The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter.

Pathological expansion of a G4C2 repeat, located in the 5' regulatory region of C9orf72, is the most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 patients have highly variable onset ages suggesting the presence of modifying factors and/or anticipation. We studied 72 Belgian index patients with FTLD, FTLD-ALS or ALS and 61 relatives with a C9orf72 repeat expansion. We assessed the effect of G4C2 expansion size on onset age, the role of anticipation and the effect of repeat size on methylation and C9orf72 promoter activity. G4C2 expansion sizes varied in blood between 45 and over 2100 repeat units with short expansions (45-78 units) present in 5.6% of 72 index patients with an expansion. Short expansions co-segregated with disease in two families. The subject with a short expansion in blood but an indication of mosaicism in brain showed the same pathology as those with a long expansion. Further, we provided evidence for an association of G4C2 expansion size with onset age (P<0.05) most likely explained by an association of methylation state of the 5' flanking CpG island and expansion size in blood (P<0.0001) and brain (P<0.05). In several informative C9orf72 parent-child transmissions, we identified earlier onset ages, increasing expansion sizes and/or increasing methylation states (P=0.0034) of the 5' CpG island, reminiscent of disease anticipation. Also, intermediate repeats (7-24 units) showed a slightly higher methylation degree (P<0.0001) and a decrease of C9orf72 promoter activity (P<0.0001) compared with normal short repeats (2-6 units). Decrease of transcriptional activity was even more prominent in the presence of small deletions flanking G4C2 (P<0.0001). Here we showed that increased methylation of CpGs in the C9orf72 promoter may explain how an increasing G4C2 size lead to loss-of-function without excluding repeat length-dependent toxic gain-of-function. These data provide insights into disease mechanisms and have important implications for diagnostic counseling and potential therapeutic approaches.

Rationale and clinical data supporting nutritional intervention in Alzheimer's disease.

Adequate nutrition plays an important role in the maintenance of cognitive function, particularly during aging. Malnutrition is amongst the risk factors for developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Epidemiological studies have associated deficiencies in some nutrients with a higher risk of cognitive dysfunction and/or AD. Cognitive decline in AD is correlated with synaptic loss and many of the components required to maintain optimal synaptic function are derived from dietary sources. As synapses are part of the neuronal membrane and are continuously being remodelled, the availability of sufficient levels of nutritional precursors (mainly uridine monophosphate, choline and omega-3 fatty acids) to make the phospholipids required to build neuronal membranes may have beneficial effects on synaptic degeneration in AD. In addition, B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Despite this, no randomized controlled trial has hitherto provided evidence that any single nutrient has a beneficial effect on cognition or lowers the risk for AD. However, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders like AD leading to synaptic degeneration. Here we review the clinical evidence for supplementation, based on a multi-target approach with a focus on key nutrients with a proposed role in synaptic dysfunction. Based on preclinical evidence, a nutrient mixture, Souvenaid(®) (Nutricia N.V., Zoetermeer, The Netherlands) was developed. Clinical trials with Souvenaid(®) have shown improved memory performance in patients with mild AD. Further clinical trials to evaluate the effects of nutritional intervention in MCI and early dementia due to AD are on-going.

[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.

How does Parkinson's disease and aging affect temporal expectation and the implicit timing of eye movements?

Anticipatory eye movements are often evoked by the temporal expectation of an upcoming event. Temporal expectation is based on implicit timing about when a future event could occur. Implicit timing emerges from observed temporal regularities in a changing stimulus without any voluntary estimate of elapsed time, unlike explicit timing. The neural bases of explicit and implicit timing are likely different. It has been shown that the basal ganglia (BG) play a central role in explicit timing. In order to determine the influence of BG in implicit timing, we investigated the influence of early Parkinson's disease (PD) and aging on the latency of anticipatory eye movements. We hypothesized that a deficit of implicit timing should yield inadequate temporal expectations, and consequently abnormally timed anticipatory eye movements compared with age-matched controls. To test this hypothesis, we used an oculomotor paradigm where anticipation of a salient target event plays a central role. Participants pursued a visual target that moved along a circular path at a constant velocity. After a randomly short (1200 ms) or long (2400 ms) forward path, the target reversed direction, returned to its starting position and stopped. Target motion reversal caused an abrupt 'slip' of the pursued target image on the retina and was a particularly salient event evoking anticipatory eye movements. Anticipatory eye movements were less frequent in PD patients. However, the timing of anticipation of target motion reversal was statistically similar in PD patients and control subjects. Other eye movements showed statistically significant differences between PD and controls, but these differences could be attributed to other factors. We conclude that all anticipatory eye movements are not similarly impaired in PD and that implicit timing of salient events seems largely unaffected by this disease. The results support the hypothesis that implicit and explicit timing are differently affected by BG dysfunction.

Mild cognitive impairment: differential atrophy in the hippocampal subfields.

BACKGROUND AND PURPOSE: Hippocampus volumetry is a useful surrogate marker for the diagnosis of Alzheimer disease, but it seems insufficiently sensitive for the aMCI stage. We postulated that some hippocampus subfields are specifically atrophic in aMCI and that measuring hippocampus subfield volumes will improve sensitivity of MR imaging to detect aMCI. MATERIALS AND METHODS: We evaluated episodic memory and hippocampus subfield volume in 15 patients with aMCI and 15 matched controls. After segmentation of the whole hippocampus from clinical MR imaging, we applied a new computational method allowing fully automated segmentation of the hippocampus subfields. This method used a Bayesian modeling approach to infer segmentations from the imaging data. RESULTS: In comparison with controls, subiculum and CA2-3 were significantly atrophic in patients with aMCI, whereas total hippocampus volume and other subfields were not. Total hippocampus volume in controls was age-related, whereas episodic memory was the main explanatory variable for both the total hippocampus volume and the subfields that were atrophic in patients with aMCI. Segmenting subfields increases sensitivity to diagnose aMCI from 40% to 73%. CONCLUSIONS: Measuring CA2-3 and subiculum volumes allows a better detection of aMCI.

Poliomyelitis-like syndrome with matching magnetic resonance features in a case of Lyme neuroborreliosis.

Lyme disease is a multisystemic disorder caused by an epizootic organism of the spirochete group, called Borrelia burgdorferi, which is transmitted to humans by ticks of the genus Ixodes. Lyme neuroborreliosis may occur during the early dissemination phase, most often as a painful meningo-radiculitis and very rarely as a radiculo-myelitis, whereas encephalomyelitis is observed in the late phase. We report the case of a patient with an early subacute poliomyelitis-like syndrome closely matching the selective involvement of the anterior horns and roots of the cervical spinal cord seen on magnetic resonance imaging. This condition improved with appropriate antibiotics.

Poliomyelitis-like syndrome with matching magnetic resonance features in a case of Lyme neuroborreliosis.

Lyme disease is a multisystemic disorder caused by an epizootic organism of the spirochete group, called Borrelia burgdorferi (Bb), which is transmitted to humans by ticks of the genus Ixodes. Lyme neuroborreliosis may occur during the early dissemination phase, most often as a painful meningo-radiculitis and very rarely as a radiculo-myelitis, whereas encephalomyelitis is observed in the late phase. We report the case of a patient with an early subacute poliomyelitis-like syndrome closely matching the selective involvement of the anterior horns and roots of the cervical spinal cord seen on magnetic resonance (MR) imaging. This condition improved with appropriate antibiotics.

Optimization of encoding specificity for the diagnosis of early AD: the RI-48 task.

The aim of this study was to evaluate the discriminant validity of the RI-48 test, a shorter French version of the Category Cued Recall portion of the Double Memory Test developed initially by Buschke and colleagues (1997), in the diagnosis of mild and very mild Alzheimer disease (AD). The distinctive feature of the RI-48 task is that encoding specificity was increased by adding an immediate cued recall stage at the encoding phase. The results show that the RI-48 task seems to be well adapted to the clinical context and to have good psychometric properties, in particular a lack of a ceiling effect. Moreover, this task appears to be especially well suited for the diagnosis of both mild and very mild AD (sensitivity of 93% and 83.8%). From a more theoretical point of view, this study confirms the importance of optimizing the encoding specificity for the diagnosis of very mild AD, since the more encoding specificity is accentuated, the more discriminating power is increased for the diagnosis of very mild AD.

Clinical, electrophysiological and brain imaging features during recurrent ictal cortical blindness associated with chronic liver failure.

Transient neuroimaging features indicating primary cortical and secondary subcortical white matter cytotoxic oedema have been described in association with prolonged or intense seizures. We describe the unusual condition of recurrent ictal cortical blindness due to focal occipital status epilepticus, in the context of chronic hepatic failure. There was a close association between the onset and disappearance of clinical, electrophysiological and magnetic resonance imaging abnormalities.

Acquisition of a novel vocabulary in an amnesic patient.

This study explored the ability of a severe amnesic patient (AC) to acquire new vocabulary words. We compared AC's knowledge of words entered into the French lexicon during three different periods: before 1920, between 1965 and 1985, and after 1986 (i.e. after the onset of his amnesia). AC's knowledge was assessed by asking him to give, for each word, its definition (word-definition task), the general domain to which the word belonged ("domain" task), and to generate a sentence containing the word (sentence-generation task). Finally, we administered a recognition task in which AC had to select, for each word, its correct definition amongst four definitions. For all of these tasks, the results showed that AC's performance was similar to that of four control subjects matched for age, education, and profession. In particular, there was no difference with regard to AC's knowledge of words entered into the language after the onset of his amnesia. Therefore, these results indicate that, despite his profound amnesia, AC was able to learn normally new vocabulary words. More generally, they confirm that, at least is some cases, semantic learning can be spared in amnesia.

Cerebral blood flow and glucose metabolism in hypothyroidism: a positron emission tomography study.

Hypothyroidism is often associated with defective memory, psychomotor slowing, and depression. However, the relationship between thyroid status and cognitive or psychiatric disturbances remains unclear. Using psychometric scales, 10 patients who had undergone total thyroidectomy for thyroid carcinoma were evaluated for depression, anxiety, and psychomotor slowing; they were examined both when euthyroid and hypothyroid after thyroid hormone withdrawal. Positron emission tomography was used, with oxygen-15-labeled water and fluorine-18F-labeled 2-deoxy-2fluoro-D-glucose as the tracers, to correlate the regional cerebral blood flow and cerebral glucose metabolism with the mental state in patients. Two different image analysis techniques (regions of interest and statistical parametric maps) were applied. In hypothyroidism, there was a generalized decrease in regional cerebral blood flow (23.4%, P < 0.001) and in cerebral glucose metabolism (12.1%, P < 0.001) and there were no specific local defects. Patients were also significantly more depressed (P < 0.001), anxious (P < 0.001) and psychomotor slowed (P < 0.005) in hypo than in euthyroid status. These results indicate that the brain activity was globally reduced in severe hypothyroidism of short duration without the regional modifications usually observed in primary depression.

Comparison of regional cerebral blood flow and glucose metabolism in the normal brain: effect of aging.

The regional cerebral blood flow (rCBF) and metabolic rate for glucose (rCMRGlc) are associated with functional activity of the neural cells. The present work reports a comparison study between rCBF and rCMRGlc in a normal population as a function of age. 10 young (25.9+/-5.6 years) and 10 old (65.4+/-6.1 years) volunteers were similarly studied at rest. In each subject, rCBF and rCMRGlc were measured in sequence, during the same session. Both rCBF and rCMRGlc values were found to decrease from young (mean rCBF=43.7 ml/100 g per min; mean rCMRGlc=40.6 micromol/100 g per min) to old age (mean rCBF=37.3 ml/100 g per min; mean rCMRGlc=35.2 micromol/100 g per min), resulting in a drop over 40 years of 14.8% (0.37%/year) and 13.3% (0.34%/year), respectively. On a regional basis, the frontal and the visual cortices were observed to have, respectively, the highest and the lowest reduction in rCBF, while, for rCMRGlc, these extremes were observed in striatum and cerebellum. Despite these differences, the ratio of rCBF to rCMRGlc was found to have a similar behavior in all brain regions for young and old subjects as shown by a correlation coefficient of 88%. This comparative study indicates a decline in rCBF and rCMRGlc values and a coupling between CBF and CMRGlc as a function of age.

A standardized blood sampling scheme in quantitative FDG-PET studies.

Quantitative estimation of brain glucose metabolism (rCMRGlc) with positron emission tomography and fluorodeoxyglucose involves arterial blood sampling to estimate the delivery of radioactivity to the brain. Usually, for an intravenous injection of 30 s duration, an accurate input curve requires a frequency of one sample every 5 s or less to determine the peak activity in arterial plasma during the first 2 min after injection. In this work, 13 standardized sampling times were shown to be sufficient to accurately define the input curve. This standardized input curve was subsequently fitted by a polynomial function for its rising part and by spectral analysis for its decreasing part. Using the measured, the standardized, and the fitted input curves, rCMRGlc was estimated in 32 cerebral regions of interest in 20 normal volunteers. Comparison of rCMRGlc values obtained with the measured and the fitted input curves showed that both procedures gave consistent results, with a maximal relative error in mean rCMRGlc of 1% when using the autoradiographic method and 2% using kinetic analysis of dynamic data. This input-curve-fitting technique, which is not dependent on the peak time occurrence, allows an accurate determination of the input-curve shape from reduced sampling schemes.

Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF.

OBJECTIVE: To evaluate CSF levels of beta-amyloid(1-42) (Abeta42) alone and in combination with CSF tau for distinguishing AD from other conditions. METHODS: At 10 centers in Europe and the United States, 150 CSF samples from AD patients were analyzed and compared with 100 CSF samples from healthy volunteers or patients with disorders not associated with pathologic conditions of the brain (CON), 84 patients with other neurologic disorders (ND), and 79 patients with non-Alzheimer types of dementia (NAD). Sandwich ELISA techniques were used on site for measuring Abeta42 and tau. RESULTS: Median levels of Abeta42 in CSF were significantly lower in AD (487 pg/mL) than in CON (849 pg/mL; p = 0.001), ND (643 pg/mL; p = 0.001), and NAD (603 pg/mL; p = 0.001). Discrimination of AD from CON and ND was significantly improved by the combined assessment of Abeta42 and tau. At 85% sensitivity, specificity of the combined test was 86% (95% CI: 81% to 91%) compared with 55% (95% CI: 47% to 62%) for Abeta42 alone and 65% (95% CI: 58% to 72%) for tau. The combined test at 85% sensitivity was 58% (95% CI: 47% to 69%) specific for NAD. The APOE e4 gene load was negatively correlated with Abeta42 levels not only in AD but also in NAD. CONCLUSIONS: The combined measure of CSF Abeta42 and tau meets the requirements for clinical use in discriminating AD from normal aging and specific neurologic disorders.

Physostigmine results in an increased decrement in brain glucose consumption in Alzheimer's disease.

The responsibility of cerebral cholinergic lesions for the weak clinical response to cholinergic neurotransmission enhancement of Alzheimer's disease (AD) was studied by measuring the effects of physostigmine on glucose consumption and neuropsychological tests. Ten AD and ten aged normals (AN) were examined twice, under placebo and under maximal tolerated dose of physostigmine, in randomized order and blind fashion. Under physostigmine, both groups showed better performances in tests measuring attention (P < 0.05-0.001) but not long-term memory, and cerebral glucose consumption was regionally modified (P < 0.0001). We observed a regional decrease in AD and in AN which was larger in AD, where each patient exhibited a mean metabolic decrease. With normalized values, AD and AN showed a similar decrease in the metabolic values of prefrontal cortex and striatum (P = 0.0003). These findings suggest that cholinergic neurotransmission enhancement depresses glucose consumption and increases selective attention in similar ways in both groups, but to a larger extent in AD. This suggests that brain metabolism in AD over-responds to enhancement of cholinergic neurotransmission. The observed weak response of clinical symptomatology to anticholinesterase agents does not appear to be due to the failure to enhance the activity of the cholinergic system in AD.

Cholinergic neurotransmission has different effects on cerebral glucose consumption and blood flow in young normals, aged normals, and Alzheimer's disease patients.

Cerebral blood flow (CBF) and glucose consumption (GC) are both tracers of brain metabolic activity used to image the human brain in vivo. To know if both tracers reacted in the same manner when brain cholinergic neurotransmission was activated, CBF and GC were measured in young normals (YN), aged normals (AN), and Alzheimer's Disease patients (AD) using positron emission tomography (PET), H2 15O, and 18F-FDG. Each subject was studied twice, under placebo and physostigmine, in randomized order and blind fashion using the maximal tolerated dose of physostigmine individually determined. Under physostigmine CBF increased significantly (P = 0.0007) in posterior regions of the cerebral cortex and in the subcortical structures. Inversely, GC was decreased significantly in most regions. The largest decrease was seen in the prefrontal region of the cerebral cortex (P < 0.0001). Significant regional decreases were registered in all three groups of subjects, but were larger in AD than in controls. Looking at the absolute values of prefrontal cortex metabolism we found no correlation (r = 0.04) between the responses of CBF and GC. After normalization of the regional values for the mean we found a significant positive correlation between the responses of CBF and GC (r = 0.71, P < 0.0001). These findings suggest two components in the CBF response to physostigmine: one metabolic, depressive, and regional which follows the GC response; and one vascular, larger, diffuse, and opposite in direction to the metabolic component. These results have implications for the interpretation of CBF values as tracer of brain metabolic activity when brain cholinergic neurotransmission is manipulated.