Alterations in resting-state network dynamics along the Alzheimer's disease continuum.

Human brain activity is intrinsically organized into resting-state networks (RSNs) that transiently activate or deactivate at the sub-second timescale. Few neuroimaging studies have addressed how Alzheimer's disease (AD) affects these fast temporal brain dynamics, and how they relate to the cognitive, structural and metabolic abnormalities characterizing AD. We aimed at closing this gap by investigating both brain structure and function using magnetoencephalography (MEG) and hybrid positron emission tomography-magnetic resonance (PET/MR) in 10 healthy elders, 10 patients with subjective cognitive decline (SCD), 10 patients with amnestic mild cognitive impairment (aMCI) and 10 patients with typical Alzheimer's disease with dementia (AD). The fast activation/deactivation state dynamics of RSNs were assessed using hidden Markov modeling (HMM) of power envelope fluctuations at rest measured with MEG. Correlations were sought between temporal properties of HMM states and participants' cognitive test scores, whole hippocampal grey matter volume and regional brain glucose metabolism. The posterior default-mode network (DMN) was less often activated and for shorter durations in AD patients than matched healthy elders. No significant difference was found in patients with SCD or aMCI. The time spent by participants in the activated posterior DMN state did not correlate significantly with cognitive scores, nor with the whole hippocampal volume. However, it correlated positively with the regional glucose consumption in the right dorsolateral prefrontal cortex (DLPFC). AD patients present alterations of posterior DMN power activation dynamics at rest that identify an additional electrophysiological correlate of AD-related synaptic and neural dysfunction. The right DLPFC may play a causal role in the activation of the posterior DMN, possibly linked to the occurrence of mind wandering episodes. As such, these data might suggest a neural correlate of the decrease in mind wandering episodes reported in pathological aging.

[An update on treatment of dementia and Alzheimer's diseases?] / Actualisation des traitements des démences et de la maladie d'Alzheimer.

Major and minor neurocognitive disorders are common and increase with age. In the 70s, similarities between " senile " and " presenile " dementia led to their homogenization in a unique illness, the Alzheimer's disease. Systematic specific psychosocial support of patients and caregivers is crucial and allows to discuss an advance care plan. We propose such a multidisciplinary program and discuss some of them. Various drugs and a variety of possible physiopathogenic targets are actually studied and should in the near future offer new therapeutics in dementia and Alzheimer's disease.

Les troubles neurocognitifs sont fréquents et augmentent avec l'âge. Dans les années 70, la similarité entre démences dites " séniles " et " préséniles " mena à leur homogénéisation en une maladie unique, la " maladie " ou " démence d'Alzheimer ". Un soutien psychosocial du patient et de ses proches sera toujours indispensable. Il s'accompagne et s'assimile de fait à une planification anticipée de soins en même temps qu'une actualisation de la prise en charge. Avec AREMIS et Alzheimer Belgique, l'hôpital Erasme propose un tel programme de soin mul tidisciplinaire aux patients présentant un syndrome démentiel. De très nombreuses molécules aux modes d'actions variées sont actuellement à l'étude et devraient ainsi nous offrir de nouvelles voies thérapeutiques dans la démence en général et la MA en particulier.

[Signs and symptoms of major neurocognitive disorders]. / Signes et symptômes precoces des troubles neurocognitifs majeurs.

Cognitive disorders are a common problem, especially for older people. Dementia, recently renamed "major neurocognitive disorder" in DSM-5 is a complex subject. Age, vascular risk factors, subjective decline and its objectivation, are all risk factor for such neurocognitive disorders. Face to minor neurocognitive disorder, decline seemed more associated with the presence of structural atrophy or functional metabolic modification. It seems however more and more clear that, at least actually, such a diagnosis should not be done as early as possible but well timely and individually correct. This patient-centred approach requires the peculiar involvement of its familial, general physician. But when early detection tools will be used, for any legitimate reason, it will also be important to address specialized teams. In case of neurocognitive disorders, particularly major, psychoeducative programs are the most effective therapeutic on both patient and caregiver qualities of live. Such multidisciplinary program of care for patients with neurocognitive disorder and his/her caregiver has just obtained a financial agreement via the specific protocol 3 and should be known to be efficient.

[Dementia, end of life and euthanasia]. / Troubles cognitifs, fin de vie et euthanasia.

Among legislative criteria granting the right to practice euthanasia or assisted suicide, there are systematically four major elements. Precisely, any request must be voluntary, persistent, to be well thought and well informed. Such euthanasia raises numerous difficult questions in case of dementia. It also justifies thinking about possibilities that can offer specific arrangements of anticipated demands in such peculiar cases. Empirical experiences show us that it applies with difficulties in practice. Finally, to avoid that a big majority of these demands would find themselves not applied in practice, it would certainly be necessary to add to it structural valuation of advance care planning, and assure its recognition and development. These should not be limited to a single pathological target but would address all of us to increase advance care planning initiation, which remains the most limiting factor of such any early but continuous procedure.

[Biomarkers of the Alzheimer's disease: concepts and clinical case]. / Les biomarqueurs de la maladie d'Alzheimer: concepts et cas clinique.

Concepts and knowledge evolve gradually our ways of diagnosing and treating many diseases, but also our views and some kind of stigmatization that could be associated with them. Alzheimer's disease seems to evolve over several years before leading any perceptible clinical sign. To redefine its semantics seems thus essential. This way, new diagnostic criteria should allow refining diagnosis in case of dementia but also and especially before the apparition of any clinical manifestations or in case of mild suggestive cognitive disorders. Moreover, they allow, in case of other cognitive disorders presentations (aphasia or apraxia), diagnosing its unusual atypical form. However, the possibility that they also offer to set such diagnosis of Alzheimer's disease to people who do not present any slights clinical signs raises numerous ethical considerations, especially in view of the current absence of curative treatment. Noteworthy that, in theory, a biomarker is the objective indicator of a biological process associated with the pathogenicity. In Alzheimer's disease, pathogenicity and scientific bases to propose these biomarkers remains at least controversial. All of these crucial questions leading to their exclusive use by team specialized in their practices and interpretations. An exemplary clinical case is presented.

The Addenbrooke's Cognitive Examination Revised is as effective as the original to detect dementia in a French-speaking population.

INTRODUCTION: This paper presents the validation of the French version of the Addenbrooke's Cognitive Examination Revised (ACE-R). METHODS: The variability of the 3 versions of the ACE-R (A, B and C), performed by the same observer, hence mainly 2 or 3 times on 119 patients showing no progression, was first calculated by Cronbach's alpha coefficient, t test and linear regression. The alpha coefficients of the 3 versions were obtained showing that the ACE-R versions can be considered as one, and an analysis of the interobserver variability was performed by Cohen's kappa coefficient, t test and linear regression on 12 patients. Eventually, we performed a receiver operating characteristic (ROC) analysis to compare the sensitivities and specificities to detect dementia of the ACE, the ACE-R and Mini Mental State Examination on 319 consecutive patients. RESULTS: The ROC areas of sensitivities and specificities of the ACE and ACE-R were very similar. Two cutoffs were identified at 83/100 and 89/100 with a specificity to normality of 98.6% if the ACE-R score was ≥83 and a sensitivity to dementia of 98.4% if the ACE-R score was ≤89. CONCLUSION: ACE-R in French is as reliable and valid as the original version to detect dementia.

[Evaluation of our psycho-educative program by participating caregivers]. / Evaluation de notre programme de psychoéducation par les accompagnants de patients déments.

Facing difficulties due to dementia syndromes, systemic care is necessary. Amongst therapies assessed specifically to caregivers, psychoeducative steps seem to be the strongest effective one on neuropsychiatrics symptoms. Psychoeducations tend to teach the caregivers to modify their interactions with patients via a better understanding of illnesses and patients. Our training "Pour mieux vivre avec la maladie d'Alzheimer", applied in groups of eight to twelve persons, consists in twelve sessions of two hours each. To assure the biggest possible availability, we recently incorporated the concomitant coverage of patients into artistic workshops. These sessions of art-therapy realized in parallel to our psychoeducative program will thus be estimated according to the same rigorous methodology. The critical evaluations realized by participants at the end of our program reflect the outcome of our main objective (to teach to modify interactions with the patients) while contributing to the improvement of social contacts and to the learning of calling to existing helps. These preliminary results strongly argue for the pursuit and even extension of this kind of caregiver's management.

[New promising caregiver's psychoeducation training program: a Belgian experience in dementing disorders]. / La psychoéducation des accompagnants de patients déments comme nouvelle approche thérapeutique à l'efficacité démontrée.

Facing difficulties due to dementia syndromes, systemic care is necessary. But nevertheless, caregivers are generally lacking in medical welfare. Therapies assessed specifically to caregivers are missing. Amongst these, psychoeducative steps seem to be the strongest effective's one on neuropsychiatrics symptoms. Psychoeducations tend to learn to caregivers to modify their interactions with patients via a better understanding of illnesses and patients. Our training "Pour mieux vivre avec la maladie d'Alzheimer ", done in groups of eight to twelve persons, is constituted of twelve sessions of two hours each. Complete formation includes behavioural and cognitive aspects of the disease and proposes some multidimensional approach which content at least pedagogical, psychological and cognitivo behavioural aspects. We illustrate here with the use of two peculiar cases that our program can reach its objectives. These preliminary results strongly argue for the pursuit and even extension of this kind of caregiver's management.

[An unusual hospitalization under constraint]. / Une mise en observation peu ordinaire.

The case report describes a 45-year old man presenting of the behavioral problems and an aphasia of Wernicke, hospitalized under constraint. The urinary screening in the search of psychotropic substances is positive for the cannabis and the amphetamines. The neurological localization is confirmed by cerebral CT-scan. The discussion relates on the differential diagnosis between a schizophasia and an aphasia of Wernicke, on the difficulty of a somatic diagnosis among patients agitated under the effect of a drug and to the tendency to hospitalize those too quickly under constraint, on the noxious effect of drugs on the brain.

[Misdiagnosis of sinus thrombosis with reversible posterior leucoencephalopathy]. / Thrombose ou hypoplasie veineuse cérébrale avec leucoencéphalopathie postérieure réversible.

Reversible posterior leucoencephalopathy and cerebral venous thrombosis share many symptoms. Both of them may lead to coma, and cause epilepsy or focal neurological signs. Moreover, diffuse leucoencephalopathy can be observed in both cases. Cerebral venous thrombosis needs anticoagulation which is not a riskless treatment. We describe a case of reversible posterior leucoencephalopathy in an hypertensed, seventy-year old man, presenting with a left lateral sinus hypoplasia whose clinical history and paramedical results first suggested a cerebral veinous thrombosis. Our case shows the misleadings a congenital vascular asymmetry can induce when confronted with a subacute coma.

The French Addenbrooke's cognitive examination is effective in detecting dementia in a French-speaking population.

We evaluated the sensitivity and specificity of our French version of Addenbrooke's cognitive examination (ACE) to detect dementia in our patient population. One hundred and fifty-eight cases were included in the study. In our patient series, the sensitivity for diagnosing dementia with a Mini-Mental State Examination (MMSE) score of < or = 24/30 was 48.5%, the sensitivity of an MMSE score of < or = 27/30 was 82.5% with a specificity of 72.1%, the sensitivity of an ACE score of < or = 83/100 was 86.6% with a specificity of 70.5% and the sensitivity of an ACE score of < or = 88/100 was 97.9% with a specificity of 59%. We conclude that the French version of the ACE is a very accurate test for the detection of dementia, and should be widely used in clinical practice.

[Memantine (Ebixa), glutaminergic modulator]. / La mémantine (Ebixa), modulateur glutamatergique.

Alzheimer's disease (AD) is the most common etiology of dementia. Its incidence increases with age following an exponential trend of line between 60 and 90 years old. Anti-cholinesterasic drugs reduce modestly AD symptoms. However, they have no basic impact on the pathological evolution of the disease. Memantine offers another therapeutic approach in AD with a dissimilar mechanism of action, confronting neurotoxic effects of glutamate overload. It prevents the elevation of glutamate which destroys cholinergic neurons by inhibiting the N-methyl-D-aspartate (NMDA) receptors. Its clinical efficiency has been demonstrated during 28 weeks with 20 mg/day, in patients presenting moderate or severe AD and mild or moderately vascular dementia. Its use in association with anti-cholinesterasic (donepezil) revealed more interesting results with a significant improvement of cognitive functions and activities of daily live, compared to association placebo-donepezil. We are waiting for results of further lenghter studies, including more, well-defined, patients.

Is the Addenbrooke's cognitive examination effective to detect frontotemporal dementia?

We evaluated the Addenbrooke's cognitive examination (ACE), a simple instrument to differentiate frontotemporal dementia (FTD) from Alzheimer's disease (AD), in our dementia patients clinic population. The Verbal-Language/Orientation-Memory (VLOM) ratio, which compares its language and memory scores, determines whether FTD or AD is more likely. The ACE was translated into French with adaptation maintaining the number of words in the name and address learning and delayed recall test, and with cultural adaptation for the semantic memory. The 85 included subjects had no evidence of two or more organic pathologies, after at least six months of follow-up, and an MMSE score>or=20/30. Patients with cognitive impairment due to alcohol intake were excluded. The diagnosis of a specific dementing illness was based on the consensus of the neurologist and neuropsychologists in the team. Thereafter, another neurologist expert in dementia, blinded to the ACE result and to the diagnosis and treatment, reviewed all cases files and proposed a diagnosis. A diagnostic agreement was reached for 79 cases (92.9%) with 40 (50.6%) dementia: 25 AD (62.5 %), 9 FTD (22.5 %). We estimated that the sensitivity for detecting dementia of an ACE score3.2 was 72%,with a specificity of 69.4%. We conclude that, when used as originally proposed, ACE is very accurate for the detection of dementia, but much less effective in discriminating the most common frontal variant of FTD.