Bruno Dubois

Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline

The aim of this international guideline on dementia was to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimers disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta‐analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimers disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinsons disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.

MDS clinical diagnostic criteria for Parkinson's disease

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinsons disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

MDS research criteria for prodromal Parkinson's disease

This article describes research criteria and probability methodology for the diagnosis of prodromal PD. Prodromal disease refers to the stage wherein early symptoms or signs of PD neurodegeneration are present, but classic clinical diagnosis based on fully evolved motor parkinsonism is not yet possible. Given the lack of clear neuroprotective/disease‐modifying therapy for prodromal PD, these criteria were developed for research purposes only. The criteria are based upon the likelihood of prodromal disease being present with probable prodromal PD defined as ≥80% certainty. Certainty estimates rely upon calculation of an individuals risk of having prodromal PD, using a Bayesian naïve classifier. In this methodology, a previous probability of prodromal disease is delineated based upon age. Then, the probability of prodromal PD is calculated by adding diagnostic information, expressed as likelihood ratios. This diagnostic information combines estimates of background risk (from environmental risk factors and genetic findings) and results of diagnostic marker testing. In order to be included, diagnostic markers had to have prospective evidence documenting ability to predict clinical PD. They include motor and nonmotor clinical symptoms, clinical signs, and ancillary diagnostic tests. These criteria represent a first step in the formal delineation of early stages of PD and will require constant updating as more information becomes available.

Clinicometabolic dissociation of cognitive functions and social behavior in frontal lobe lesions.

Objective/background: Case studies suggest a dissociation between cognitive functions that have been impaired after damage to the dorsolateral prefrontal cortex and social skills disturbed when the ventromedial prefrontal areas are affected. Because this dissociation had not been confirmed in a clinical setting, clinicometabolic correlations were sought in 13 patients with various lesions of the prefrontal cortex. Design/methods: The clinical assessment included extensive testing of executive functions and evaluation of behavioral abnormalities based on an informant questionnaire. Regional cerebral glucose metabolism (rCMRGlu) was measured with [18F] fluorodeoxyglucose ([18F] FDG) and 31-slide high-resolution PET. Results: Executive-function test performance was significantly correlated with rCMRGlu in the dorsolateral prefrontal cortex (Brodmanns areas 8, 9, 45, 46, and 47) and anterior cingulate cortex (Brodmanns areas 24 and 32). Behavioral scores were significantly correlated with rCMRGlu in the frontopolar (Brodmanns area 10) and orbitofrontal cortex (Brodmanns areas 11, 12, 13, and 14). Conclusion: These results show that impaired executive functions and serial skill deficits are associated with distinct metabolic patterns in patients with frontal lobe pathology. In agreement with activation studies in normal subjects, our data suggest the existence of a modular organization of the frontal cortex in humans, as previously reported in nonhuman primates.

Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease

Background: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). Methods: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. Results: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 ± 10.3 years (range, 41–84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. Conclusions: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

Outcome of patients with HIV-1-related cognitive impairment on highly active antiretroviral therapy.

ObjectiveTo examine the impact of highly active antiretroviral therapy (HAART) on the outcome of HIV-1-related cognitive impairments using a neuropsychological (NP) battery to assess separately the psychomotor, executive function and memory fields. DesignA longitudinal study of HIV-1-infected patients based on serial NP tests in a Paris University Hospital. MethodsA group of 91 HIV-1-infected patients, of whom 47 were already taking HAART at their first NP examination, were initially categorized as cognitively impaired (n = 53) or non-impaired (n = 38) and underwent one to six serial NP batteries (mean follow-up 12.3 ± 8.3 months). Generalized estimating equations (GEE) were used to evaluate performance in a given NP test according to the number of days on HAART. ResultsDespite a 25% mortality rate among patients who had cognitive impairment at their first NP examination, GEE showed a positive relationship between the duration of HAART and cognitive performance. Performance in psychomotor tests (e.g. Purdue Pegboard dominant hand) improved continuously during the study period, while memory test performance (e.g. Grober and Buschke free recall) tended to reach a plateau. ConclusionsHAART improves subcortical cognitive functions during the first year of treatment. Distinct neuropathological mechanisms appear to underlie psychomotor and memory dysfunctions in AIDS.

Drug development in Alzheimer’s disease: the path to 2025

The global impact of Alzheimer’s disease (AD) continues to increase, and focused efforts are needed to address this immense public health challenge. National leaders have set a goal to prevent or effectively treat AD by 2025. In this paper, we discuss the path to 2025, and what is feasible in this time frame given the realities and challenges of AD drug development, with a focus on disease-modifying therapies (DMTs). Under the current conditions, only drugs currently in late Phase 1 or later will have a chance of being approved by 2025. If pipeline attrition rates remain high, only a few compounds at best will meet this time frame. There is an opportunity to reduce the time and risk of AD drug development through an improvement in trial design; better trial infrastructure; disease registries of well-characterized participant cohorts to help with more rapid enrollment of appropriate study populations; validated biomarkers to better detect disease, determine risk and monitor disease progression as well as predict disease response; more sensitive clinical assessment tools; and faster regulatory review. To implement change requires efforts to build awareness, educate and foster engagement; increase funding for both basic and clinical research; reduce fragmented environments and systems; increase learning from successes and failures; promote data standardization and increase wider data sharing; understand AD at the basic biology level; and rapidly translate new knowledge into clinical development. Improved mechanistic understanding of disease onset and progression is central to more efficient AD drug development and will lead to improved therapeutic approaches and targets. The opportunity for more than a few new therapies by 2025 is small. Accelerating research and clinical development efforts and bringing DMTs to market sooner would have a significant impact on the future societal burden of AD. As these steps are put in place and plans come to fruition, e.g., approval of a DMT, it can be predicted that momentum will build, the process will be self-sustaining, and the path to 2025, and beyond, becomes clearer.

VBM anticipates the rate of progression of Alzheimer disease. A 3-year longitudinal study

Objective: To determine whether regional atrophy or neuropsychological factors can predict the rate of decline in patients with mild Alzheimer disease (AD). Background: Despite important implications for planning the care and treatment strategy, few prognostic factors of severe AD progression are known. Methods: Twenty-three patients with mild AD were followed up every 6 months over the course of 3 years. At baseline, patients with AD and 18 controls underwent a neuropsychological battery and a brain MRI. At the end of the 3 years, patients with AD were dichotomized into slow decliners (SLD) or fast decliners (FD) groups on the basis of their decline in Mini-Mental State Examination score over time. We compared baseline cognitive performance and imaging data using voxel-based morphometry (VBM). Results: SLD and FD groups did not differ in age, gender, level of education, mean estimated duration of illness, and standard neuropsychological data at inclusion, except for the Attentional Battery of the Cambridge Neuropsychological Tests Automated Battery (speed processing in shifting condition). VBM comparison between SLD and FD groups demonstrated more gray matter tissue loss in the FD group in the medial occipitoparietal areas, especially in the precuneus, the lingual gyrus, the cuneus, and the surrounding cortex of the parieto-occipital sulcus bilaterally. Conclusion: Voxel-based morphometry analysis demonstrated that patients who will have a faster decline at 3 years already had a more extensive cortical atrophy than SLD patients, especially in the medial occipitoparietal areas, which was not yet detected by clinical and neuropsychological assessment.

Validity of the Free and Cued Selective Reminding Test in predicting dementia The 3C Study

Objective: We assessed the validity of the Free and Cued Selective Reminding Test (FCSRT) in predicting dementia 2 and 5 years after initial evaluation in a population-based cohort over age 65 years participating in the French 3 Cities (3C) study. Methods: The FCSRT was administered at baseline along with demographics, cognitive and functional scales, and a memory-complaint questionnaire. Two and 5 years later, subjects were assessed for dementia using a 2-stage design. We calculated the sensitivity, specificity, and positive and negative predictive values of various cutoff FCSRT scores in dementia prediction. Results: Among 1,761 participants at the Bordeaux 3C center, 98 were excluded because of existing dementia, leading to 1,663 candidate participants. Among them, 1,464 underwent FCSRT and other mental status testing. Of these, 1,299 subjects were reassessed at 2 years, and 1,160 were seen 5 years later. At 2 years, 23 subjects had developed dementia; by 5 years, 60 additional subjects showed dementia. With optimized cutoff scores, the subtests of free and total recall from the FCSRT showed good sensitivity and fair specificity for the diagnosis of dementia, and the negative predictive values were high. However, positive predictive values were low: many subjects with low scores for free and total recall on FCSRT remained free of dementia at 5 years. Conclusions: In a population-based setting, despite good sensitivity, low Free and Cued Selective Reminding Test (FCSRT) scores must be interpreted with caution. Those subjects, who often do not have memory complaints, may have unrecognized poor memory status. High FCSRT scores are useful to rule out dementia.

Parkinson's disease dementia can be easily detected in routine clinical practice.

Parkinsons disease (PD) is mainly characterized by its motor manifestations, but it is also frequently associated with dementia. Early diagnosis of PD dementia (PDD) is particularly important because effective cholinesterase inhibitor treatments are available. This study aimed at validating a short procedure for screening for PDD in routine clinical practice and which adopts recently published diagnostic criteria. One hundred eighty‐eight patients with PD participated in the study. The examination procedure comprised three steps: standard clinical examination, a short cognitive function assessment fulfilling the requirements of the Movement Disorders Society (Mini Mental State Examination, five‐word test, word generation task, and impact on daily life, including a questionnaire on compliance with medication) and an extensive evaluation of cognitive functions and behavior. After each step, the suspected presence or absence of dementia was recorded. After the short cognitive function assessment, PDD was suspected in 18.62% of the patients [95% confidence interval (CI): 13.32‐24.93%]. After the extensive assessment, 21.81% (95% CI: 16.13‐28.40%) met the criteria for probable PDD. The short batterys sensitivity and specificity were 65.85% (95% CI = 49.41‐79.92%) and 94.56% (95% CI = 89.56‐97.62%), respectively. A stepwise logistic regression analysis showed that use of a specific cut‐off considerably enhanced the short batterys sensitivity (85.37%, 95% CI = 70.83‐94.43%) without decreasing its specificity (83.67%, 95% CI = 76.69‐89.25%). With an easy‐to‐use, short battery of tests that are commonly used in routine clinical practice, it is possible to diagnose PDD in accordance with reference criteria and with the same sensitivity and specificity as in a more extensive evaluation.