Validation in French of the Montreal Cognitive Assessment 5-Minute, a brief cognitive screening test for phone administration.

BACKGROUND: The prevalence of cognitive impairment and dementia is high and steadily increasing. Early detection of cognitive decline is crucial since some interventions can reduce the risk of progression to dementia. However, there is a lack of manageable scales for assessing cognitive functions outside specialized consultations. Recently, the MoCA-5min, a short version of the Montreal Cognitive assessment (MoCA), phone-administered, was validated for screening for vascular cognitive impairment. The aim of the present study was to validate the MoCA-5min in French in diverse clinical populations. METHODS: The Cantonese version of the MoCA-5min was adapted for French language. Healthy volunteers and patients with possible or established cognitive impairment (Alzheimer's disease or related disorders, Parkinson's disease, Huntington's disease, type-2 diabetes) participated in the study. The original MoCA and the MoCA-5min were administered, by phone, with a 30-day interval. Alternate forms were used to reduce learning effects. RESULTS: The scores of the original MoCA and MoCA-5min correlated significantly (Spearman rho=0.751, P<0.0001, 95% confidence interval 0.657 to 0.819). Internal consistency was good (Cronbach alpha=0.795). The area under the ROC curve was 0.870 and the optimal cut-off value for separating patients with and without cognitive impairment with the MoCA-5min was≤27 with 87.32% sensitivity and 76.09% specificity. Interrater and test-retest reliability were adequate. CONCLUSION: This study demonstrates that the French version of the MoCA-5min is a valid and reliable scale for detecting cognitive impairment in different clinical populations. It is administrable by phone and thus suitable for remote assessment as well as for large-scale screening and epidemiological studies.

[Supervised off-label prescribing of methylphenidate in adult ADHD]. / Prescriptions hors AMM supervisées de méthylphénidate dans le TDAH de l'adulte.

OBJECTIVE: Off-label prescription is a common practice in psychiatry, raising health and economic concerns. Collegial consultation could allow a framed prescription of treatments that are not authorized in specific indications. Attention Deficit Hyperactivity in adult populations (ADHD) is a striking example of a pathology where off-label prescription is frequent. First considered to be a childhood disorder, the awareness of this condition in adults is increasing, leading to the development of new clinical practices and treatments. However, the adult ADHD diagnosis and its management are still emerging in France despite a high prevalence. Treatment of adult ADHD relies on methylphenidate prescription, but the initiation of this drug is not authorized in adult populations. Methylphenidate is a central nervous system stimulant that is structurally close to amphetamine and acts as a norepinephrine and dopamine reuptake inhibitor. Due to these pharmacological properties, neuropsychiatric and cardiovascular side-effects could occur. Furthermore, its addictive potential has led France to classify it as a psychoactive drug, dispensed via secured prescription. The first prescription and the one-year follow-up are restricted to neurologists, paediatrics, psychiatrists and sleep disorders specialists at hospital. The objective of this article is to propose a multidisciplinary framework for the off-label prescription of methylphenidate in adult ADHD. METHODS: The Multidisciplinary Advice Consultation for Exceptional Addiction Treatments (Consultation d'Avis Multidisciplinaire de Traitements d'Exception en Addictologie CAMTEA) was first set up in Lille for the prescription of baclofen in alcohol dependence and was then extended to topiramate in binge eating disorder. This procedure has been adapted to the particularities of ADHD in adult populations, the differential diagnosis (bipolar disorder, depressive disorder, anxious disorder, personality disorder, substance use disorder) and the co-morbidities requiring a full psychiatric and neuropsychological assessment. Moreover, a particular attention has been paid to the monitoring of neuropsychiatric, cardiovascular and misuse risk because of the potential side-effects of methylphenidate. RESULTS: The proposed prescription framework is structured into several specialized consultations. A first psychiatric evaluation aims to diagnose adult ADHD, using the French version of the Diagnostisch Interview Voor ADHD 2.0 questionnaire (DIVA 2.0), and to assess the quality of life impact with the Weiss Functional Inventory Rating Scale (WIFRS). It also searches for the presence of differential diagnosis or co-morbidities. The second appointment consists of a pharmacological evaluation that aims to search for contraindications and potential drug interaction. A neuropsychological evaluation based on standardized tests (Weschler Adulte Intelligence Scale [WAIS IV], Conner's Continuous Performance Test 3 [CPT] and the Minnesota Multiphasic Personnality Inventory [MMPI]) is also required to evaluate neurocognitive disabilities and personality features. Once the parameters of the different assessments have been collected, the synthesis is presented during a multidisciplinary meeting in order to assess the risk-benefit ratio for each patient. Several specialties are involved in this multidisciplinary meeting: psychiatry, addictology, general medicine, addictovigilance, pharmacovigilance and neuropsychology. One strategy among three possibilities can be decided: (1) contraindication to treatment with methylphenidate, (2) attention deficit disorder that does not require medication management, and (3) indication of treatment with methylphenidate with the choice of the pharmacological form (immediate or prolonged release). A biological check-up and an electrocardiogram are carried out systematically before any treatment. If the decision is made to initiate treatment, it is started at the lowest dosage and followed by a titration phase. A weekly follow-up is carried out during the titration phase in order to assess treatment efficacy and safety. After treatment stabilization, the general practitioner can carry out the renewal, and the patient will be reassessed within the framework of the multidisciplinary consultation every 3 months. CONCLUSION: When an off-label prescription is being considered, it must comply with the basic rules of good clinical practice, and the benefit/risk ratio should be constantly reassessed. The proposed multidisciplinary framework, adapted to the characteristics of adult ADHD and the pharmacological properties of methylphenidate, appears to be an interesting strategy to meet the requirements of the good clinical practice. The complementary assessments carried out and the collegial framework allow enhancing the patient's follow-up and minimize the drug risk, particularly in the psychiatric, addictive and cardiovascular adverse events. Finally, this framework could also help the monitoring of other off-label treatments for ADHD, such as atomoxetine or guanfacine.

Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson's disease?

In Parkinson's disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia.

Are the results of intravenous thrombolysis trials reproduced in clinical practice? Comparison of observed and expected outcomes with the stroke-thrombolytic predictive instrument (STPI).

AIM: In patients with cerebral ischemia, intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) increases survival without handicap or dependency despite an increased risk of bleeding. This study evaluated whether the results of randomized controlled trials are reproduced in clinical practice. METHOD: Data from a registry of consecutive patients treated by rt-PA at Lille University Hospital were retrospectively analyzed for outcomes, using modified Rankin Scale (mRS) scores, at 3 months. The observed outcomes were then compared with the probability of good (mRS 0-1) and of catastrophic (mRS 5-6) outcomes, as predicted by the stroke-thrombolytic predictive instrument (STPI). RESULTS: Of the 1000 consecutive patients (469 male, median age 74 years, median baseline National Institutes of Health Stroke Scale 11, median onset-to-needle time 143min), 438 (43.8%) had a good outcome, 565 (56.5%) had an mRS score 0-2 or similar to their pre-stroke mRS, 155 (15.5%) died within 3 months and 74 (7.4%) developed symptomatic intracerebral hemorrhage according to ECASS-II (Second European-Australasian Acute Stroke Study) criteria. Of the 613 patients (61.3%) eligible for evaluation by the s-TPI, the observed rate of good outcomes was 41.3% (95% CI: 37.5-45.3%), while expected rates with and without rt-PA were 48.8% (95% CI: 44.8-52.7%) and 32.5% (95% CI: 28.8-36.2%), respectively; the observed rate of catastrophic outcomes was 17.0% (95% CI: 14.0-19.9%), while the expected rate was 19.2% (95% CI: 16.1-22.4%) with or without rt-PA. CONCLUSION: In clinical practice, the rate of good outcomes is slightly lower than expected, according to the s-TPI, except for the most severe cases, whereas the rate of catastrophic outcomes is roughly similar. However, the rate of good outcomes is higher than predicted without treatment. This finding suggests that rt-PA is effective for improving outcomes in clinical practice.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Blood biomarkers in the early stage of cerebral ischemia.

In ischemic stroke patients, blood-based biomarkers may be applied for the diagnosis of ischemic origin and subtype, prediction of outcomes and targeted treatment in selected patients. Knowledge of the pathophysiology of cerebral ischemia has led to the evaluation of proteins, neurotransmitters, nucleic acids and lipids as potential biomarkers. The present report focuses on the role of blood-based biomarkers in the early stage of ischemic stroke-within 72h of its onset-as gleaned from studies published in English in such patients. Despite growing interest in their potential role in clinical practice, the application of biomarkers for the management of cerebral ischemia is not currently recommended by guidelines. However, there are some promising clinical biomarkers, as well as the N-methyl-d-aspartate (NMDA) peptide and NMDA-receptor (R) autoantibodies that appear to identify the ischemic nature of stroke, and the glial fibrillary acidic protein (GFAP) that might be able to discriminate between acute ischemic and hemorrhagic strokes. Moreover, genomics and proteomics allow the characterization of differences in gene expression, and protein and metabolite production, in ischemic stroke patients compared with controls and, thus, may help to identify novel markers with sufficient sensitivity and specificity. Additional studies to validate promising biomarkers and to identify novel biomarkers are needed.

Transcranial magnetic stimulation and aging: Effects on spatial learning and memory after sleep deprivation in Octodon degus.

The benefits of neuromodulatory procedures as a possible therapeutic application for cognitive rehabilitation have increased with the progress made in non-invasive modes of brain stimulation in aged-related disorders. Transcranial magnetic stimulation (TMS) is a non-invasive method used to examine multiple facets of the human brain and to ameliorate the impairment in cognition caused by Alzheimer's disease (AD). The present study was designed to evaluate how a chronic TMS treatment could improve learning and memory functions after sleep deprivation (SD) in old Octodon degus. SD was executed by gently handling to keep the animals awake throughout the night. Thirty young and twenty-four old O. degus females were divided in six groups (control, acute and chronic TMS treatment). Behavioral tests included; Radial Arm Maze (RAM), Barnes Maze (BM) and Novel Object Recognition (NOR). Although learning and memory functions improved in young animals with only one session of TMS treatment, a significant improvement in cognitive performance was seen in old animals after 4 and 7days of TMS, depending on the task that was performed. No side effects were observed following, which showed therapeutic potential for improving age-related cognitive performance.

[What criteria for an ideal antipsychotic treatment?]. / Quels critères pour un traitement antipsychotique idéal ?

Antipsychotics are, by definition, drugs to treat all symptomatic dimensions of schizophrenia, even if, following the discovery of chlorpromazine, the effect assessment has been focused on the ability to reduce positive symptoms. Nevertheless, expectations of treatment are no longer limited to only support this one dimension, but integrate the need to treat negative, cognitive and affective symptoms, through long-term modulation of dopamine transmission but also non-dopaminergic pathways. Beyond symptomatic treatment, it is also necessary to have a treatment modifying the evolution course of the disease (disease modifier), acting by a long-term effect on neuropathological and neurochemical abnormalities. The limitation of long-term effect remains the issue of therapeutic observance. Moreover, this concern for efficiency should be at the cost of reduced induction of adverse effects to maximize the benefit/risk ratio. All these dimensions should the components to profile an ideal antipsychotic treatment in 2015.

Iron deposits in post-mortem brains of patients with neurodegenerative and cerebrovascular diseases: a semi-quantitative 7.0 T magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Accumulation of iron (Fe) is often detected in brains of people suffering from neurodegenerative diseases. However, no studies have compared the Fe load between these disease entities. The present study investigates by T2*-weighted gradient-echo 7.0 T magnetic resonance imaging (MRI) the Fe content in post-mortem brains with different neurodegenerative and cerebrovascular diseases. METHODS: One hundred and fifty-two post-mortem brains, composed of 46 with Alzheimer's disease (AD), 37 with frontotemporal lobar degeneration (FTLD), 11 with amyotrophic lateral sclerosis, 13 with Lewy body disease, 14 with progressive supranuclear palsy, 16 with vascular dementia (VaD) and 15 controls without a brain disease, were examined. The Fe load was determined semi-quantitatively on T2*-weighted MRI serial brain sections in the claustrum, caudate nucleus, putamen, globus pallidus, thalamus, subthalamic nucleus, hippocampus, mamillary body, lateral geniculate body, red nucleus, substantia nigra and dentate nucleus. The disease diagnosis was made on subsequent neuropathological examination. RESULTS: The Fe load was significantly increased in the claustrum, caudate nucleus and putamen of FTLD brains and to a lesser degree in the globus pallidus, thalamus and subthalamic nucleus. In the other neurodegenerative diseases no Fe accumulation was observed, except for a mild increase in the caudate nucleus of AD brains. In VaD brains no Fe increase was detected. CONCLUSIONS: Only FTLD displays a significant Fe load, suggesting that impaired Fe homeostasis plays an important role in the pathogenesis of this heterogeneous disease entity.

Influence of cognitive impairment on the management of ischaemic stroke.

BACKGROUND: Because of ageing of the population, it is more and more frequent to treat ischaemic stroke patients with pre-stroke cognitive impairment (PSCI). Currently, there is no specific recommendation on ischaemic stroke management in these patients, both at the acute stage and in secondary prevention. However, these patients are less likely to receive treatments proven effective in randomised controlled trials, even in the absence of contra-indication. OBJECTIVE: To review the literature to assess efficacy and safety of validated therapies for acute ischaemic stroke and secondary prevention in PSCI patients. RESULTS: Most randomised trials did not take into account the pre-stroke cognitive status. The few observational studies conducted at the acute stage or in secondary prevention, did not provide any information that the benefit could be either lost or replaced by harm in the presence of PSCI. CONCLUSIONS: There is no reason not to treat ischaemic stroke patients with PSCI according to the currently available recommendations for acute management and secondary prevention. Further observational studies are needed and pre-stroke cognition should be taken into account in future stroke trials.

[Involvement of pharmacists in systems for supervising off-label medications: example of the CAMTEA system for the prescription of baclofen in alcohol use disorder in Northern France]. / CAMTEA, un dispositif original de prescription encadrée hors-AMM de baclofène dans le Nord-Pas-de-Calais : quels rôles pour le pharmacien ?

Off-label prescribing matches the using of medications outside the summary of product characteristics. Adverse drug reactions are often poorly studied in off-label situations, which may expose patients to additional safety risks, and impose taking specific precautions. The current off-label prescribing practice of baclofen for alcohol-dependence in France is a typical illustration of such a situation. CAMTEA is a regional system set up in 2010 in Northern France, which gathers addiction and pharmacovigilance specialists, and aims at strengthening the prescription supervising and the monitoring of some off-label medication used for addictive disorders, especially baclofen. Until now, institution or office-based pharmacists have not been implicated, whereas they engaged their liability when delivering off-labeled treatment and they may highly contribute to the patient monitoring and the spotting of adverse events. We propose hereby possible measures for involving pharmacists into the patient supervising system developed within CAMTEA. In the current French context concerning the off-label use of baclofen, which will be the first off-label prescribing practice to be framed by a new legal disposition called "temporary use recommendation", the key role of pharmacists should be highlighted.

The acute inhibition of rapid eye movement sleep by citalopram may impair spatial learning and passive avoidance in mice.

Rapid eye movement (REM) sleep is known to be essential for memory. Hence, REM sleep deprivation impairs memory processes. The frequently prescribed selective serotonin reuptake inhibitors (SSRIs) are known to cause REM sleep deprivation and to impair cognitive performance in humans and rodents. We suggested that impaired memory processes by citalopram in C57/BL6 mice could be explained by the acute inhibition of REM sleep. We hypothesized that those acute citalopram 5 and 10 mg/kg injections induced REM sleep deprivation, altered cognitive performance in passive avoidance, impaired spatial memory compared to controls. Three experiments have been realized: (1) mice received successively physiological saline, injection of citalopram 5 and 10 mg/kg and were recorded by polysomnographic recording after each injection. (2) Cognitive performance was evaluated in the passive avoidance with two groups of mice. One group received citalopram before training and one, after training. (3) Spatial learning was evaluated with another group of animals in the Y-maze test. At 5 and 10 mg/kg, citalopram delayed REM sleep onset and decreased REM sleep amounts (vs. controls). The same doses were administrated in the passive avoidance test and have significantly shortened latency to enter the dark compartment. In the Y-maze, citalopram-treated mice showed a decreased percentage of time spent in the novel arm in contrast to the two other arms compared with controls. We showed that citalopram impaired cognitive performance in behavioral tasks. Those impairments could be linked to REM sleep deprivation induced by citalopram although causal relationship needs to be investigated in further studies.

Superficial siderosis of the central nervous system: a post-mortem 7.0-tesla magnetic resonance imaging study with neuropathological correlates.

BACKGROUND: Superficial siderosis (SS) is a rare finding on T2*-weighted magnetic resonance imaging (MRI), regarded as a radiological marker of cerebral amyloid angiopathy (CAA). The present study investigates with 7.0-tesla MRI the prevalence of SS and its underlying pathological substrate in a consecutive series of post-mortem brains of elderly patients with various neurodegenerative and cerebrovascular lesions. MATERIALS AND METHODS: The prevalence of SS and associated lesions was screened using 7.0-tesla MRI and their neuropathological correlates in 120 post-mortem brains of patients with various neurodegenerative and cerebrovascular diseases. RESULTS: Eighty-three separate zones of SS were detected in 45 brains (37.5%), including 25 areas of disseminated SS (dSS) and 58 areas of focal SS (fSS), restricted to less than 3 sulci. dSS was spatially related to sequels of 14 lobar haematomas and 11 cerebral infarcts, while fSS was connected to 19 microbleeds and 39 micro-infarcts (p < 0.001). Comparison of the 15 CAA to the 30 non-CAA brains showed that dSS was due to an old lobar haematoma in 53% of the former group compared to 3% of the latter group (p = 0.003). fSS was due to a microbleed in 7% of the CAA brains and to 40% of the non-CAA brains (p = 0.03). CONCLUSIONS: SS is associated with both haemorrhagic and ischaemic underlying lesions. It is frequently observed on T2*-weighted 7.0-tesla MRI, and two types of SS may be described. Clinicians should keep in mind that SS may be found in other settings than CAA.

Evaluation of symptomatic drug effects in Alzheimer's disease: strategies for prediction of efficacy in humans.

In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.

Differential susceptibility to the PPAR-γ agonist pioglitazone in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine rodent models of Parkinson's disease.

A growing body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists are valuable candidates as disease modifiers in Parkinson's disease (PD) and may thus enable neuroprotection and preserve motor function. The present study sought to evaluate the effect of the PPAR-gamma agonist pioglitazone in two different animal models of PD. The study was based on nigral dopaminergic neuron labelling and the assessment of motor behaviour in (i) the frequently investigated MPTP mouse model and (ii) the less well-known bilateral 6-OHDA rat model. In MPTP-injected mice, pioglitazone reversed body weight loss and the reduction in rearing frequency and induced significant neuroprotection of the nigrostriatal dopaminergic pathway (by 24%, compared with vehicle). In contrast, pioglitazone did not have any effect on the 73.5% loss of dopaminergic neurons or motor impairments (a reduced rearing frequency and a loss of strength in the forepaws) in bilateral 6-OHDA rats. The PPAR-gamma agonist pioglitazone had a significant neuroprotective effect in MPTP mice but not in bilateral 6-OHDA rats. The various effects of PPAR agonists in both models can be accounted by the different action mechanism of the 2 toxins or by the fact that 3µg 6-OHDA injection was too harmful to be alleviated by the compound. This work supports PPAR-agonists to be relevant in the therapeutic strategy research in Parkinson's disease and highlights the importance in evaluating neuroprotective agent in different models.

Detection of microbleeds in post-mortem brains of patients with frontotemporal lobar degeneration: a 7.0-Tesla magnetic resonance imaging study with neuropathological correlates.

BACKGROUND: Microbleeds (MBs) are frequently detected in brains of patients with Alzheimer dementia and rare in those with frontotemporal lobar degeneration (FTLD). This study investigates for the first time the topographic distribution of MBs on a T2*-weighted gradient-echo 7.0-T magnetic resonance imaging (MRI) in post-mortem FTLD brains. PATIENTS AND METHODS: The neuropathological and MRI findings in 12 FTLD brains were compared with eight age-matched controls. The presence of cerebrovascular lesions was evaluated on a coronal section of a cerebral hemisphere at the level of the mamillary body and on a horizontal section through pons and cerebellum. On MRI, the distribution and the number of cortical focal signal intensity losses, representing MBs, were assessed on coronal sections at the frontal, the central and the occipital level of a cerebral hemisphere. RESULTS: Overall, cerebrovascular lesions were rare. Only white matter damage was significantly more severe in FTLD brains compared with controls (P = 0.03). On MRI, MBs were only significantly prevalent in the deep cortical layers (P < 0.01) and borderline increased in the middle cortical layers (P = 0.07) of the frontal section. CONCLUSIONS: Cerebrovascular lesions are rare in FTLD. The white matter damage has to be considered as part of the neurodegenerative process. MBs prevail in the frontal regions with the most severe neuronal damage and probably represent associated disruption of the blood-brain barrier.

Comparison of 7.0-T T2*-magnetic resonance imaging of cerebral bleeds in post-mortem brain sections of Alzheimer patients with their neuropathological correlates.

BACKGROUND: In view of the increasing recognition of cerebral microbleeds (MCBs) with MRI, there is a need to validate their detection in post-mortem brains in patients with cerebrovascular diseases and dementia. MATERIALS AND METHODS: Out of 20 post-mortem brains of patients with Alzheimer dementia and with different cerebrovascular lesions, 45 large sections of the cerebral hemispheres, brainstem and cerebellum were submitted to a 7.0-T T2*-weighted MRI, and afterwards compared to the histological detection of haematomas, MCBs and mini-bleeds (MNBs). RESULTS: The sensitivity, specificity, predictive positive value and predictive negative value of the T2* imaging to detect MCBs and MNBs were excellent for those in the cortico-subcortical regions. There was a significant overestimation of MNBs in the striatum due to iron deposits unrelated to old haemorrhages. Also in the deep white matter, 42% of MNBs were not detected, while 31% of T2* hyposignals were not due to MNBs but to vessels filled with post-mortem thrombi. CONCLUSIONS: When evaluating the 'bleeding load' with 7.0-T T2*-weighted MRI in post-mortem brain sections of patients with dementia and vascular risk factors, only quantification of small cerebral bleeds in the cortico-subcortical regions is reliable.

Functional connectivity and cognitive changes after donepezil treatment in healthy participants.

RATIONALE: Donepezil is a potent, noncompetitive, reversible, clinically effective acetylcholinesterase inhibitor. The effects of this drug on healthy brains have seldom been investigated. OBJECTIVES: The primary objective of the present study was to identify possible functional connectivity markers of the effect of donepezil in healthy young adult volunteers. METHODS: The study had a double-blind, randomized, crossover design. 30 healthy adult volunteers underwent resting-state MRI scans during 15 days of donepezil or placebo treatment, in accordance with the design. RESULTS: Results showed significant differences in intrinsic functional connectivity between donepezil and placebo, mainly in the right executive control network (RECN). More specifically, we found a decrease in the connectivity of the right inferior parietal node with other RECN nodes. Analysis using the cingulate cortex and parahippocampal regions as seeds also revealed complex modulation of functional connectivity in the donepezil condition. CONCLUSIONS: In conclusion, donepezil treatment for 15 days may result in reorganization of resting-state networks, compared with placebo.

Sevoflurane pre- and post-conditioning protect the brain via the mitochondrial K ATP channel.

BACKGROUND: This study aimed to evaluate whether exposure to sevoflurane at the onset of reperfusion provides protection similar to sevoflurane preconditioning and whether the effect depends on mitochondrial potassium ATP-dependent channel (mitoK(ATP)) in a rat model of focal cerebral ischaemia. METHODS: Adult Wistar male rats were subjected to focal cerebral ischaemia for 1 h followed by 24 h or 7 days of reperfusion. Preconditioning consisted of 15 min exposure to sevoflurane at 1 minimum alveolar concentration (2.6%) 72 h before ischaemia. Post-conditioning was performed by exposure to sevoflurane immediately at the onset of reperfusion or by a delayed exposure 5 min after the onset of reperfusion. The role of the mitoK(ATP) channel was assessed by i.p. injection of the selective blocker 5-hydroxydecanoate before each sevoflurane administration or by the mitoK(ATP) channel opener, diazoxide (DZX), given in place of sevoflurane. Cerebral infarct size, neurological deficit score, and motor coordination were evaluated 24 h and 7 days after reperfusion. RESULTS: Sevoflurane preconditioning and early post-conditioning reduced both cerebral infarct size and neurological defect score at 24 h of reperfusion whereas the sole sevoflurane post-conditioning improved motor coordination. At 7 days, only infarct volume remained lower in pre- and post-conditioned animals. Neuroprotection mediated by sevoflurane was lost when it was given 5 min after the onset of reperfusion and was abolished by inhibition of mitoK(ATP). DZX alone mimicked sevoflurane-induced pre- and post-conditioning. CONCLUSIONS: The pretreatment with sevoflurane or its early administration at reperfusion provides neuroprotection via mitoK(ATP) in a rat model of focal cerebral ischaemia.