egyptian patients. A case control study involving 100 SLE patients and 100 unrelated healthy controls. Polymerase chain reaction and restriction fragment length polymorphism methods were applied to detect genetic polymorphism. We found that TNF?308 genotype AA was significantly increase by 26 % in SLE patients compared to 10 % in the control group (p = 0.003; OR 3.16; CI 1.43–6.98) and the frequency of the A allele of the TNF promoter ?308 was significantly higher in the SLE patients (42 %) than in the control subjects (24 %) (p < 0.001; OR 2.29; 95 % CI 1.49–3.52). Genotype LTA 252 GG showed a significant increase by 22 % in SLE patients compared to 6 % in the control group (p = 0.001; OR 4.42; 95 % CI 1.71–11.44), and the frequency of the G allele of the LTA was significantly higher in the SLE patients (38 %) than in the control subjects (21 %) (p < 0.001; OR 2.31; 95 % CI 1.48–3.6). Genotype (AA+GA) of TNF was significantly associated with clinical manifestations as malar rash, arthritis, oral ulcers, serositis and systemic lupus erythematosus disease activity index. Genotype (GG+GA) of LTA was significantly associated with arthritis. These results suggest that TNF and LTA genetic polymorphisms contribute to SLE susceptibility in the Egyptian population and are associated with disease characteristics. TNF?308 and LTA+252 polymorphic markers may be used for early diagnosis of SLE and early prediction of clinical manifestations, like arthritis.     

TWEAK: a novel biomarker for lupus nephritis?

Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal, lacking both sensitivity and specificity. In the previous issue of Arthritis Research & Therapy, Schwartz and colleagues demonstrated the potential value of urinary TNF-like weak inducer of apoptosis (uTWEAK) as a biomarker for LN. They showed that uTWEAK is elevated in subjects with LN at diagnosis compared with those with systemic lupus erythematosus but no renal disease, and correlates with the degree of clinical disease activity. These data are thought-provoking and provide the platform for future longer-term studies.     

Postural stability during static strain before and after a submaximal aerobic bicycle test in athletes

Control of static balance was studied in wrestlers (n = 31) in the normal state and against the background of physical fatigue, i.e., before and after a bicycle PWC ₁₇₀ test, respectively. The static balance was evaluated using a Ritm force platform (Russia) during normal basic stance (BS) and static strain (half-squatting position (HS) with the eyes open). Before physical exercise, i.e., during BS, the differences in postural control of the center of pressure (CP) between athletes and control subjects (n = 40) were nonsignificant. In the HS position, both linear and angular sway velocities of CP (LSV and ASV, respectively) were significantly lower in wrestlers (p < 0.001), and these parameters were negatively correlated with the PWC ₁₇₀ index (r = −0.454 and r = −455, p < 0.001 for LSV and ASV, respectively), which suggests that up to 20% of the sway velocity variance during static strain is dependent on the working capacity of the subjects. After the PWC ₁₇₀ test, the sway velocities of CP increased in both groups during BS (p < 0.01) and HS (p < 0.001), which testifies to the important role of muscular fatigue in the decrease in postural stability in both groups. During BS, an increase in LSV and ASV was about the same in both groups; however, during HS, an increase in the sway velocities of CP after PWC ₁₇₀ was lower in wrestlers (the intergroup differences at p = 0.037 and p = 0.008 for LSV and ASV, respectively); this parameter was negatively correlated with the recovery of the heart rate (HR) after the bicycle test (r = −0.378, p < 0.001 and r = −0.265, p < 0.05 for LSV and ASV, respectively), which suggests that rapid recovery contributes to a certain extent (about 6.5–14.2%) to the postural stability during static strain of wrestlers against the background of their physical fatigue.     

Oral health‐related quality of life in hospitalised stroke patients

doi:10.1111/j.1741‐2358.2009.00330.x
Oral health‐related quality of life in hospitalised stroke patients Objective: The aim of this study was to test the hypothesis that impairment of orofacial function following stroke affects the patients’ oral health‐related quality of life (OHRQoL). Material and methods: From the University Hospitals of Geneva, 31 stroke patients (18 men, 13 women, mean age 69.0 ± 12.7 years) with unilateral facial and limb palsy were recruited (patient group, PG). In the study, the Oral Health Impact Profile (OHIP)‐EDENT was utilised to assess OHRQoL. Further examinations comprised a test of masticatory efficiency and lip force, stroke severity National Institute of Health Stroke Scale and dental state. The control group (CG) consisted of 24 subjects with similar age, gender and dental state. Results: The PG mean OHIP‐EDENT sum score was 18.8 ± 15.5 and proved higher than one of the CG, indicating a lower OHRQoL in the PG (p < 0.01). The score of the sub‐domains ‘functional limitation’ and ‘physical pain’ were significantly higher in PG (p < 0.03 and p < 0.02, respectively). The masticatory efficiency was significantly lower in the PG (p < 0.0001) and was associated with the OHIP‐EDENT sum score and its sub‐domains, except for ‘physical disability’. This effect was not present in the CG. Conclusion: The OHRQoL is significantly reduced in hospitalised stroke patients whereby functional impairment seems predominant when compared with psychological and psycho‐social aspects.     

The effects of depression,anxiety and sleep disturbances on cognitive impairment in patients with chronic obstructive pulmonary disease

The purpose of this study was to investigate the effects of depression, anxiety and sleep disturbances on cognitive functions in chronic obstructive pulmonary disease (COPD) patients. In this prospective case-control study, demographic data, smoking history, depression, anxiety, sleep quality and cognitive status of 48 COPD patients and 36 healthy volunteers aged 40–90 years were recorded. The Beck depression inventory (BDI), the Beck anxiety inventory (BAI), and Pittsburgh Sleep Quality Index (PSQI) were used to assess depression, anxiety and sleep quality, respectively in COPD patients. Cognitive performance was studied by the mini-mental state examination. The mean age of patients with COPD was 65.3 ± 9.4 years, and disease duration was 9.6 ± 7.8 years. Male sex ratio, smoking, BDI score, BAI score, total PSQI score, sleep latency, sleep duration, average use of sleep aids and sleep disturbances in patients with COPD were significantly higher than the control group (p < 0.05). When cognitive impairment was compared by age, FVC, FEV, FEV/FVC, PEF values and smoking, no statistically significant relationship was found (p > 0.05). A statistically significant relationship was established between cognitive impairment and severity of disease, presence of anxiety, presence of depression and sleep quality. In our study, we found that sleep disorders, depression and anxiety comorbid with COPD increased cognitive impairment as well as the severity of disease. We believe that this finding is important in terms of reducing the risk of cognitive impairment, preventing misdiagnosis and treatment of the aforementioned comorbid diseases.     

Patients with Systemic Lupus Erythematosus Have Higher Prevalence of Thyroid Autoantibodies: A Systematic Review and Meta-Analysis

Background

Thyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder and can be associated with other autoimmune endocrine disorders or non-endocrine diseases. Systemic lupus erythematosus is a prototypical autoimmune disorder with multifactorial etiology. The pathogenesis and development of the disease may result from a loss of immune tolerance and the resulting synthesis of autoantibodies against nuclear antigens. Autoimmune factors may be common features of both thyroid autoimmunity and systemic lupus erythematosus, making it likely that both conditions may coexist within some patients.

Methods and Findings

A number of studies have investigated whether an association between thyroid autoimmunity and systemic lupus erythematosus exists. However, the results of these studies have been inconsistent. Furthermore, most of these studies have had relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is an association between systemic lupus erythematosus and thyroid autoimmunity. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and systemic lupus erythematosus by combining the primary data from all relevant studies. Literature databases were searched, including the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases, from January 1970 to May 2014. A total of 1076 systemic lupus erythematosus cases and 1661 healthy controls were included in this study. From these data, the odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated. The meta-analysis results showed that the prevalence of thyroid autoantibody positivity in patients with systemic lupus erythematosus was higher than in healthy controls (TgAb: OR = 2.99, 95% CI = 1.83–4.89; TPOAb: OR = 2.20, 95% CI = 1.27–3.82, respectively).

Conclusion

The results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with systemic lupus erythematosus than in a control group.     

Complex genetic association of 6q23 with autoimmune rheumatic conditions

In the paper by Dieguez-Gonzalez and colleagues in the present issue of Arthritis Research & Therapy, the results of a detailed genetic investigation of the recently identified rheumatoid arthritis and systemic lupus erythematosus susceptibility region at 6q23 containing the TNFAIP3 gene are reported. Their data confirm the complex nature of the association involving both the TNFAIP3 locus and a region >150 kb upstream that does not encode any known gene. These data are consistent with recent studies of systemic lupus erythematosus susceptibility confirming the presence of several independent genetic contributions to autoimmune rheumatic diseases arising from 6q23.     

Effort‐Related Calf Pain in the Obese and Long‐Term Changes after Surgical Obesity Treatment**

Objective: To compare the prevalence of effort‐related calf pain in an obese and a general population and to analyze the incidence of and recovery from such pain after surgical and conventional obesity treatment. Research Methods and Procedures: A random sample of 1135 subjects from a general population was compared with 6328 obese subjects in the Swedish Obese Subjects study. Obese subjects were followed longitudinally, and information about calf pain was obtained from surgically and conventionally treated patients for up to 6 years. Results: In both sexes, self‐reported calf pain was more common in the obese than in the general population [odds ratios (ORs) 5.0 and 4.0 in men and women, respectively, p < 0.001]. Obese patients undergoing surgery had a lower 6‐year incidence of calf pain compared with the conventionally treated control group (ORs 0.39 and 0.61, p < 0.05). Among subjects reporting symptoms at baseline, the 6‐year recovery rate was higher in the surgical group compared with the control group (ORs 15.3 and 5.9, p < 0.001). Discussion: Obese subjects have markedly more problems with effort‐related calf pain than the general population. Surgical obesity treatment reduces the long‐term risk of developing claudication symptoms and increases the likelihood of recovering from such symptoms.     

Serum tissue inhibitor of metalloproteinase‐1 and risk of cognitive impairment after acute ischaemic stroke

The expression of tissue inhibitor metalloproteinase‐1 (TIMP‐1) significantly increased after acute cerebral ischaemia and involved in neurodegeneration. The purpose was to prospectively investigate the relationship between serum TIMP‐1 with post‐stroke cognitive impairment. Our participants were from an ancillary study of China Antihypertensive Trial in Acute Ischemic Stroke. 598 ischaemic stroke patients from seven participating hospitals were included. Cognitive impairment was evaluated using Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months. 316 (52.84%) or 384 (64.21%) participants had cognitive impairment according to MMSE or MoCA, respectively. Compared with the first quartile of TIMP‐1, the multivariate‐adjusted odds ratios (95% confidence intervals) for the highest quartile were 1.80 (1.09‐2.97) for cognitive impairment defined by MMSE and 2.55 (1.49‐4.35) by MoCA. Multiple‐adjusted spline regression models showed linear associations between TIMP‐1 concentrations and cognitive impairment (P value for linearity < 0.01). The addition of TIMP‐1 to models including conventional factors improved reclassification for cognitive impairment, as shown by net reclassification index or integrated discrimination improvement (P < 0.05). Participants with both higher TIMP‐1 and matrix metalloproteinase‐9 levels simultaneously had highest risk of cognitive impairment. Higher serum TIMP‐1 levels were associated with increased risk of cognitive impairment after acute ischaemic stroke, independently of established risk factors.     

Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study

We studied the clinical and immunological effects of Rituximab (anti-CD20) therapy in patients with lupus nephritis. In an open clinical trial, 22 patients with active systemic lupus erythematosis and renal involvement (mainly class III and IV according to the WHO classification) that was refractory to conventional therapy were studied. In all these patients, Rituximab (0.5 to 1.0 g at days 1 and 15) was added to the immunosuppressive therapy and its therapeutic effect was evaluated. In addition, the levels and function of regulatory T lymphocytes and the apoptosis of immune cells were assessed. We found a significant reduction in disease activity (p < 0.05, MEX-SLEDAI index), and proteinuria (p < 0.05) at days 60 and 90 of Rituximab therapy. Although most patients showed improvement in creatinine clearance and erythrocyturia, no significant changes in these parameters were detected. In most patients (20/22), B cell depletion was observed, but no clear-cut effect of Rituximab on complement levels or auto-antibody titers was detected (p > 0.05 in all cases). One patient died at day 70 with invasive histoplasmosis. No important adverse effects of Rituximab therapy were registered in other patients. A significant enhancement in the levels of different CD4+ regulatory cells (T_REG, Th3, Tr1), but not CD8+ Ts lymphocytes, was observed at day 30. This increase was sustained for T_REG cells at day 90, and accompanied by an improvement in their regulatory function. In addition, we observed an unexpected increase in the apoptosis of T cells at day 30. Interestingly, the enhancement in the suppressive function of T_REG cells was not observed in the two patients that showed the poorest clinical response to Rituximab. We conclude that the data obtained in this open clinical trial suggest that Rituximab is a promising candidate for randomized controlled trials in patients with lupus nephritis refractory to the conventional immunosuppressive therapy. The effects of Rituximab on regulatory cells and apoptosis of T lymphocytes are interesting and its possible role in the putative effect of this biological agent in systemic lupus erythematosis deserves additional studies.     

Tissue plasminogen activator inhibitor in patients with systemic lupus erythematosus and thrombosis.

OBJECTIVE--To examine the relations among tissue plasminogen activator antigen, plasminogen activator inhibitor, the lupus anticoagulant, and anticardiolipin antibodies in patients with systemic lupus erythematosus. DESIGN--Prospective study of blood samples (a) from selected patients with systemic lupus erythematosus whose disease was and was not complicated by a history of thrombosis or recurrent abortions, or both, and (b) from a series of healthy controls with a similar age and sex distribution. SETTING--University based medical clinic. SUBJECTS--23 Patients with definite systemic lupus erythematosus (American Rheumatism Association criteria), of whom 11 (eight women) aged 26-51 had a history of thrombosis or recurrent abortions, or both, and 12 (10 women) aged 23-53 had no such history. 15 Healthy subjects (10 women) aged 25-58 served as controls. MAIN OUTCOME MEASURES--Tissue plasminogen activator concentrations, plasminogen activator inhibitor activities, detection of the lupus anticoagulant, and values of anticardiolipin antibodies in the two groups of patients and in the patients with a history of thrombosis or abortions compared with controls. Other measurements included concentrations of proteins that are known to change during the acute phase of systemic lupus erythematosus--namely, fibrinogen, C3 and C4, and C reactive protein. RESULTS--Patients with a history of thrombosis or abortions, or both, had significantly higher values of tissue plasminogen activator and plasminogen activator inhibitor than patients with no such history. A significant correlation between tissue plasminogen activator and plasminogen activator inhibitor (r = 0.80) was found only in the patients with a history of complications of their disease. The lupus anticoagulant was detected in six of the 11 patients with a history of thrombosis or abortions when tested by measuring the activated partial thromboplastin time but was found in all 11 patients when tested by measuring the diluted activated partial thromboplastin time. Nine of these 11 patients had raised values of anticardiolipin antibodies. The findings showed no relation to the activity of the disease. CONCLUSIONS--A significant correlation between tissue plasminogen activator concentrations and plasminogen activator inhibitor activities was found only in patients whose systemic lupus erythematosus was complicated by a history of thrombosis or recurrent abortions. The findings show that these patients have raised plasminogen activator inhibitor activities, and the frequent association between these raised activities and the presence of the lupus anticoagulant suggests that the two may be linked.     

The Implications of Body Fat Mass and Fat Distribution for Cognitive Function in Elderly Women

Objective: To investigate how body fat mass, an established source of endogenous estrogen after menopause, influences cognitive impairment in elderly women. Research Methods and Procedures: Study participants were 5607 generally healthy postmenopausal women with mean age of 63.8 years at baseline followed for an average of 7.3 years. Cognitive function assessed at follow‐up using the short Blessed test was related to baseline body weight, the yearly change in weight, and follow‐up measures of body fat depots assessed by DXA. Cognitive function was also related to various surrogates of lifetime estrogen exposure. Results: Women with the worst cognitive performance (score ≥ 9) at follow‐up were the ones who lost the most body weight and revealed the lowest central fat mass (CFM). The association of weight loss with worse cognitive performance was apparent across all age groups except for those more than 80 years old. In the multivariate logistic model, the risk of cognitive impairment was 18% lower in women in the second quartile of CFM (p = 0.14), 32% lower in the third (p = 0.01), and 48% lower in the fourth (p < 0.001) compared with those in the first quartile. CFM showed significant correlation with the simultaneously measured serum estradiol (r = 0.25; p < 0.001). Cognitive score showed an inverse linear relationship with the duration of reproductive period and bone mineral density assessed at follow‐up. Discussion: These findings argue for a protective association of body fat mass with cognitive impairment in elderly women. This association seems to involve a more prominent exposure to endogenous estrogens.     

Comparison of β2-microglobulin serum level between Alzheimer’s patients,cognitive healthy and mild cognitive impaired individuals

Background: Several studies performed in the last years on the brain, showed that beta2-microglobulin (β2m) and MHC can act independently of their canonical immune function to regulate normal brain development, synaptic plasticity and behaviour. Increased systemic levels of soluble β2m have been implicated in cognitive impairments like that associated with chronic haemodialysis, or aortic valve replacement. Increased soluble β2m has also been detected in the cerebral spinal fluid (CSF) of patients with HIV-associated dementia and Alzheimer’s disease (AD).

Objective: To compare plasma β2m levels in healthy subjects and subjects with dementia or cognitive impairment.

Methods: We measured the concentration of β2m in a cohort of 245 individuals and compared sex matched, cognitive healthy individuals.

Results: We found higher levels of β2m in AD patients compared to non-AD MCI and healthy controls (2063?ng/mL ±852 versus 1613?±?503 and 1832?±?382?ng/mL, pp?>?0.05).

Conclusions: Our data confirm that β2m could play a role in AD. However, a replication study in an independent cohort would be necessary to confirm our preliminary results.     

Gene polymorphisms of CETP and apolipoprotein E in elderly subjects with cognitive impairment

The association of cholesteryl ester transfer protein (CETP) and apolipoprotein E (APOE) gene polymorphisms with mild cognitive impairment (MCI) is under debate. Our aim was to evaluate the relationship between APOE and CETP genotypes with healthy ageing. We analysed 267 elderly subjects (55 to 80+ years), 163 with MCI and 104 healthy, and 50 healthy control subjects (35 to 55 years) from a Romanian population. Biochemical parameters and thyroid hormones were assayed in plasma. APOE and CETP TaqIB gene polymorphisms were determined. Elderly subjects had higher frequency of ɛ3/ɛ2 genotype (14.6% vs. 4%, P<0.001) than controls. Elderly subjects with MCI had lower high density lipoproteins (HDL) cholesterol (P=0.031), apoA-I (P=0.018), T3 (P=0.002), T4 (P=0.028) and TSH (P=0.001) hormone levels, higher systolic blood pressure (P=0.005), lower frequency of CETP B2 allele than the age-matched subjects. Healthy elderly subjects had CETP B2 allele associated with higher plasma apoA-I (P=0.021), lower circulating collagen (P=0.001) levels, and an increased frequency of the combined APOE ɛ2- CETP B2 genotype (18.3%) relative to MCI elderly subjects (7.6%, P=0.011). Healthy elderly subjects are characterized by higher HDL cholesterol, apoA-I levels and higher frequency of the combined APOE ɛ2 and CETP B2 alleles, indicating this pattern as representative for healthy ageing.     

Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction

Macrophagic myofasciitis (MMF) is an emerging condition, characterized by specific muscle lesions assessing long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients mainly complain of arthromyalgias, chronic fatigue, and cognitive difficulties. We designed a comprehensive battery of neuropsychological tests to prospectively delineate MMF-associated cognitive dysfunction (MACD). Compared to control patients with arthritis and chronic pain, MMF patients had pronounced and specific cognitive impairment. MACD mainly affected (i) both visual and verbal memory; (ii) executive functions, including attention, working memory, and planning; and (iii) left ear extinction at dichotic listening test. Cognitive deficits did not correlate with pain, fatigue, depression, or disease duration. Pathophysiological mechanisms underlying MACD remain to be determined. In conclusion, long-term persistence of vaccine-derived aluminum hydroxide within the body assessed by MMF is associated with cognitive dysfunction, not solely due to chronic pain, fatigue and depression.     

Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis

The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.     

Reduction of Plasma Leptin Concentrations by Arginine but Not Lipid Infusion in Humans

Objective: We examined short-term effects of arginine infusion on plasma leptin in diabetic and healthy subjects. Research Methods and Procedures: Arginine stimulation tests were performed in C-peptide negative type 1 [DM1; hemoglobin A_1c; 7.3 ± 0.3%], hyperinsulinemic type 2 diabetic (DM2; 7.6 ± 0.7%), and nondiabetic subjects (CON; 5.4 ± 0.1%). Results: Fasting plasma leptin correlated linearly with body mass index among all groups (r = 0.61, p = 0.001). During arginine infusion, peak plasma insulin was lower in DM1 than in DM2 (p < 0.05) and CON (p < 0.01). Plasma leptin decreased within 30 minutes by ∼11% in DM1 (p < 0.001), DM2 (p < 0.01), and CON (p < 0.005), slowly returning to baseline thereafter. Plasma free fatty acids (FFAs) were higher in DM1 (0.6 ± 0.1 mM) and DM2 (0.6 ± 0.1 mM) than in CON (0.4 ± 0.1 mM, p < 0.05) and transiently declined by ∼50% (p < 0.05) at 45 minutes in all groups before rebounding toward baseline. To examine the direct effects of FFAs on plasma leptin, we infused healthy subjects with lipid/heparin and glycerol during fasting, and somatostatin-insulin (∼35 pM) -glucagon (∼90 ng/mL) clamps were performed. In both protocols, plasma leptin continuously declined by ∼25% (p < 0.05) during 540 minutes without any difference between the high and low FFA conditions. Discussion: Arginine infusion transiently decreased plasma leptin concentrations both in insulin-deficient and hyperinsulinemic diabetic patients, indicating a direct inhibitory effect of the amino acid but not of insulin or FFAs.