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1.  Anti-dementia drugs and changes in gait: a pre-post quasi-experimental pilot study 
BMC Neurology  2013;13:184.
Anti-dementia drugs may improve gait performance. No comparison between acetylcholinesterase inhibitors (CEIs) and memantine-related changes in gait variability has been reported. The objectives of this study were to 1) quantify and compare the mean values and coefficients of variation (CoV) of stride time in demented patients with Alzheimer’s disease and related disorders (ADRD) before and after the use of CEIs or memantine, and in age- and gender-matched controls patients with ADRD using no anti-dementia drugs; and 2) to determine whether changes in CoV of stride time differed between CEIs or memantine.
A total of 120 demented patients with mild-to-moderate ADRD were prospectively included in this pre-post quasi-experimental study with two intervention groups (43 patients taking CEIs, and 41 taking memantine) and a control group (36 age- and gender matched patients without any anti-dementia drugs). CoV of stride time and walking speed were measured with GAITRite® system while usual walking at steady state. Age, gender, number of drugs daily taken, use of psychoactive drugs, body mass index and time between the two visits were also recorded.
There was no difference between groups for the time between baseline and follow-up assessments (232.9 ± 103.7 days for patients without anti-dementia drugs, 220.0 ± 67.5 days for patients with CEIs, 186.7 ± 96.2 days for patients with memantine, P = 0.062). Patients with memantine had a lower (i.e., better) CoV of stride time at follow-up assessment compared to those with CEIs (4.2 ± 2.4% versus 5.8 ± 4.2%, P = 0.010). Patients with memantine had a greater decrease in CoV of stride time compared to those with CEIs (−1.90% versus 0.93%, P = 0.010) and mixed-effects linear regressions showed that this decrease was specifically explained by memantine (P = 0.028).
Our results showed that patients with ADRD and treated with memantine, but not those with CEIs, decreased their gait variability, and thus improved their gait safety (Trial registration number: NCT01315704).
PMCID: PMC3898226  PMID: 24261605
Gait; Stride time variability; Anti-dementia drugs; Alzheimer disease
2.  Do brain T2/FLAIR white matter hyperintensities correspond to myelin loss in normal aging? A radiologic-neuropathologic correlation study 
White matter hyperintensities (WMH) lesions on T2/FLAIR brain MRI are frequently seen in healthy elderly people. Whether these radiological lesions correspond to irreversible histological changes is still a matter of debate. We report the radiologic-histopathologic concordance between T2/FLAIR WMHs and neuropathologically confirmed demyelination in the periventricular, perivascular and deep white matter (WM) areas.
Inter-rater reliability was substantial-almost perfect between neuropathologists (kappa 0.71 - 0.79) and fair-moderate between radiologists (kappa 0.34 - 0.42). Discriminating low versus high lesion scores, radiologic compared to neuropathologic evaluation had sensitivity / specificity of 0.83 / 0.47 for periventricular and 0.44 / 0.88 for deep white matter lesions. T2/FLAIR WMHs overestimate neuropathologically confirmed demyelination in the periventricular (p < 0.001) areas but underestimates it in the deep WM (0 < 0.05). In a subset of 14 cases with prominent perivascular WMH, no corresponding demyelination was found in 12 cases.
MRI T2/FLAIR overestimates periventricular and perivascular lesions compared to histopathologically confirmed demyelination. The relatively high concentration of interstitial water in the periventricular / perivascular regions due to increasing blood–brain-barrier permeability and plasma leakage in brain aging may evoke T2/FLAIR WMH despite relatively mild demyelination.
PMCID: PMC3893472  PMID: 24252608
3.  Selective Determinants of Low Bone Mineral Mass in Adult Women with Anorexia Nervosa 
We investigated the relative effect of amenorrhea and insulin-like growth factor-I (sIGF-I) levels on cancellous and cortical bone density and size. We investigated 66 adult women with anorexia nervosa. Lumbar spine and proximal femur bone mineral density was measured by DXA. We calculated bone mineral apparent density. Structural geometry of the spine and the hip was determined from DXA images. Weight and BMI, but not height, as well as bone mineral content and density, but not area and geometry parameters, were lower in patients with anorexia nervosa as compared with the control group. Amenorrhea, disease duration, and sIGF-I were significantly associated with lumbar spine and proximal femur BMD. In a multiple regression model, we found that sIGF-I was the only significant independent predictor of proximal femur BMD, while duration of amenorrhea was the only factor associated with lumbar spine BMD. Finally, femoral neck bone mineral apparent density, but not hip geometry variables, was correlated with sIGF-I. In anorexia nervosa, spine BMD was related to hypogonadism, whereas sIGF-I predicted proximal femur BMD. The site-specific effect of sIGF-I could be related to reduced volumetric BMD rather than to modified hip geometry.
PMCID: PMC3619547  PMID: 23634145
4.  Natural History of Older Adults with Impaired Kidney Function: The InCHIANTI Study 
Rejuvenation Research  2011;14(5):513-523.
The aim of this study was to assess the kidney function of an older community-dwelling population at baseline and appraise its evolution after 3 years of follow-up in terms of chronic kidney disease (CKD) stage progression, magnitude of glomerular filtration rate (GFR) changes, and value of serum creatinine. This was a prospective population-based study of 676 Italian participants, aged 65 years and older. GFR was estimated using the Cockcroft–Gault equation and the Modification of Diet in Renal Disease Study equation. Using the Cockcroft–Gault equation. A total of 33% of participants had criteria of CKD (GFR < 60 mL/min) at baseline; among them, the majority remained stable, 10% improved, and 7% progressed to more severe CKD stages at follow-up. Loss of GFR in participants with GFR < 60 mL/min was significantly lower (1.4 mL/min per year) than in participants with GFR ≥ 60 mL/min (3.3 mL/min per year) at baseline. Most participants classified with CKD stage 2 (GFR 60–89 mL/min) or stage 3 (GFR 30–59 mL/min) at baseline did not change stage, whereas 55% of people with CKD stage 1 (GFR > 90 mL/min) at baseline worsened to stage 2 and 10% worsened to stage 3. An abnormal high level of serum creatinine at baseline did not help to predict who might worsen at follow-up. Older people with CKD displayed a low progression of renal disease and therefore are at higher risk for co-morbidities related to CKD than for progression to end-stage renal disease.
PMCID: PMC3198123  PMID: 21954982
5.  Event-related potentials and changes of brain rhythm oscillations during working memory activation in patients with first-episode psychosis 
Earlier contributions have documented significant changes in sensory, attention-related endogenous event-related potential (ERP) components and θ band oscillatory responses during working memory activation in patients with schizophrenia. In patients with first-episode psychosis, such studies are still scarce and mostly focused on auditory sensory processing. The present study aimed to explore whether subtle deficits of cortical activation are present in these patients before the decline of working memory performance.
We assessed exogenous and endogenous ERPs and frontal θ event-related synchronization (ERS) in patients with first-episode psychosis and healthy controls who successfully performed an adapted 2-back working memory task, including 2 visual n-back working memory tasks as well as oddball detection and passive fixation tasks.
We included 15 patients with first-episode psychosis and 18 controls in this study. Compared with controls, patients with first-episode psychosis displayed increased latencies of early visual ERPs and phasic θ ERS culmination peak in all conditions. However, they also showed a rapid recruitment of working memory–related neural generators, even in pure attention tasks, as indicated by the decreased N200 latency and increased amplitude of sustained θ ERS in detection compared with controls.
Owing to the limited sample size, no distinction was made between patients with first-episode psychosis with positive and negative symptoms. Although we controlled for the global load of neuroleptics, medication effect cannot be totally ruled out.
The present findings support the concept of a blunted electroencephalographic response in patients with first-episode psychosis who recruit the maximum neural generators in simple attention conditions without being able to modulate their brain activation with increased complexity of working memory tasks.
PMCID: PMC3297068  PMID: 22146152
6.  Gait control: a specific subdomain of executive function? 
Few studies looked at the association between gait variability and executive subdomains (ESD). The aim of this study was to examine the association between ESD (i.e., information updating and monitoring) and stride time variability among healthy older adults.
Seventy-eight healthy older adults (mean age 69.9 ± 0.9 years, 59% women) were divided into 3 groups according to stride time variability (STV) tertiles while steady state walking. Coefficient of variation of stride time was used as a marker of STV. Scores on cognitive tests evaluating information updating and monitoring (Digit Span test), mental shifting (Trail Making Test part A and part B) and cognitive inhibition (Stroop Color Word test) were used as measures of ESD.
The full adjusted and the stepwise backward logistic regression models showed that the highest tertile (i.e., the worst performance) of STV was only associated with lower Digit Span performance (Odds ratio = 0.78 with P = 0.020 and Odds ratio = 0.81 with P = 0.019).
Information updating and monitoring are associated with STV in the sample of studied participants, suggesting that walking may be a complex motor task depending specifically of this subdomain of executive functions.
PMCID: PMC3308913  PMID: 22321772
Gait disorders; Cognition; Motor impairment; Normal aging; Executive functions; Aging research
7.  Neuropathological analysis of lacunes and microvascular lesions in late-onset depression 
Previous neuropathological studies documented that small vascular and microvascular pathology is associated with cognitive decline. More recently, we showed that thalamic and basal ganglia lacunes are associated with post-stroke depression and may affect emotional regulation. The present study examines whether this is also the case for late-onset depression.
We performed a detailed analysis of small macrovascular and microvascular pathology in the postmortem brains of 38 patients with late-onset major depression (LOD) and 29 healthy elderly controls. A clinical diagnosis of LOD was established while the subjects were alive using the DSM-IV criteria. Additionally, we retrospectively reviewed all charts for the presence of clinical criteria of vascular depression. Neuropathological evaluation included bilateral semiquantitative assessment of lacunes, deep white matter and periventricular demyelination, cortical microinfarcts and both focal and diffuse gliosis. The association between vascular burden and LOD was investigated using Fisher’s exact test and univariate and multivariate logistic regression models.
Neither the existence of lacunes nor the presence of microvascular ischaemic lesions was related to occurrence of LOD. Similarly, there was no relationship between vascular lesion scores and LOD. This was also the case within the subgroup of LOD patients fulfilling the clinical criteria for vascular depression.
Our results challenge the vascular depression hypothesis by showing that neither deep white matter nor periventricular demyelination is associated with LOD. In conjunction with our previous observations in stroke patients, they also imply that the impact of lacunes on mood may be significant solely in the presence of acute brain compromise.
PMCID: PMC2962688  PMID: 20609111
brain ischaemia; elderly; mood; neuropathology; vascular depression
8.  Centenarians Today: New Insights on Selection from the 5-COOP Study 
The number of oldest old grew tremendously over the past few decades. However, recent studies have disclosed that the pace of increase strongly varies among countries. The present study aims to specify the level of mortality selection among the nonagenarians and centenarians living currently in five low mortality countries, Denmark, France, Japan, Switzerland, and Sweden, part of the 5-Country Oldest Old Project (5-COOP). All data come from the Human Mortality Database, except for the number of centenarians living in Japan. We disclosed three levels of mortality selection, a milder level in Japan, a stronger level in Denmark and Sweden and an intermediary level in France and Switzerland. These divergences offer an opportunity to study the existence of a trade-off between the level of mortality selection and the functional health status of the oldest old survivors which will be seized by the 5-COOP project.
PMCID: PMC3056212  PMID: 21423541
9.  Who will care for the oldest people in our ageing society? 
BMJ : British Medical Journal  2007;334(7593):570-571.
The number of informal carers for frail elderly people is set to fall steeply. Jean-Marie Robine and colleagues propose a new way to assess the trend that should help policy makers plan for the deficit
PMCID: PMC1828348  PMID: 17363829
10.  Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging 
Background and purpose
Most of the neuropathological studies in brain aging were based on the assumption of a symmetric right-left hemisphere distribution of both Alzheimer's disease (AD) and vascular pathology. To explore the impact of asymmetric lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts.
Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle (NFT) and Aß-deposition staging, microvascular pathology and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and CDR scores was assessed using ordered logistic regression.
Unlike Braak NFT and Aß deposition staging, vascular scores were significantly higher in the left hemisphere for all CDR scores. A negative relationship was found between Braak NFT, but not Aß, staging and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak NFT staging was the main determinant of cognitive decline followed by vascular scores and Aß deposition staging. The concomitant predominance of AD and vascular pathology in the right hemisphere was associated with significantly higher CDR scores.
Our data show that the cognitive impact of AD and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and AD burden in the right hemisphere may increase the risk for dementia in this group.
PMCID: PMC2674266  PMID: 19118241
Alzheimer; cerebral infarct; cognition; white matter disease
11.  Clinical presentation, demographics and outcome of Tuberculosis (TB) in a low incidence area: a 4-year study in Geneva, Switzerland 
The incidence of tuberculosis (TB) in developed countries has decreased since the 1990s, reflecting worldwide efforts to identify and treat TB according to WHO recommendations. However TB remains an important public health problem in industrialized countries with a high proportion of cases occurring among subjects originating from high prevalence countries. The aim of this study was to describe clinical and social characteristics of patients with TB and their outcome in a low incidence area with a high immigration rate.
Four-year retrospective study based on a computerized database and subsequent review of medical records of all patients with TB followed at the outpatient section of the Division of Pulmonary Diseases, Geneva University Hospital, Switzerland.
252 patients (84% foreigners, 25% asylum seekers) aged 38 ± 19 yrs were studied (11% co-infected with HIV). TB was intrapulmonary (TBP) in 158 cases (63%), extrapulmonary (TBE) in 137 (54%), and both in 43 cases (17%). TBP was smear (S)+/culture (C)+ in 59%, S-/C+ in 37%, S-/C- in 4%. Smoking was significantly associated with cavitary disease.
Time from onset of symptoms to diagnosis was 2.1 ± 3.1 months. Initially, 10% were asymptomatic; 35% had no general symptoms. Despite systematic sputum analysis (induced or spontaneous), TBP was confirmed only by bronchoscopy in 38 subjects (24% of TBP). Side effects requiring changes in treatment occurred in 38 cases (11%).
Treatment was completed in 210 (83%) patients. In 42 cases, follow up was unsuccessful; causes were: failure (n = 2; 0.8%), defaulters (n = 8; 3%), transfer out (n = 28; 11%) and death (n = 4; 1.6%). Relapse rate was 0.24 per 100 patient-years. Considering S+ TBP only, success rate was 87%.
TB in our area is predominantly a disease of young foreign-born subjects. Smoking appears as a possible risk factor for cavitary TBP. Time to diagnosis remains long. Compliance to treatment is satisfactory. Success rate for S+ TBP is within WHO objectives.
PMCID: PMC2807871  PMID: 20043847
12.  Stereologic estimates of total spinophilin-immunoreactive spine number in area 9 and the CA1 field: relationship with the progression of Alzheimer’s disease 
Neurobiology of aging  2007;29(9):1296-1307.
The loss of presynaptic markers is thought to represent a strong pathologic correlate of cognitive decline in Alzheimer’s disease (AD). Spinophilin is a postsynaptic marker mainly located to the heads of dendritic spines. We assessed total numbers of spinophilin-immunoreactive puncta in the CA1 and CA3 fields of hippocampus and area 9 in 18 elderly individuals with various degrees of cognitive decline. The decrease in spinophilin-immunoreactivity was significantly related to both Braak neurofibrillary tangle (NFT) staging and clinical severity but not Aβ deposition staging. The total number of spinophilin-immunoreactive puncta in CA1 field and area 9 were significantly related to MMSE scores and predicted 23.5% and 61.9% of its variability. The relationship between total number of spinophilin-immunoreactive puncta in CA1 field and MMSE scores did not persist when adjusting for Braak NFT staging. In contrast, the total number of spinophilin-immunoreactive puncta in area 9 was still significantly related to the cognitive outcome explaining an extra 9.6% of MMSE and 25.6% of the Clinical Dementia Rating scores variability. Our data suggest that neocortical dendritic spine loss is an independent parameter to consider in AD clinicopathologic correlations.
PMCID: PMC2569870  PMID: 17420070
Alzheimer’s disease; cognition; synapses; tangles
13.  Walking speed-related changes in stride time variability: effects of decreased speed 
Conflicting results have been reported regarding the relationship between stride time variability (STV) and walking speed. While some studies failed to establish any relationship, others reported either a linear or a non-linear relationship. We therefore sought to determine the extent to which decrease in self-selected walking speed influenced STV among healthy young adults.
The mean value, the standard deviation and the coefficient of variation of stride time, as well as the mean value of stride velocity were recorded while steady-state walking using the GAITRite® system in 29 healthy young adults who walked consecutively at 88%, 79%, 71%, 64%, 58%, 53%, 46% and 39% of their preferred walking speed.
The decrease in stride velocity increased significantly mean values, SD and CoV of stride time (p < 0.001), whereas the repetition of trials (p = 0.534, p = 0.177 and p = 0.691 respectively for mean, SD, CoV); and step asymmetry (p = 0.971, p = 0.150 and p = 0.288 for mean, SD and CoV) had no significant effect. Additionally, the subject's effect was significant for all stride parameters (p < 0.001). The relationship between a decrease in walking speed and all stride parameters (i.e., mean values, SD and CoV of stride time) was significantly quadratic and showed higher STV at a slow speed (p < 0.001).
The results support the assumption that gait variability increases while walking speed decreases and, thus, gait might be more unstable when healthy subjects walk slower compared with their preferred walking speed. Furthermore, these results highlight that a decrease in walking speed can be a potential confounder while evaluating STV.
PMCID: PMC2731039  PMID: 19656364
14.  BRIEF REPORT: Beyond Clinical Experience: Features of Data Collection and Interpretation That Contribute to Diagnostic Accuracy 
Journal of General Internal Medicine  2006;21(12):1302-1305.
Clinical experience, features of data collection process, or both, affect diagnostic accuracy, but their respective role is unclear.
Prospective, observational study, to determine the respective contribution of clinical experience and data collection features to diagnostic accuracy.
Six Internists, 6 second year internal medicine residents, and 6 senior medical students worked up the same 7 cases with a standardized patient. Each encounter was audiotaped and immediately assessed by the subjects who indicated the reasons underlying their data collection. We analyzed the encounters according to diagnostic accuracy, information collected, organ systems explored, diagnoses evaluated, and final decisions made, and we determined predictors of diagnostic accuracy by logistic regression models.
Several features significantly predicted diagnostic accuracy after correction for clinical experience: early exploration of correct diagnosis (odds ratio [OR] 24.35) or of relevant diagnostic hypotheses (OR 2.22) to frame clinical data collection, larger number of diagnostic hypotheses evaluated (OR 1.08), and collection of relevant clinical data (OR 1.19).
Some features of data collection and interpretation are related to diagnostic accuracy beyond clinical experience and should be explicitly included in clinical training and modeled by clinical teachers. Thoroughness in data collection should not be considered a privileged way to diagnostic success.
PMCID: PMC1924750  PMID: 17105525
clinical reasoning; clinical data collection; experience; expertise; medical education; internal medicine
15.  Stride-to-stride variability while backward counting among healthy young adults 
Little information exists about the involvement of attention in the control of gait rhythmicity. Variability of both stride time and stride length is closely related to the control of the rhythmic stepping mechanism. We sought 1) to determine whether backward counting while walking could provoke significant gait changes in mean values and coefficients of variation of stride velocity, stride time and stride length among healthy young adults; and 2) to establish whether change in stride-to-stride variability could be related to dual-task related stride velocity change, attention, or both.
Mean values and coefficients of variation of stride velocity, stride time and stride length were recorded using the Physilog®-system, at a self-selected walking speed in 49 healthy young adults (mean age 24.1 ± 2.8 years, women 49%) while walking alone and walking with simultaneous backward counting. Performance on backward counting was evaluated by recording the number of figures counted while sitting alone and while walking.
Compared with walking alone, a significant dual-task-related decrease was found for the mean values of stride velocity (p < 0.001), along with a small but significant increase for the mean values and coefficients of variation of stride time (p < 0.001 and p = 0.015, respectively). Stride length parameters did not change significantly between both walking conditions. Dual-task-related increase of coefficient of variation of stride time was explained by changing stride velocity and variability between subjects but not by backward counting. The number of figures counted while walking decreased significantly compared to backward counting alone. Further, the dual-task related decrease of the number of enumerated figures was significantly higher than the dual-task related decrease of stride velocity (p = 0.013).
The observed performance-changes in gait and backward counting while dual tasking confirm that certain aspects of walking are attention-demanding in young adults. In the tested group of 49 young volunteers, dual tasking caused a small decrease in stride velocity and a slight increase in the stride-to-stride variability of stride time, while stride velocity variability was not affected by the attention-demanding task. The increase in stride time variability was apparently the result of a change in gait speed, but not a result of dual tasking. This suggests that young adults require minimal attention for the control of the rhythmic stepping mechanism while walking.
PMCID: PMC1190208  PMID: 16095533
Dual-task; Stride-to-stride variability; Attention; Gait control; Healthy young adults

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