Personality, Alzheimer's disease and behavioural and cognitive symptoms of dementia: the PACO prospective cohort study protocol.

BACKGROUND: Alzheimer's disease is characterised by a loss of cognitive function and behavioural problems as set out in the term "Behavioural and Psychological Symptoms of Dementia". These behavioural symptoms have heavy consequences for the patients and their families. A greater understanding of behavioural symptoms risk factors would allow better detection of those patients, a better understanding of crisis situations and better management of these patients. Some retrospective studies or simple observations suggested that personality could play a role in the occurrence of behavioural symptoms. Finally, performance in social cognition like facial recognition and perspective taking could be linked to certain personality traits and the subsequent risks of behavioural symptoms. We propose to clarify this through a prospective, multicentre, multidisciplinary study. Main Objective: -To assess the effect of personality and life events on the risk of developing behavioural symptoms. Secondary Objectives: -To evaluate, at the time of inclusion, the connection between personality and performance in social cognition tests; -To evaluate the correlation between performance in social cognition at inclusion and the risks of occurrence of behavioural symptoms; -To evaluate the correlation between regional cerebral atrophy, using brain Magnetic Resonance Imaging at baseline, and the risk of behavioural symptoms. METHODS/DESIGN: Study type and Population: Prospective multicentre cohort study with 252 patients with Alzheimer's disease at prodromal or mild dementia stage. The inclusion period will be of 18 months and the patients will be followed during 18 months. The initial evaluation will include: a clinical and neuropsychological examination, collection of behavioural symptoms data (Neuropsychiatric-Inventory scale) and their risk factors, a personality study using both a dimensional (personality traits) and categorical approach, an inventory of life events, social cognition tests and an Magnetic Resonance Imaging. Patients will be followed every 6 months (clinical examination and collection of behavioural symptoms data and risk factors) during 18 months. DISCUSSION: This study aims at better identifying the patients with Alzheimer's disease at high risk of developing behavioural symptoms, to anticipate, detect and quickly treat these disorders and so, prevent serious consequences for the patient and his caregivers. TRIAL REGISTRATION: ClincalTrials.gov: NCT01297140.

Blood pressure variability and risk of dementia in an elderly cohort, the Three-City Study.

BACKGROUND: The relationship between blood pressure and dementia is incompletely understood in elderly individuals. Blood pressure variability may have a role in the risk of dementia. METHODS: This investigation was a cohort study of 6506 elderly individuals followed-up for 8 years (1999-2001 through 2008) with assessments at years 2, 4, and 7-8. Blood pressure was measured by electronic devices at baseline and at 2- and 4-year follow-up examinations. Cox proportional hazard models adjusted for potential confounders were used to estimate the risk of incident dementia according to blood pressure (means and coefficients of variation of the three measures). RESULTS: During the 40,151 person-years of follow-up 474 participants developed dementia. We observed no association between mean blood pressure and risk of dementia. In contrast, an increase of 1 standard deviation in the coefficient of variation of blood pressure was associated with a 10% increased risk of dementia. Analysis by deciles of the coefficient of variation showed that the higher the variability, the higher the risk of dementia (P<.02 for trend). In the fully adjusted Cox model, the risk of dementia for those in the highest decile of the coefficient of variation of systolic blood pressure was 1.77 (1.17-2.69) compared with the lowest decile. CONCLUSIONS: In this cohort study, variability of blood pressure during follow-up was associated with an increased risk of incident dementia, whereas mean blood pressure was not. Limitation of blood pressure fluctuation may be an important target to preserve cognitive function in the elderly.

Prodromal characteristics of dementia with Lewy bodies: baseline results of the MEMENTO memory clinics nationwide cohort.

BACKGROUND: Isolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline. METHODS: Participants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done. RESULTS: The pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years. CONCLUSIONS: Patients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients. TRIAL REGISTRATION: Clinicaltrials.gov , NCT01926249.

Non-REM Sleep Characteristics Predict Early Cognitive Impairment in an Aging Population.

Objective: Recent research suggests that sleep disorders or changes in sleep stages or EEG waveform precede over time the onset of the clinical signs of pathological cognitive impairment (e.g., Alzheimer's disease). The aim of this study was to identify biomarkers based on EEG power values and spindle characteristics during sleep that occur in the early stages of mild cognitive impairment (MCI) in older adults. Methods: This study was a case-control cross-sectional study with 1-year follow-up of cases. Patients with isolated subjective cognitive complaints (SCC) or MCI were recruited in the Bordeaux Memory Clinic (MEMENTO cohort). Cognitively normal controls were recruited. All participants were recorded with two successive polysomnography 1 year apart. Delta, theta, and sigma absolute spectral power and spindle characteristics (frequency, density, and amplitude) were analyzed from purified EEG during NREM and REM sleep periods during the entire second night. Results: Twenty-nine patients (8 males, age = 71 ± 7 years) and 29 controls were recruited at T0. Logistic regression analyses demonstrated that age-related cognitive impairment were associated with a reduced delta power (odds ratio (OR) 0.072, P < 0.05), theta power (OR 0.018, P < 0.01), sigma power (OR 0.033, P < 0.05), and spindle maximal amplitude (OR 0.002, P < 0.05) during NREM sleep. Variables were adjusted on age, gender, body mass index, educational level, and medication use. Seventeen patients were evaluated at 1-year follow-up. Correlations showed that changes in self-reported sleep complaints, sleep consolidation, and spindle characteristics (spectral power, maximal amplitude, duration, and frequency) were associated with cognitive impairment (P < 0.05). Conclusion: A reduction in slow-wave, theta and sigma activities, and a modification in spindle characteristics during NREM sleep are associated very early with a greater risk of the occurrence of cognitive impairment. Poor sleep consolidation, lower amplitude, and faster frequency of spindles may be early sleep biomarkers of worsening cognitive decline in older adults.

Co-occurrence of neuropsychiatric syndromes in demented and psychotic institutionalized elderly.

OBJECTIVES: To explore and determine the clinical figures of behavioral syndromes from the factor structure of the Neuropsychiatric Inventory-Nursing Home version (NPI-NH) in demented and psychotic patients. SETTING: Two nursing homes and two long-term care homes. DESIGN: Observational, cross-sectional. PARTICIPANTS: One hundred and sixty-three institutionalized elderly with dementia or psychosis (66.9% female), mean age 80.9 +/- 9.1 years. MEASUREMENTS: The NPI-NH includes 12 neuropsychiatric symptoms and a distress scale. The product score of frequency (F) and severity (S) ratings provides an overall score for each of the 12 items. An exploratory principal component analysis with Varimax rotation was performed on the F x S scores according to patients' diagnosis. RESULTS: High internal consistency of the NPI-NH was found (alpha = 0.8). In demented patients a 4-factor solution was found that explained 63.9% of the variance, with the syndromes: (a) 'hyperactivity'; (b) 'affective'; (c) 'psychosis'; and (d) 'Hallucinations'. A four-factor solution was also found in psychotic patients, explaining 61.3% of variance, with syndromes: (a) 'affective'; (b) 'frontal lobe symptoms'; (c) 'sundowning'; and (d) 'psychomotor agitation'. A syndrome was unlikely to appear alone but was most likely to occur with other syndromes. A specific pattern of syndrome co-occurrence were found in demented (a + b + c in 30.5% of cases) and psychotic patients (a + b + c + d in 35.2% of cases). CONCLUSION: The syndrome taxonomies are consistent with the diagnostic criteria. The clinical use of syndrome co-occurrence could help to further understand and evaluate behavioral changes in pharmacological and non-pharmacological treatments.

Cognitive and imaging markers in non-demented subjects attending a memory clinic: study design and baseline findings of the MEMENTO cohort.

BACKGROUND: The natural history and disease mechanisms of Alzheimer's disease and related disorders (ADRD) are still poorly understood. Very few resources are available to scrutinise patients as early as needed and to use integrative approaches combining standardised, repeated clinical investigations and cutting-edge biomarker measurements. METHODS: In the nationwide French MEMENTO cohort study, participants were recruited in memory clinics and screened for either isolated subjective cognitive complaints (SCCs) or mild cognitive impairment (MCI; defined as test performance 1.5 SD below age, sex and education-level norms) while not demented (Clinical Dementia Rating [CDR] <1). Baseline data collection included neurological and physical examinations as well as extensive neuropsychological testing. To be included in the MEMENTO cohort, participants had to agree to undergo both brain magnetic resonance imaging (MRI) and blood sampling. Cerebral 18F-fluorodeoxyglucose positon emission tomography and lumbar puncture were optional. Automated analyses of cerebral MRI included assessments of volumes of whole-brain, hippocampal and white matter lesions. RESULTS: The 2323 participants, recruited from April 2011 to June 2014, were aged 71 years, on average (SD 8.7), and 62% were women. CDR was 0 in 40% of participants, and 30% carried at least one apolipoprotein E ε4 allele. We observed that more than half (52%) of participants had amnestic mild cognitive impairment (17% single-domain aMCI), 32% had non-amnestic mild cognitive impairment (16.9% single-domain naMCI) and 16% had isolated SCCs. Multivariable analyses of neuroimaging markers associations with cognitive categories showed that participants with aMCI had worse levels of imaging biomarkers than the others, whereas participants with naMCI had markers at intermediate levels between SCC and aMCI. The burden of white matter lesions tended to be larger in participants with aMCI. Independently of CDR, all neuroimaging and neuropsychological markers worsened with age, whereas differences were not consistent according to sex. CONCLUSIONS: MEMENTO is a large cohort with extensive clinical, neuropsychological and neuroimaging data and represents a platform for studying the natural history of ADRD in a large group of participants with different subtypes of MCI (amnestic or not amnestic) or isolated SCCs. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01926249 . Registered on 16 August 2013.

Delirium symptoms and low dietary intake in older inpatients are independent predictors of institutionalization: a 1-year prospective population-based study.

OBJECTIVE: To assess the effects of delirium on the institutionalization rate, taking into account geriatric syndromes and nutritional status. METHODS: This population-based study took place in an acute care unit and included participants older than 75 years, arriving from home and later discharged. Confusion Assessment Method (CAM) symptoms were recorded by the nurses within 24 hours after admission and every 3 days. Delirium was defined using the CAM algorithm, and subsyndromal delirium responded to symptoms not fulfilling the CAM algorithm. These delirium categories were either present at admission (prevalent) or occurred during the hospital stay (incident). Participants were classified as having a low dietary intake when energy intake was at any time lower than 600 kcal/d. Age, sex, known cognitive impairment, weight, functional dependency, and laboratory testing as well as diagnoses were also recorded. Step-by-step backward logistic regression was used to identify predictors of institutionalization. RESULTS: Among 427 patients, 310 (72.6%) were discharged and were compared with 117 (27.4%) participants admitted to an institution. Female sex (odds ratio [OR]: OR 2.15, 95% confidence interval [CI]: CI 1.22-3.78), prevalent delirium (OR 3.19, 95% CI 1.33-7.64), subsyndromal delirium (OR 2.72, 95% CI 1.48-5.01), incident subsyndromal delirium (OR 4.27, 95% CI 2.17-8.39), low dietary intake (OR 2.50, 95% CI 1.35-4.63), and a fall (OR 2.16, 95% CI 1.22-3.84) or a diagnosis of stroke (OR 2.03, 95% CI 1.04-3.94) were independent predictors of institutionalization. CONCLUSIONS: Symptoms of delirium and severe nutritional impairment led patients to geriatric institutions. Therefore, these institutions need to implement policies that address both of these issues.

[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.

Seizures in the elderly: development and validation of a diagnostic algorithm.

Seizures are frequent in the elderly, but their diagnosis can be challenging. The objective of this work was to develop and validate an expert-based algorithm for the diagnosis of seizures in elderly people. A multidisciplinary group of neurologists and geriatricians developed a diagnostic algorithm using a combination of selected clinical, electroencephalographical and radiological criteria. The algorithm was validated by multicentre retrospective analysis of data of patients referred for specific symptoms and classified by the experts as epileptic patients or not. The algorithm was applied to all the patients, and the diagnosis provided by the algorithm was compared to the clinical diagnosis of the experts. Twenty-nine clinical, electroencephalographical and radiological criteria were selected for the algorithm. According to criteria combination, seizures were classified in four levels of diagnosis: certain, highly probable, possible or improbable. To validate the algorithm, the medical records of 269 elderly patients were analyzed (138 with epileptic seizures, 131 with non-epileptic manifestations). Patients were mainly referred for a transient focal deficit (40%), confusion (38%), unconsciousness (27%). The algorithm best classified certain and probable seizures versus possible and improbable seizures, with 86.2% sensitivity and 67.2% specificity. Using logistical regression, 2 simplified models were developed, the first with 13 criteria (Se 85.5%, Sp 90.1%), and the second with 7 criteria only (Se 84.8%, Sp 88.6%). In conclusion, the present study validated the use of a revised diagnostic algorithm to help diagnosis epileptic seizures in the elderly. A prospective study is planned to further validate this algorithm.

Infrared spectroscopy: a reagent-free method to distinguish Alzheimer's disease patients from normal-aging subjects.

The physiopathogenesis of Alzheimer's disease (AD) is related to various biochemical mechanisms that may be reflected by changes in plasma components. In the current study, Fourier transform-infrared (FT-IR) spectroscopy was used to identify these biochemical variations by monitoring spectral differences in the plasma of 40 AD patients compared with those of 112 control subjects. A hierarchical classification in the whole mid-infrared region allowed a clear separation between AD and controls (C) that was optimized by using a restricted spectral range (1480-1428 cm(-1)). Spectral changes confirmed vibration differences between AD and C mostly related to modified lipid and nucleic acid structures involved in oxidative stress-dependent processes of AD. Moreover, the analysis of samples in the 1480-910-cm(-1) region allowed the distinction between C and AD with an accuracy of 98.4% and showed 2 subgroups C(1) and C(2) within the C group. Interestingly, the C(1) subgroup was located closer to the AD group than the C(2) subgroup, which suggests biochemical differences within the nondemented subjects. Biochemical studies revealed a significant increase in a specific marker of oxidative stress, F8-isoprostanes (8-epi-PGF2alpha) levels, in the plasma of AD patients as compared with total controls and subgroup C(2) but not subgroup C(1). Thus, these results suggest that use of FT-IR spectroscopy could be valuable to distinguish AD patients from normal-aging subjects.

A longitudinal study of quantitative and qualitative features of category verbal fluency in incident Alzheimer's disease subjects: results from the PAQUID study.

Category fluency tests were administered at baseline and after 3 and 5 years on two subgroups of subjects from a population-based cohort of elderly subjects: 52 cases of incident possible and probable Alzheimer's disease (AD) and 104 age- and education-matched subjects who remained nondemented. Quantitative and qualitative features of category fluency were assessed to determine how changes occur within 5 years of the diagnosis of AD. Consistent with previous results, we found that the number of words produced on this task was already significantly lower 5 years before the diagnosis in subjects with incident AD as compared with subjects who did not become demented. However, the rate of repetitions only significantly increased in AD subjects at the time of diagnosis, and the rate of intrusions remained low and not significantly different between the two groups. Thus, it is concluded that dysfunction in cognitive processes underlying repetitions and intrusions in verbal fluency tasks, such as inhibitory processes and working memory, may not be the main cause of the very early deficit in verbal fluency occurring in AD.

[Comprehensive geriatric assessment: a useful tool for prevention of acute situations in the elderly]. / L'évaluation gérontologique: un outil de prévention des situations à risque chez les personnes âgées.

Comprehensive geriatric assessment is a useful complement to the standard clinical examination of elderly people. It focuses on a systematic evaluation of functional status, dependency, cognitive functions, psychological status, continence, nutritional status and social way of life, administered by a multidisciplinary team. Standardized test, well-validated in the elderly, are used. Most studies have demonstrated the efficacy of geriatric assessment programs in outpatients, hospitalized patients or in emergency unit patients. Mostly useful in frail elderly patients, geriatric assessment results in a decrease in morbidity and dependency, shorter hospital stays and fewer referrals to nursing homes. By introducing adequate medical and social interventions, comprehensive geriatric assessment, even in very old people, is useful in preventing acute situations leading to emergency referrals.

One-year incidence of hyperosmolar states and prognosis in a geriatric acute care unit.

BACKGROUND: Hyperosmolar syndromes are associated with high mortality rates, yet little is known about their incidence and their prognosis. OBJECTIVE: To determine the 1-year incidence of hyperosmolar states and the prognostic factors for in-hospital and 1-year mortality. METHOD: A 6-month prospective cohort study was conducted in a 40-bed acute care geriatric unit and included all patients who developed plasma osmolarity of 320 mosm/l or greater. Age, sex and known cognitive impairment as possible risk factors of hyperosmolarity were assessed. In-hospital and 1-year mortality were calculated and risk factors for death among baseline patient characteristics were sought. RESULTS: 48 (11) of the 436 inpatients in the study were identified as hyperosmolar. Diabetic hyperosmolarity was found in 8 patients. Cognitive impairment was a risk factor for hyperosmolarity (relative risk 2.39, 95% confidence interval 2.18-3.33, p < 0.001), but not age or sex. Infections were accompanied by hyperosmolarity in 30 (62.5). Thirty-five patients (72.9) were bed- or chair-ridden. In-hospital mortality was higher in hyperosmolar patients (35.4) than in the others (16.7%, p = 0.003). Causes of death were infection in 5 (29.4), terminal cachexia in 5, thrombosis in 3, gastric bleeding in 1, renal failure in 2 and heart failure in 1. Functional dependency for mobility was a risk factor for in-hospital mortality but not the degree of hyperosmolarity. One-year mortality was 68.7%. Functional dependency and pressure ulcers were independent predictors of 1-year mortality (p = 0.005 and p = 0.044, respectively). CONCLUSION: Hyperosmolar states occurred in cognitively impaired and dependent patients and resulted in high mortality rates at short and at mid-term. Mortality was related to functional dependency rather than to hyperosmolarity.