An Analysis of the Public Financial Support Eligibility Rule for French Dependent Elders with Alzheimer's Disease.

BACKGROUND: It is crucial to define health policies that target patients with the highest needs. In France, public financial support is provided to dependent patients: it can be used to finance informal care time and nonmedical care use. Eligibility for public subsidies and reimbursement of costs is associated with a specific tool: the autonomie gérontologie groupes iso-ressources (AGGIR) scale score. OBJECTIVE: Our objective was to explore whether patients with Alzheimer's disease who are eligible for public financial support have greater needs than do noneligible patients. METHODS: Using data from the Dépendance des patients atteints de la maladie d'Alzheimer en France study, we calculated nonmedical care expenditures (in €) using microcosting methods and informal care time demand (hours/month) using the Resource Use in Dementia questionnaire. We measured the burden associated with informal care provision with Zarit Burden Interview. We used a modified two-part model to explore the correlation between public financial support eligibility and these three variables. RESULTS: We find evidence of higher informal care use, higher informal caregivers' burden, and higher care expenditures when patients have an AGGIR scale score corresponding to public financial support eligibility. CONCLUSIONS: The AGGIR scale is useful to target patients with the highest costs and needs. Given our results, public subsidies could be used to further sustain informal caregivers networks by financing programs dedicated to lowering informal caregivers' burden.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review.

INTRODUCTION: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia. METHODS: The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review. RESULTS: In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer's disease and healthy controls. CONCLUSION: IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey.

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aß42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P < .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature.

Compensatory mechanisms in higher-educated subjects with Alzheimer's disease: a study of 20 years of cognitive decline.

A better knowledge of long-term trajectories of cognitive decline is a central feature of the study of the process leading to Alzheimer's dementia. Several factors may mitigate such decline, among which is education, a major risk factor for Alzheimer's disease. The aim of our work was to compare the pattern and duration of clinical trajectories before Alzheimer's dementia in individuals with low and high education within the PAQUID cohort involving 20 years of follow-up. The sample comprises 442 participants with incident Alzheimer's disease (27.2% were male)--171 with low education (mean age=86.2 years; standard deviation=5.3 years) and 271 with higher education (mean age=86.5; standard deviation=5.4)--and 442 control subjects matched according to age, sex and education. At each visit and up to the 20-year follow-up visit, several cognitive and clinical measures were collected and incident cases of Alzheimer's disease clinically diagnosed. The evolution of clinical measures in pre-demented subjects and matched controls was analysed with a semi-parametric extension of the mixed effects linear model. The results show that the first signs of cognitive decline occurred 15 to 16 years before achieving dementia threshold in higher-educated subjects whereas signs occurred at 7 years before dementia in low-educated subjects. There seemed to be two successive periods of decline in higher-educated subjects. Decline started ∼15 to 16 years before dementia with subtle impairment restricted to some cognitive tests and with no impact during the first 7 to 8 years on global cognition, cognitive complaints, or activities of daily living scales. Then, ∼7 years before dementia, global cognitive abilities begin to deteriorate, along with difficulties dealing with complex activities of daily living, the increase in self-perceived difficulties and depressive symptoms. By contrast, lower-educated subjects presented a single period of decline lasting ∼7 years, characterized by decline concomitantly affecting specific and more global cognitive function along with alteration in functional abilities. This study demonstrates how early cognitive symptoms may emerge preceding Alzheimer's dementia particularly in higher-educated individuals, for whom decline occurred up to 16 years before dementia. It also demonstrates the protective role of education in the clinical trajectory preceding Alzheimer's dementia. We suggest that the initial decline in cognition occurs at the onset of comparable Alzheimer's disease pathology in both groups, and is associated with immediate decline to dementia in the lower education group. In contrast, higher education protects against further cognitive decline for ∼7 years until pathology becomes more severe.

Playing board games, cognitive decline and dementia: a French population-based cohort study.

OBJECTIVES: To study the relationship between board game playing and risk of subsequent dementia in the Paquid cohort. DESIGN: A prospective population-based study. SETTING: In the Bordeaux area in South Western France. PARTICIPANTS: 3675 non-demented participants at baseline. PRIMARY OUTCOME MEASURE: The risk of dementia during the 20 years of follow-up. RESULTS: Among 3675 non-demented participants at baseline, 32.2% reported regular board game playing. Eight-hundred and forty participants developed dementia during the 20 years of follow-up. The risk of dementia was 15% lower in board game players than in non-players (HR=0.85, 95% CI 0.74 to 0.99; p=0.04) after adjustment on age, gender, education and other confounders. The statistical significance disappeared after supplementary adjustment on baseline mini-mental state examination (MMSE) and depression (HR=0.96, 95% CI 0.82 to 1.12; p=0.61). However, board game players had less decline in their MMSE score during the follow-up of the cohort (ß=0.011, p=0.03) and less incident depression than non-players (HR=0.84; 95% CI 0.72 to 0.98; p<0.03). CONCLUSIONS: A possible beneficial effect of board game playing on the risk of dementia could be mediated by less cognitive decline and less depression in elderly board game players.

Short- versus long-term prediction of dementia among subjects with low and high educational levels.

BACKGROUND: Using simple measures of cognition and disability in a prospective community-living cohort of normal elderly persons, the main objectives of our study were to distinguish short- and long-term predictors for dementia according to educational level and to propose a tool for early detection of subjects at high risk of dementia. METHODS: Data derived from the French cohort study Paquid (Personnes Agées QUID), which included 3777 subjects, older than 65 years of age, who were followed for a 20-year period. The risk of dementia at 3 years and 10 years was estimated by logistic regression for repeated measures combining data from all the 3- and 10-year windows throughout the follow-up. Predictors included disability assessed by the number of dependent items among four instrumental activities of daily living (IADLs), four neuropsychological tests, five Mini-Mental State Examination (MMSE) subtests, and four items of subjective memory complaints. RESULTS: Of the 2882 included subjects, the number of IADLs remained a predictor of short- and long-term conversion to dementia for those with low educational level (combined with only one cognitive test) whereas the best predictors for more educated subjects combined subjective memory complaints and memory and executive function tests. The episodic memory subtest was the only predictive MMSE subtest. In the high-education-level group, the areas under the receiver-operating characteristic curve of the selected models were 0.85 for 3-year prediction and 0.78 for 10-year prediction. CONCLUSION: Early predictors of dementia are different according to educational level. Among subjects reaching the secondary school level, early detection of those at high risk of dementia is possible with good predictive performance, with a few simple objective and subjective cognitive evaluations.

[Paquid 2012: illustration and overview]. / Paquid 2012 : illustration et bilan.

Paquid (personnes âgées quid) is a population-based cohort specifically designed to study the epidemiology of brain aging and dependency in activities of daily living in elderly people. At baseline screening, 3.777 subjects older than 65 were randomly selected in 75 different parishes from Gironde and Dordogne, and two administrative districts around Bordeaux in South-Western France. The participation rate was 68%. Subjects were followed up every two to three years with repeated measures of cognition, instrumental and basic activities of daily living collected by a trained psychologist, and a systematic detection of incident cases of dementia. The participation rate of each follow-up screening was around 75%. The detection of dementia was conducted with a two-stage design, with a first stage conducted by the psychologist and the confirmation of the diagnosis made at home by a physician, specialist in Alzheimer disease and related disorders (ADRD). Over 20 years of follow-up more than 800 subjects developed incident dementia and more than 2.500 died. Paquid remains the only representative cohort of elderly people living at home in France, giving estimations of prevalence, incidence and duration of ADRD and dependency. Thirty six risk factors of dementia and/or AD have been studied. On the basis of the Paquid data, we have shown that the prodromal phase of AD was longer than ten years and that dementia represented the major cause of dependency in the elderly.

Prediction of subacute infarct size in acute middle cerebral artery stroke: comparison of perfusion-weighted imaging and apparent diffusion coefficient maps.

PURPOSE: To compare perfusion-weighted (PW) imaging and apparent diffusion coefficient (ADC) maps in prediction of infarct size and growth in patients with acute middle cerebral artery infarct. MATERIALS AND METHODS: This study was approved by the local institutional review board. Written informed consent was obtained from all 80 patients. Subsequent infarct volume and growth on follow-up magnetic resonance (MR) images obtained within 6 days were compared with the predictions based on PW images by using a time-to-peak threshold greater than 4 seconds and ADC maps obtained less than 12 hours after middle cerebral artery infarct. ADC- and PW imaging-predicted infarct growth areas and infarct volumes were correlated with subsequent infarct growth and follow-up diffusion-weighted (DW) imaging volumes. The impact of MR imaging time delay on the correlation coefficient between the predicted and subsequent infarct volumes and individual predictions of infarct growth by using receiver operating characteristic curves were assessed. RESULTS: The infarct volume measurements were highly reproducible (concordance correlation coefficient [CCC] of 0.965 and 95% confidence interval [CI]: 0.949, 0.976 for acute DW imaging; CCC of 0.995 and 95% CI: 0.993, 0.997 for subacute DW imaging). The subsequent infarct volume correlated (P<.0001) with ADC- (ρ=0.853) and PW imaging- (ρ=0.669) predicted volumes. The correlation was higher for ADC-predicted volume than for PW imaging-predicted volume (P<.005), but not when the analysis was restricted to patients without recanalization (P=.07). The infarct growth correlated (P<.0001) with PW imaging-DW imaging mismatch (ρ=0.470) and ADC-DW imaging mismatch (ρ=0.438), without significant differences between both methods (P=.71). The correlations were similar among time delays with ADC-predicted volumes but decreased with PW imaging-based volumes beyond the therapeutic window. Accuracies of ADC- and PW imaging-based predictions of infarct growth in an individual prediction were similar (area under the receiver operating characteristic curve [AUC] of 0.698 and 95% CI: 0.585, 0.796 vs AUC of 0.749 and 95% CI: 0.640, 0.839; P=.48). CONCLUSION: The ADC-based method was as accurate as the PW imaging-based method for evaluating infarct growth and size in the subacute phase.

Safety, tolerability, and antibody response of active Aß immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study.

BACKGROUND: Immunotherapy targeting the amyloid ß (Aß) peptide is a potential strategy to slow the progression of Alzheimer's disease. We aimed to assess the safety and tolerability of CAD106, a novel active Aß immunotherapy for patients with Alzheimer's disease, designed to induce N-terminal Aß-specific antibodies without an Aß-specific T-cell response. METHODS: We did a phase 1, double-blind, placebo-controlled, 52-week study in two centres in Sweden. Participants, aged 50-80 years, with mild-to-moderate Alzheimer's disease were entered into one of two cohorts according to time of study entry and then randomly allocated (by use of a computer-generated randomisation sequence) to receive either CAD106 or placebo (4:1; cohort one received CAD106 50 µg or placebo, cohort two received CAD106 150 µg or placebo). Each patient received three subcutaneous injections. All patients, caregivers, and investigators were masked to treatment allocation throughout the study. Primary objectives were to assess the safety and tolerability of CAD106 and to identify the Aß-specific antibody response. Safety assessment was done by recording of all adverse events, assessment of MRI scans, physical and neurological examinations, vital signs, electrocardiography, electroencephalography, and laboratory analysis of blood and CSF. Patients with Aß-IgG serum titres higher than 16 units at least once during the study were classified as responders. This study is registered with ClinicalTrials.gov, number NCT00411580. FINDINGS: Between August, 2005, and March, 2007, we randomly allocated 31 patients into cohort one (24 patients to CAD106 treatment and seven to placebo) and 27 patients into cohort two (22 patients to CAD106 treatment and five to placebo). 56 of 58 patients reported adverse events. In cohort one, nasopharyngitis was the most commonly reported adverse event (10 of 24 CAD106-treated patients). In cohort two, injection site erythema was the most commonly reported adverse event (14 of 22 CAD106-treated patients). Overall, nine patients reported serious adverse events--none was thought to be related to the study drug. We recorded no clinical or subclinical cases of meningoencephalitis. 16 of 24 (67%) CAD106-treated patients in cohort one and 18 of 22 (82%) in cohort two developed Aß antibody response meeting pre-specified responder threshold. One of 12 placebo-treated patients (8%) had Aß-IgG concentrations that qualified them as a responder. INTERPRETATION: Our findings suggest that CAD106 has a favourable safety profile and acceptable antibody response in patients with Alzheimer's disease. Larger trials with additional dose investigations are needed to confirm the safety and establish the efficacy of CAD106. FUNDING: Novartis Pharma AG.

Gender differences in the prodromal signs of dementia: memory complaint and IADL-restriction. a prospective population-based cohort.

Subjective memory complaint (SMC) and restriction in cognitively-complex activities of daily living (such as instrumental ADL) are two early symptoms observed in the prodromal phase of dementia and may represent useful alarm signals for general practitioners for an increased risk of subsequent dementia. We here studied in a large population-based epidemiological cohort on aging, the risk of dementia associated with SMC and restriction in IADL, with a specific interest in a potential interaction by gender. The sample included 2,901 subjects, aged 65 years and over, initially free of dementia and followed over 15 years. After controlling for education, marital status, depressive symptomatology, and global cognition (MMSE), IADL-restriction was associated with an increased risk of dementia only in men (HR = 2.04, 1.27 to 3.29), whereas SMC was not (p = 0.95). The reverse was observed in females, in whom SMC almost doubled the risk of dementia (1.48 to 2.41), with no association with IADL-restriction (p = 0.74). Finally, we distinguished the risk of dementia at short-term (in the first 5 years), mid-term (between 5 and 10 years), and long-term (between 10 and 15 years). In women, SMC was significantly associated with greater risk of dementia whatever the risk period considered, even at longer term (HR = 1.61, p = 0.0216), whereas in men the increased risk was also observed with IADL-restriction and only in the first 5 years. To conclude, women would report the first symptoms very early in the process by SMC, whereas men would tend to later report their difficulties and only in terms of IADL-restriction.

Improved mitochondrial function in brain aging and Alzheimer disease - the new mechanism of action of the old metabolic enhancer piracetam.

Piracetam, the prototype of the so-called nootropic drugs' is used since many years in different countries to treat cognitive impairment in aging and dementia. Findings that piracetam enhances fluidity of brain mitochondrial membranes led to the hypothesis that piracetam might improve mitochondrial function, e.g., might enhance ATP synthesis. This assumption has recently been supported by a number of observations showing enhanced mitochondrial membrane potential, enhanced ATP production, and reduced sensitivity for apoptosis in a variety of cell and animal models for aging and Alzheimer disease. As a specific consequence, substantial evidence for elevated neuronal plasticity as a specific effect of piracetam has emerged. Taken together, this new findings can explain many of the therapeutic effects of piracetam on cognition in aging and dementia as well as different situations of brain dysfunctions.

Normal cerebrovascular reactivity in Stroke-like Migraine Attacks after Radiation Therapy syndrome.

Stroke-like Migraine Attacks after Radiation Therapy (SMART) syndrome is a rare complication of cranial irradiation. Radiation is well-known to impair vascular vessel architecture and function. We investigated the hypothesis of radiation-induced cerebral vascular reserve dysfunction as the underlying mechanism of SMART. Interictal cerebrovascular reactivity was investigated using Tc-99m hexamethylpropyleneamine oxime-SPECT and acetazolamide challenge in 3 patients. We found interictal hypoperfusion and normal cerebrovascular reactivity in all patients. Neither ictal restriction of the apparent diffusion coefficient nor MR angiography abnormalities were observed. These findings do not support a vascular mechanism in SMART syndrome. Postradiation neuronal dysfunction may be the underlying mechanism. Further investigations on larger series are needed to confirm this hypothesis.

Use of the Triage Stroke Panel in a neurologic emergency service.

BACKGROUND: Acute stroke is associated with serum elevations of numerous markers. We evaluated the additive accuracy of the Triage Stroke Panel (D-dimer, B-natriuretic peptide, matrix metalloproteinase 9, and S-100beta) to the triaging nurse for acute stroke diagnosis. METHODS: Consecutive patients with suspected stroke were included in this prospective, controlled, single-center study. A well-trained stroke center triage nurse assigned a probability that the patient had experienced a stroke (certain, very probable, probable, not likely, doubtful, or other); then, the Triage Stroke Panel testing was performed. Patients' diagnosis was based on clinical and imaging data by a neurologist blinded to the test results. RESULTS: Two hundred four patients were evaluated. Confirmed strokes and transient ischemic attacks (TIAs) were observed in 131 patients. When considering an experienced stroke nurse's assessment of "other," "doubtful," or "not likely" to be negative for stroke and categorizing TIA with stroke, the stroke panel's Multimarker Index (MMX) value had identical accuracy (approximately 70%) and equivalent sensitivity (approximately 94%) and specificity (approximately 24%) for stroke diagnosis to that of the nurse. Combining nurse assessment with the MMX result significantly improved the specificity of diagnosing "mimic" vs stroke + TIA from 25.4% (nurse assessment only) to 46.0% (nurse assessment + MMX; P < .001). CONCLUSIONS: The Triage Stroke Panel provides objective information that complements a triage nurse in the assessment of a suspected stroke patient. Its performance compares favorably with that of a well-trained stroke center triage nurse, suggesting potential use in nonexpert centers for improving the accuracy of stroke diagnosis.

Safety and tolerability of the rivastigmine patch: results of a 28-week open-label extension.

The primary objective of the open-label extension was to evaluate the long-term safety and tolerability of a transdermal rivastigmine patch up to 1 year, as a novel approach to treatment in Alzheimer disease. This was a 28-week extension to a 24-week, double-blind, double-dummy, placebo-controlled, and active-controlled study evaluating rivastigmine patches [9.5 mg/24 h (10 cm2) and 17.4 mg/24 h (20 cm2)] and oral capsules (3 to 6 mg twice-daily). Patients entering the extension were switched directly to 9.5 mg/ 24 h rivastigmine patch and increased to 17.4 mg/24 h patch, irrespective of their double-blind study treatment. Primary measures included safety and tolerability assessments, including adverse events and serious adverse events. Of 1195 patients randomized to treatment, 870 (72.8%) completed the double-blind study and entered the open-label extension. During weeks 1 to 4 of the extension, 9.5 mg/24 h rivastigmine patch was well tolerated overall by patients formerly randomized to rivastigmine capsule or patch groups: < or =2.5% reported nausea and < or =1.9% reported vomiting. No unexpected safety issues arose, and skin tolerability was good; similar to the double-blind study. During the 28-week, open-label extension phase, the patch seemed to be well tolerated with a favorable safety profile.

Inter- and intraobserver reliability of five MRI sequences in the evaluation of the final volume of cerebral infarct.

PURPOSE: To evaluate the reproducibility of fluid attenuated inversion recovery (FLAIR) and four other magnetic resonance imaging (MRI) sequences in the quantitative assessment of final cerebral infarct volume. MATERIALS AND METHODS: FLAIR, T1-3D, magnetization transfer ratio (MTR)-map, diffusion-weighted trace (DWI)-trace, and apparent diffusion coefficient (ADC)-map, were acquired and measured in 33 patients 30-45 days after onset of a first-ever ischemic stroke. The infarct area was visually detected and manually delineated two times by two readers separately after images and sequences randomization. The reliability was assessed by using an intraclass correlation coefficient (ICC) and its two-sided 95% confidence interval (95% CI). RESULTS: DWI-trace had the best reliability, with an ICC of 0.96 (95% CI = 0.93-0.98). FLAIR had an ICC of 0.86 (95% CI = 0.73-0.93), and a much higher volume. T1-3D, MTR-map and ADC-map had lower reliability or excessive volume values equal to 0 in comparison to DWI-trace. CONCLUSION: DWI-trace performed within 30th and 45th day following onset of acute ischemic stroke was the most reliable sequence for final infarct volume quantification. This sequence should be added to FLAIR evaluation to strengthen the statistical results of the pharmacological trials and reduce their variability.

Methodological issues in primary prevention trials for neurodegenerative dementia.

The prevention of neurodegenerative dementias, such as Alzheimer's disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition.

Prodromal Alzheimer's disease: successive emergence of the clinical symptoms.

OBJECTIVE: Whereas cognitive deficits are known to be detectable long before the typical symptoms of Alzheimer's disease (AD) are evident, previous studies have failed to determine when cognitive functioning actually begins to decline before dementia. Utilizing the long follow-up of the PAQUID study, we examined the emergence of the first clinical symptoms over a 14-year period of follow-up before the dementia phase of AD. METHODS: This study relies on a case-control sample selected from the PAQUID cohort. Of the 3,777 initial subjects of the cohort, 350 subjects experienced development of AD during the 14 years of follow-up. The cases were matched to 350 elderly control subjects. The evolution of scores on cognitive, functional, and depression scales was described throughout the 14-year follow-up using a semiparametric extension of the mixed-effects linear model. RESULTS: The first decline in cognitive performances appeared as early as 12 years before dementia in measures of semantic memory and conceptual formation. Then, more global deficits appeared that were concomitant with an increase in memory complaints and depressive symptoms. About 2 years later, as a consequence of cognitive dysfunction, the subjects started to become slightly dependent in their activities of daily living. In the last 3 years, the impairment significantly worsened until the subjects reached the dementia phase. INTERPRETATION: This approach, describing the 14 years preceding dementia, provides a clear illustration of the particularly long and progressive prodromal phase of AD, and shows the successive emergence of cognitive deficits, depressive symptoms, and functional impairment during this phase.

Seropositivity to herpes simplex virus antibodies and risk of Alzheimer's disease: a population-based cohort study.

BACKGROUND: Herpes Simplex Virus (HSV) infection has been proposed as a possible risk factor of Alzheimer's Disease (AD) notably because it is neurotropic, ubiquitous in the general population and able to establish lifelong latency in the host. The fact that HSV was present in elderly subjects with AD suggests that the virus could be a co-factor of the disease. We investigated the risk of developing AD in anti-HSV immunoglobulin G (IgG) positive subjects (indicator of a lifelong infection to HSV) and IgM-positive subjects (indicator of primary infection or reactivation of the virus) in a longitudinal population-based cohort of elderly subjects living in the community. METHODS: Cox proportional hazard models were used to study the risk of developing AD according to the presence or not of anti-HSV IgG and IgM antibodies, assessed in the sera of 512 elderly initially free of dementia followed for 14 years. RESULTS: During the follow-up, 77 incident AD cases were diagnosed. Controlled for age, gender, educational level and Apolipoprotein E4 (APOE4) status, IgM-positive subjects showed a significant higher risk of developing AD (HR = 2.55; 95% CI [1.38-4.72]), although no significant increased risk was observed in IgG-positive subjects (HR = 1.67; 95%CI [0.75-3.73]). No modification effect with APOE4 status was found. CONCLUSION: Reactivation of HSV seropositivity is highly correlated with incident AD. HSV chronic infection may therefore be contributive to the progressive brain damage characteristic of AD.

Gender and education impact on brain aging: a general cognitive factor approach.

In cognitive aging research, the study of a general cognitive factor has been shown to have a substantial explanatory power over the study of isolated tests. The authors aimed at differentiating the impact of gender and education on global cognitive change with age from their differential impact on 4 psychometric tests using a new latent process approach, which intermediates between a single-factor longitudinal model for sum scores and an item-response theory approach for longitudinal data. The analysis was conducted on a sample of 2,228 subjects from PAQUID, a population-based cohort of older adults followed for 13 years with repeated measures of cognition. Adjusted for vascular factors, the analysis confirmed that women performed better in tests involving verbal components, while men performed better in tests involving visuospatial skills. In addition, the model suggested that women had a slightly steeper global cognitive decline with oldest age than men, even after excluding incident dementia or death. Subjects with higher education exhibited a better mean score for the 4 tests, but this difference tended to attenuate with age for tests involving a speed component.

Natural history of decline in instrumental activities of daily living performance over the 10 years preceding the clinical diagnosis of dementia: a prospective population-based study.

OBJECTIVES: To study the subtle changes in instrumental activities of daily living (IADLs) over the 10 years preceding the clinical diagnosis of dementia. DESIGN: Prospective cohort designed in 1988 to study cerebral and functional aging. SETTING: Community-based study in southwestern France. PARTICIPANTS: The sample included 104 incident cases of dementia at the 10-year follow-up (T10) and 882 subjects free of dementia at the same visit, all forming part of the PAQUID Study. MEASUREMENTS: Restriction in four IADLs was studied (telephone, transportation, medication, and finances) 2, 5, 7, and 10 years before the T10 visit. RESULTS: The future dementia cases had greater IADL restrictions 10 years before the clinical diagnosis of dementia and more-rapid functional deterioration over time. Controlled for age, sex, and education, subjects restricted in at least two IADLs at baseline had a higher risk of dementia 10 years later (odds ratio (OR)=2.59, 95% confidence interval (CI)=1.24-5.38). In finances, difficulty at baseline was a predictor of dementia 10 years later (OR=2.15, 95% CI=1.13-4.08). CONCLUSION: This study is the first to show that, 10 years before the clinical diagnosis of dementia, subjects who later developed dementia performed worse in complex activities of daily living, which may constitute an early marker of the disease. In practice, restriction in IADLs may be a simple and useful tool for screening subjects at risk of developing dementia in the long term.