Alzheimer's disease disrupts domain-specific and domain-general processes in numerosity estimation.

INTRODUCTION: This study investigated how Alzheimer's Disease (AD) affects numerosity estimation abilities (e.g., finding the approximate number of items in a collection). METHOD: Across two experiments, performance from HOA (i.e., Healthy Older Adults; N = 48) and AD patients (N = 50) was compared on dot comparison tasks. Participants were presented with two dot arrays and had to select the more numerous dot array in comparison tasks. They also took a Simon task and a number-line tasks (i.e., number-line tasks in which they had to indicate the position of a number on a line 0 to 100 or on a line 0 to 1,000 in the number-line task). RESULTS: In Experiment 1, (a) AD patients obtained significantly poorer performance while comparing collections of dots, especially harder (small-ratio) collections, (b) these deficits correlated with poorer performance on the number-line task for larger numerosities (i.e., 0 to 1,000), and (c) AD patients showed poorer performance on incongruent (where numerosity and area occupied by dots mismatched) than on congruent items (where both features matched), while HOA showed no congruency effects. Experiment 2 showed (a) congruency effects in both groups when convex hull was tested as an incongruent feature, and (b) comparable sequential modulations of congruency effects in both groups. CONCLUSIONS: Our findings showed that numerosity abilities decline in AD patients, and that this decline results from impaired domain-specific processes (i.e., numerosity processing) and domain-general processes (i.e., inhibition). These findings have important implications to further our understanding of how specific and general cognitive processes contribute to numerosity estimation/comparison performance, and how such contributions change during Alzheimer's disease.

Impact of mild traumatic brain injury on cingulate functions.

Mild traumatic brain injury (mTBI) is a condition of normal neuroimaging, because conventional MRI is not sensitive to brain lesions. Neurocognitive deficits persist for years after injury in 15% of patients. Persistent TAI can continue after the trauma and contribute to progressive disability. Neuropathologic studies underestimate the total axonal damage, by failure to identify fine-caliber unmyelinated fiber. Swollen axons represent the "tip of the iceberg" of damage. Progression of molecular changes, including mitochondrial dysfunction, leads to secondary injuries. Primary low-intensity "invisible injury" is solely detectable at ultrastructural levels. Over the long term, mTBI is not a static event but a progressive injury, increasing risk of neurodegenerative diseases. Lack of evidence of brain injury has led to the development of more sensitive methods: morphometric MRI (VBM, DTI) and functional techniques (fMRI, PET, SPECT). By deformation of the surface of gray matter cingulate gyrus and disruption of long-coursing WM of CB structures, striking the falx, mTBI causes alteration of cingulate functions. Postconcussion, blast, and whiplash-associated disorders are the main mechanisms providing behavior and cognitive symptoms after mTBI.

Cingulate cortex in pre-MCI cognition.

Studies of Alzheimer's disease over the years have focused on the prodromal stage, or mild cognitive impairment (MCI), in order to understand its evolution and to diagnose this pathology early. More recently, research has focused on an even earlier stage (pre-MCI) characterized in particular by a cognitive complaint. The purpose of this chapter is, first, to describe the different concepts defining pre-MCI, which refers to cognitive or memory complaint, and to define this concept based on biologic markers (abnormal proteins and neuroimaging). In the second part of the chapter, we describe the cognitive performance of these subjects (pre-MCI), and, finally, in the third part we describe the correlations linking cognitive performance of pre-MCI subjects to cingulate cortex, cingulate gyrus, and cingulum bundle.

[Subjective cognitive impairment and Alzheimer's disease: a two year follow up of 51 subjects during two years]. / Subjective cognitive impairment et maladie d'Alzheimer : étude d'une cohorte de 51 sujets suivis sur deux ans.

Subjective cognitive impairment (SCI) is defined by a state of subjective complaint, without objective cognitive deterioration. Amnestic mild cognitive impairment (A-MCI), which characterizes a syndrome between normal cognitive aging and early Alzheimer's disease (E-AD), is preceded by A-MCI from many years. SCI expresses a metacognitive impairment. A cohort of 51 subjects [7 normal controls (NC), 28 SCI, 12 A-MCI and 5 E-AD] was followed up during 24 months, with a neuropsychological evaluation each 6 months during 1 year (V1, V2, V3), then 1 year later (V4). Among the 28 SCI, 6 converted to A-MCI at V4 (21.42%), 1 to A-MCI-A at V3, then to E-AD at V4. These results suggest a continuum from SCI to A-MCI, and E-AD. Progressive SCI differed from non-progressive SCI on verbal episodic memory and executive functions tests at the initial examination. MRI showed anterior cingular atrophy in all SCI patients but hippocampal atrophy was only observed in 20 patients. Our results suggest that metacognition impairment is the expression of a dysfunction in the anterior pre-frontal cortex, in correlation with a syndrome of hyper-attention.

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.

Combined measurement of PEDF, haptoglobin and tau in cerebrospinal fluid improves the diagnostic discrimination between alzheimer's disease and other dementias.

Using proteomic approach in cerebrospinal fluid (CSF) we identified pigment epithelium-derived factor (PEDF) and Haptoglobin (Hp) as putative markers that could discriminate between AD and other dementias. ELISA assays were developed to measure the levels of PEDF and Hp in CSF from patients with AD (AD, n=27), non-AD (NAD, n=30) and in non-demented patients (ND, n=27). The combined assessment of PEDF, Hp and Tau levels, using Iterative Marginal Optimization, improved the differential diagnosis of AD, especially in patients with moderate to severe dementia (p<0.002). This pilot study highlights the probable different contribution of oxidative mechanisms in dementia.

Memantine in behavioral variant frontotemporal dementia: negative results.

We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). The secondary endpoints included: Neuropsychiatric Inventory (NPI), Frontal Behavioral Inventory (FBI), Mattis Dementia Rating Scale (MDRS), MMSE, Disability Assessment for Dementia (DAD), and the Zarit Burden Inventory (ZBI). Forty-nine patients were analyzed. At baseline, mean age was 65.6 years and mean MMSE was 25.0 (range: 19-30). On the CIBIC-Plus, 52 weeks after baseline, there were no significant differences between the memantine group (n = 23) and the placebo group (n = 26); p = 0.4458; however, 10 patients had worsened in the memantine group versus 17 in the placebo group. For the secondary endpoints there were no differences in the evolution of score between the memantine group and the placebo group (MMSE, p = 0.63); (MDRS, p = 0.95); (NPI, p = 0.25); (ZBI, p = 0.43); (DAD, p = 0.10) except for the FBI score, which was lower in the memantine group (p = 0.0417). Memantine was well-tolerated. This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.

Approximate quantification in young, healthy older adults', and Alzheimer patients.

Forty young adults, 40 healthy older adults, and 39 probable AD patients were asked to estimate small (e.g., 25) and large (e.g., 60) collections of dots in a choice condition and in two no-choice conditions. Participants could choose between benchmark and anchoring strategies on each collection of dots in the choice condition and were required to use either benchmark or anchoring on all configurations in the no-choice conditions (one per strategy). The benchmark strategy involves visual estimation processes whereas the anchoring strategy involves both enumeration and estimation processes. Results showed that strategy use was influenced by collection, participant, and strategy characteristics. Age-related and dementia-related differences were found in both strategy use and strategy execution. The findings have implications for our understanding of aging effects in approximate quantification, strategic variations in Alzheimer's patients, and sources of cognitive decline during early stages of Alzheimer's disease.

Progranulin null mutations in both sporadic and familial frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most frequent type of neurodegenerative dementias. Mutations in the progranulin gene (GRN, PGRN) were recently identified in FTDU-17, an FTD subtype characterized by ubiquitin-immunoreactive inclusions and linkage to chromosome 17q21. We looked for PGRN mutations in a large series of 210 FTD patients (52 familial, 158 sporadic) to accurately evaluate the frequency of PGRN mutations in both sporadic and familial FTD, and FTD with associated motoneuron disease (FTD-MND), as well as to study the clinical phenotype of patients with a PGRN mutation. We identified nine novel PGRN null mutations in 10 index patients. The relative frequency of PGRN null mutations in FTD was 4.8% (10/210) and 12.8% (5/39) in pure familial forms. Interestingly, 5/158 (3.2%) apparently sporadic FTD patients carried a PGRN mutation, suggesting the possibility of de novo mutations or incomplete penetrance. In contrast, none of the 43 patients with FTD-MND had PGRN mutations, supporting that FTDU-17 and FTD-MND are genetically distinct. The clinical phenotype of PGRN mutation carriers was particular because of the wide range in onset age and the frequent occurrence of early apraxia (50%), visual hallucinations (30%), and parkinsonism (30%) during the course of the disease. This study supports that PGRN null mutations represent a more frequent cause of FTD than MAPT mutations (4.8% vs. 2.9%) but are not responsible for FTD-MND. It also demonstrates that half of the patients with a PGRN mutation in our series had no apparent family history of dementia. Taking this into account, genetic testing should be now considered more systematically, even in patients without obvious familial history of FTD.

Demographic, neurological and behavioural characteristics and brain perfusion SPECT in frontal variant of frontotemporal dementia.

We conducted a French multicentric cross-sectional study to describe in detail the demographic, neurological and behavioural characteristics of the frontal variant of frontotemporal dementia (fvFTD) and to characterize the pattern of brain perfusion SPECT in comparison to a healthy control group. A total of 68 fvFTD patients had technetium-99m-ECD brain perfusion SPECT at inclusion, 61 of which also underwent an in-depth evaluation including 70 items assessing behaviour, language and affect/emotion at onset and at inclusion. The mean age-at-onset was 60.4 +/- 7.8 years (35-75). Twenty-six per cent of the patients were older than 65 at onset. A positive familial history consistent with an autosomal dominant inheritance was found in 18% of the patients. At onset, the behavioural profile was predominantly inert in 25% of the patients, disinhibited in 18% and mixed in others. The behavioural features progressed to predominantly mixed or inert forms. Although, inertia was associated with predominant medial frontal and cingulate hypoperfusion, and patients with disinhibition exhibited predominant ventromedial prefrontal and temporal hypoperfusion, there were no major clinical differences between disinhibited and inert patients. Forty-five per cent of the deceased patients survived <6 years (short survival), and 34% of the patients survived >8 years (long survival). This shows that the final outcome of fvFTD is highly variable. No clinical factors predictive of short or long survival were identified. Unexpected, however, was the finding that brainstem hypoperfusion distinguished patients with a short survival from patients with long survival. In conclusion, this study shows that fvFTD is clinically a rather homogeneous entity. It also provides evidence that different behavioural presentations at onset are related to different anatomical localizations of degenerative damage. Finally, it demonstrates the prognostic value of brainstem hypoperfusion in a subgroup of patients with a short survival.

[Pharmacology of Alzheimer's disease: where do we go from here?]. / Pharmacologie de la maladie d'Alzheimer: vision du futur.

Ten years after the introduction of the first drug for the treatment of Alzheimer's disease, tacrine, it seems appropriate to reappraise the pharmacological processes of innovation in the field of research in dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, in terms of experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets deserving of initial consideration. * The article first considers the use of animal models of Alzheimer's disease, which are classified according to two categories: animals with lesions of some neuronal pathways specifically implicated in clinical symptoms (i.e. lesions of the nucleus basalis of Meynert, the origin of cholinergic projections to the cortex underlying memory processes); and transgenic models, which are intended to reproduce some of the neuropathological hallmarks of Alzheimer's disease. Drugs can be tested in animals with such alterations for their effect on neuropathology, neurochemistry and behavioural disturbances. More recently, in silico models have been developed, which offer the possibility of simulating the pharmacodynamic effects of drugs in specific areas of the brain. These experiments are helpful in distinguishing purely symptomatic effects from disease-modifying effects, the latter being the ultimate goal of the modern pharmacology of dementia. * The second breakthrough considered in this article is the codification and standardisation of clinical methods for obtaining a more accurate and earlier diagnosis (the recent introduction of the concept of "Mild Cognitive Impairment", which includes patients who will later develop a true clinical dementia syndrome). In that respect, the determination of the biological markers of Alzheimer's disease (apolipoprotein E, amyloid substance, protein-tau, isoprostane) as well as progress in neuroimaging (functional positron emission tomography [fPET]-scan, single photon emission-computed tomography [SPECT], functional nuclear magnetic resonance [fNMR]) are discussed in terms of their potential as new tools in the early stages of drug development (surrogate markers). The methods used during the comparative clinical trials (phase III) have been elaborated and internationally standardised during the assessment of the different acetylcholinesterase inhibitors (AChE-I), with the knowledge that, since 1994, four of these have been officially approved: tacrine, donepezil, rivastigmine and galantamine; the same methods have been used for developing memantine, a recently-launched modulator of glutamatergic neurotransmission. The validated scales now take into consideration not only the cognitive dimensions of Alzheimer's disease but also the behavioural symptoms, with the introduction of the concept of BPSD (behavioural psychological symptoms of dementia). Some proposals to improve this clinical assessment of anti-dementia drugs are presented here. * The section of this article dealing with prospective issues considers the main pathways of interest in drug innovation and the elucidation of new targets for the future compounds. As well as their symptomatic effects on the different components of cognition, drugs should be neuroprotective and limit the lesions documented in Alzheimer's disease, with the aim of progressing far beyond the amyloid hypothesis (immunisation, beta-sheet breakers, secretase inhibitors). The field of excitotoxicity (which is mainly glutamate dependent) appears fruitful, because of the possibility of pharmacological intervention at the different steps in the excitotoxic process. All the new directions presented in this article support the concept of true disease-modifying agents. In conclusion, this prospective review should be considered as a guide in fostering drug innovation in Alzheimer's disease and related disorders and should help to decrease the gap existing between neuroscience and therapeutics.

Pharmacology of Alzheimer's disease: appraisal and prospects.

Ten years after the introduction of the first drug, tacrine, in the treatment of Alzheimer's disease, it seems appropriate to re-appraise the pharmacological processes of innovation in the research field of dementia. The aim of this review is to pinpoint concrete improvements achieved in this field, regarding experimental methods and clinical evaluation of the compounds, as well as the neurochemistry of the disease and cellular targets to consider in priority. This review deals with this objective in three parts: (1) assessment of current therapeutics, (2) discussion of the experimental models and clinical practices and (3) prospective drugs of the future. The implementation of considered strategies will require the involvement and close cooperation between political decisions, pharmaceutical companies and the scientific community.

Alzheimer's disease: the pharmacological pathway.

The current pharmacological treatment of Alzheimer's disease (AD) comes down to four marketed drugs (tacrine, donepezil, rivastigmine and galantamine) all of which are cholinesterase inhibitors, conforming to the cholinergic hypothesis. The future is clearly directed at new biological targets closely linked to the pathophysiology of the disease and more precisely, the pathological hallmark of AD which includes widespread neuronal degeneration, neuritic plaques containing beta-amyloid and tau-rich neurofibrillary tangles. For clinicians, this means that new curative drugs will have to be prescribed early in the course of the disease. This review describes the main entry pathways for drug discovery in AD: (1) supplementation therapy, (2) anti-apoptotic compounds, (3) substances with a mitochondrial impact, (4) anti-amyloid substances, (5) anti-protein aggregation and (6) lipid-lowering drugs. The rapidity at which these compounds will be at our disposal is highly dependent on the policy of the pharmaceutical companies.

Alzheimer's disease disrupts arithmetic fact retrieval processes but not arithmetic strategy selection.

Three groups of healthy younger adults, healthy older adults, and probable AD patients, performed an addition/number comparison task. They compared 128 couples of additions and numbers (e.g., 4 + 9 15) and had to identify the largest item for each problem by pressing one of two buttons located under each item. Manipulations of problem characteristics (i.e., problem difficulty and splits between correct sums and proposed numbers) enabled us to examine strategy selection and specific arithmetic fact retrieval processes. Results showed that arithmetic facts retrieval processes, which were spared with aging, were impaired in AD patients. However, AD patients were able to switch between strategies across trials according to problem characteristics as well as healthy older adults, and less systematically than healthy younger adults. We discuss implications of these findings for further understanding AD-related differences in arithmetic in particular, and problem solving in general.

Association between the extended tau haplotype and frontotemporal dementia.

BACKGROUND: Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. OBJECTIVE: To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. DESIGN: Case-control study. SETTING: Neurology departments of 12 French university hospitals. PARTICIPANTS: One hundred unrelated patients with FTD and 79 controls. METHODS: Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. RESULTS: The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P=.01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E (APOE) genotype, we found a significant interaction between APOE and tau genotypes (P=.03). CONCLUSIONS: This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD.