Michèle Puel

Early diagnosis of Alzheimer's disease using cortical thickness: impact of cognitive reserve

Brain atrophy measured by magnetic resonance structural imaging has been proposed as a surrogate marker for the early diagnosis of Alzheimers disease. Studies on large samples are still required to determine its practical interest at the individual level, especially with regards to the capacity of anatomical magnetic resonance imaging to disentangle the confounding role of the cognitive reserve in the early diagnosis of Alzheimers disease. One hundred and thirty healthy controls, 122 subjects with mild cognitive impairment of the amnestic type and 130 Alzheimers disease patients were included from the ADNI database and followed up for 24 months. After 24 months, 72 amnestic mild cognitive impairment had converted to Alzheimers disease (referred to as progressive mild cognitive impairment, as opposed to stable mild cognitive impairment). For each subject, cortical thickness was measured on the baseline magnetic resonance imaging volume. The resulting cortical thickness map was parcellated into 22 regions and a normalized thickness index was computed using the subset of regions (right medial temporal, left lateral temporal, right posterior cingulate) that optimally distinguished stable mild cognitive impairment from progressive mild cognitive impairment. We tested the ability of baseline normalized thickness index to predict evolution from amnestic mild cognitive impairment to Alzheimers disease and compared it to the predictive values of the main cognitive scores at baseline. In addition, we studied the relationship between the normalized thickness index, the education level and the timeline of conversion to Alzheimers disease. Normalized thickness index at baseline differed significantly among all the four diagnosis groups (P < 0.001) and correctly distinguished Alzheimers disease patients from healthy controls with an 85% cross-validated accuracy. Normalized thickness index also correctly predicted evolution to Alzheimers disease for 76% of amnestic mild cognitive impairment subjects after cross-validation, thus showing an advantage over cognitive scores (range 63–72%). Moreover, progressive mild cognitive impairment subjects, who converted later than 1 year after baseline, showed a significantly higher education level than those who converted earlier than 1 year after baseline. Using a normalized thickness index-based criterion may help with early diagnosis of Alzheimers disease at the individual level, especially for highly educated subjects, up to 24 months before clinical criteria for Alzheimers disease diagnosis are met.

Clinical and imaging evidence of zolpidem effect in hypoxic encephalopathy

We conducted a randomized, double‐blind, placebo‐controlled, single‐patient (N = 1) trial to evaluate the efficacy of zolpidem in a 48‐year‐old woman with an akinetic mutism. Motor and cognitive examinations and functional imaging were performed. Acute administration of zolpidem markedly improved motor performance and neuropsychological status. Cerebral metabolism (18F‐fluorodeoxyglucose positron emission tomography) increased in postrolandic territories and in frontal cortex. Using the H215O positron emission tomography, we found a drug‐induced activation in the anterior cingulate and orbitofrontal cortices. Zolpidem induced a transient improvement in motor and cognitive performances. This paradoxical effect could result from an activation of limbic loops modulating motivational processes. Ann Neurol 2007

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.

C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flow-chart for Genetic Testing

Frontotemporal dementia (FTD) refers to a disease spectrum including the behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), progressive supranuclear palsy/corticobasal degeneration syndrome (PSP/CBDS), and FTD with amyotrophic lateral sclerosis (FTD-ALS). A GGGGCC expansion in C9ORF72 is a major cause of FTD and ALS. C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion. C9ORF72 expansions were much more frequent in the large subgroup of patients with familial FTD-ALS (65.9%) than in those with pure FTD (12.8%); they were even more frequent than in familial pure ALS, according to estimated frequencies in the literature (23-50%). The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative. Mutations were detected in 6.8% of PPA patients, and in 3.2% of patients with a clinical phenotype of PSP, thus enlarging the phenotype spectrum of C9ORF72. Onset was later in C9ORF72 (57.4 years, 95%CI: 55.9-56.1) than in MAPT patients (46.8, 95%CI: 43.0-50.6; p = 0.00001) and the same as in PGRN patients (59.6 years; 95%CI: 57.6-61.7; p = 0.4). ALS was more frequent in C9ORF72 than in MAPT and PGRN patients; onset before age 50 and parkinsonism were indicative of MAPT mutations, whereas hallucinations were indicative of PGRN mutations; prioritization of genetic testing is thus possible. Penetrance was age- and gender-dependent: by age 50, 78% of male carriers were symptomatic, but only 52% of females. This can also guide genetic testing and counseling. A flowchart for genetic testing is thus proposed.

Neuropsychological outcome after a first symptomatic ischaemic stroke with 'good recovery'

Background:u2002 Neuropsychological impairment after stroke when no motor, sensory or language deficits are left remains understudied. The primary aim of this study was to assess neuropsychological outcome in a specific population of patients after a first symptomatic stroke without previous cognitive decline and with a good motor, linguistic, and functional recovery (i.e. ‘good outcome’). The secondary aims were to identify the profile of this potential impairment and relations between brain lesions and neuropsychological outcome.

Visual recognition memory: A double anatomo‐functional dissociation

There is an ongoing debate regarding the respective role of anterior subhippocampal structures and the hippocampus in recognition memory. Here, we report a double anatomo‐functional dissociation observed in two brain‐damaged patients, FRG and JMG. They both suffered from complete destruction of left MTL structures. In the right hemisphere however, FRG sustained extensive lesions to the hippocampus sparing anterior subhippocampal structures, while JMG suffered from the reversed pattern of lesion, i.e., extensive damage to anterior subhippocampal structures but preserved hippocampus. FRG was severely amnesic and failed all recall tasks involving visual material, but exhibited normal performance at a large battery of visual recognition memory tasks. JMG was not amnesic and showed the opposite pattern of performance. These results strongly support the view that right anterior subhippocampal structures are a critical relay for visual recognition memory in the human.

Proper name anomia with preserved lexical and semantic knowledge after left anterior temporal lesion: a two-way convergence defect.

This article describes the case of a patient who, following herpes simplex encephalitis (HSE), retained the ability to access rich conceptual semantic information for familiar people whom he was no longer able to name. Moreover, this patient presented the very rare combination of name production and name comprehension deficits for different categories of proper names (persons and acronyms). Indeed, besides his difficulty to retrieve proper names, SL presented a severe deficit in understanding and identifying them. However, he was still able to recognize proper names on familiarity decision, demonstrating that name forms themselves were intact. We interpret SLs deficit as a rare form of two-way lexico-semantic disconnection, in which intact lexical knowledge is disconnected from semantic knowledge and face units. We suggest that this disconnection reflects the role of the left anterior temporal lobe in binding together different types of knowledge and supports the classical convergence-zones framework (e.g., Damasio, 1989) rather than the amodal semantic hub theory (e.g., Patterson, Nestor, & Rogers, 2007).

A Case of Logopenic Primary Progressive Aphasia with C9ORF72 Expansion and Cortical Florbetapir Binding

We report the case of a 65-year-old woman, clinically diagnosed with the logopenic variant of primary progressive aphasia (PPA), and carrier of C9ORF72 expansion, despite cerebrospinal fluid biomarkers suggesting Alzheimers disease (AD). She underwent structural MRI, metabolic PET, and amyloid PET imaging using florbetapir. Comparison with healthy controls revealed widespread hypometabolism, left sided cortical atrophy, and an increased cortical amyloid load. No difference in amyloid binding was found between the patient and predemential AD patients. This case provides evidence of amyloidopathy in a carrier of C9ORF72 expansion exhibiting a clinical profile of the logopenic variant of PPA.

Neuropsychological outcome after carbon monoxide exposure following a storm: a case-control study

BackgroundThe cognitive consequences of carbon monoxide (CO) poisoning are well described. However, most studies have been carried out without an ad-hoc group of control subjects. The main aim of this study was to evaluate cognitive and psychiatric outcome after CO exposure during the storm Klaus in the South West of France (January 2009) in a homogeneous group of patients compared to a group of 1:1 paired controls.MethodsPatients and controls were asked to fill out questionnaires about quality of life and cognitive complaints. They then underwent a cognitive assessment derived from the Carbon Monoxide Neuropsychological Screening Battery. Psychiatric assessment was performed using subtests of the Mini International Neuropsychiatric Interview.Results38 patients and 38 paired controls were included (mean age 38.8 years) and evaluated 51 days after the poisoning. No difference was found between groups on the cognitive complaint questionnaire but patients had a lower quality of life than controls. Patients showed significantly lower cognitive performance than controls on processing speed, mental flexibility, inhibition and working and verbal episodic memories. Patients were more depressed than controls, and suffered more from post-traumatic stress disorder.ConclusionsWe report the first study investigating cognitive and psychiatric outcome in consecutive patients after CO poisoning during a natural disaster, using a group comparison method. CO poisoning during storms needs to be dealt with adequately and clinicians should be aware of its possible consequences.

Case report of Lewy body disease mimicking Creutzfeldt-Jakob disease in a 44-year-old man

BackgroundFew patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease.Case presentationWe document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14–3–3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on 18F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5xa0years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease.ConclusionsThis comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed.