Comparative diagnosis interest of NfL and pNfH in CSF and plasma in a context of FTD-ALS spectrum.

OBJECTIVE: The 'Frontotemporal dementia-Amyotrophic lateral sclerosis Spectrum' (FAS) encompasses different phenotypes, including cognitive disorders (frontotemporal dementia, FTD) and/or motor impairments (amyotrophic lateral sclerosis, ALS). The aim of this study was to apprehend the specific uses of neurofilaments light chain (NfL) and phosphorylated neurofilaments heavy chain (pNfH) in a context of FAS. METHODS: First, NfL and pNfH were measured in 39 paired cerebrospinal fluid (CSF) and plasma samples of FAS and primary psychiatric disorders (PPD) patients, considered as controls. Secondly, additional plasma samples were included to examine a larger cohort of 81 samples composed of symptomatic FAS and PPD patients, presymptomatic and non-carrier relatives individuals. The measures were performed using Simoa technology. RESULTS: There was a positive correlation between CSF and plasma values for NfL (p < 0.0001) and for pNfH (p = 0.0036). NfL values were higher for all phenotypes of symptomatic FAS patients compared to PPD patients (p = 0.0016 in CSF; p = 0.0003 in plasma). On the contrary, pNfH values were solely increased in FAS patients exhibiting motor impairment. Unlike symptomatic FAS patients, presymptomatic cases had comparable concentrations with non-carrier individuals. CONCLUSION: NfL, but not pNfH, appeared to be useful in a context of differential diagnosis between FTD and psychiatric patients. Nevertheless, pNfH seem more specific for the diagnosis and follow-up of motor impairments. In each specific indication, measures in CSF and plasma will provide identical interpretations.

Improving the Diagnosis of the Frontal Variant of Alzheimer's Disease with the DAPHNE Scale.

BACKGROUND: The frontal variant of Alzheimer's disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. OBJECTIVE: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. METHODS: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. RESULTS: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. CONCLUSION: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD.

Distinct effects of dopamine vs STN stimulation therapies in associative learning and retention in Parkinson disease.

Evidence has been provided in Parkinson's disease patients of cognitive impairments including visual memory and learning which can be partially compensated by dopamine medication or subthalamic nucleus stimulation. The effects of these two therapies can differ according to the learning processes involving the dorsal vs ventral part of the striatum. Here we aimed to investigate and compare the outcomes of dopamine vs stimulation treatment in Parkinson patient's ability to acquire and maintain over successive days their performance in visual working memory. Parkinson patients performed conditional associative learning embedded in visual (spatial and non spatial) working memory tasks over two consecutive days either ON or OFF dopaminergic drugs or STN stimulation depending on the group of patients studied. While Parkinson patients were more accurate and faster in memory tasks ON vs OFF stimulation independent of the day of testing, performance in medicated patients differed depending on the medication status during the initial task acquisition. Patients who learnt the task ON medication the first day were able to maintain or even improve their memory performance both OFF and ON medication on the second day after consolidation. These effects were observed only in patients with dopamine replacement with or without motor fluctuations. This enhancement in memory performance after having learnt under dopamine medication and not under STN stimulation was mostly significant in visuo-spatial working memory tasks suggesting that dopamine replacement in the depleted dorsal striatum is essential for retention and consolidation of learnt skill.

Dissociable dorsal and ventral frontostriatal working memory circuits: evidence from subthalamic stimulation in Parkinson's disease.

In this study, we investigated the neural substrates involved in visual working memory (WM) and the resulting effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD). Cerebral activation revealed by positron emission tomography was compared among Parkinson patients with (PD-ON) or without (PD-OFF) STN stimulation, and a group of control subjects (CT) in two visual WM tasks with spatial (SP) and nonspatial (NSP) components. PD-OFF patients displayed significant reaction time (RT) deficits for both memory tasks. Although there were no significant differences in RT between patients with PD-ON and -OFF stimulation, patients with PD-ON stimulation performed comparably to controls. The memory tasks were executed with normal error rates in PD-ON and -OFF stimulation. In contrast to these behavioral results, whether the corresponding prefrontal activation was differentially affected by deep brain stimulation status in patients depended on whether the WM modality was SP versus NSP. Thus, SP WM was associated with (1) abnormal reduction in dorsolateral prefrontal activity in PD-OFF and -ON stimulation and (2) abnormal overactivation in parieto-temporal cortex in PD-OFF and in limbic circuits in PD-ON stimulation. In NSP WM, normal activation of the ventral prefrontal cortex was restored in PD-ON stimulation. In both visual modalities the posterior cerebral regions including fusiform cortex and cerebellum, displayed abnormally reduced activity in PD. These results indicate that PD induces a prefrontal hypoactivation that STN stimulation can partially restore in a modality selective manner by additional recruitment of limbic structures in SP WM or by recovery of the ventral prefrontal activation in NSP WM.

[The specialist-referred patients represent 42% of the activity of an academic memory clinic]. / Le recours représente 42 % de l'activité d'une consultation mémoire neurologique d'un centre mémoire de ressources et de recherche.

OBJECTIVES: Evaluate demographic and aetiological characteristics of patients referred by specialist doctors (neurologists, geriatricians and psychiatrists) to an Academic Memory Clinic in Lyon, for the year 2008. These specialist-referred patients (SRP) constitute a specific mission of the French Academic Memory Clinics. METHODS: The outpatients consecutively referred in 2008 to our memory clinic by any persons (patients, families, general practitioners, specialist doctors) were all evaluated using clinical, neuropsychological and imaging information. We examined the distribution of patients diagnosis and differences in gender, education, and cognitive severity (MMSE). For each patient, diagnoses used clinical criteria at the first visit, and ranged from normal subjects to cognitive impaired patients with or without dementia. RESULTS: Among 384 patients, 160 (41.7%; 68 men and 92 women) were referred by specialist doctors. These 160 SRP were younger (P<0.0001) but did not differ from other patients on gender (P=0.55) nor Mini Mental State Examination (P=0.15). SRP were more often demented than the non-referred patients (respectively, 64.4% vs 39.7%; P=0.0001), and the demented SRP had less often Alzheimer's disease (AD) (30.1% vs 65.6%; P=0,0001). Dementia was present in 64.4% of the 160 SRP: among the 160, AD was the most frequent cause (19.4%), followed by Lewy body dementia (11.3%), neurological diseases (12.5% - multiple sclerosis, vascular cognitive impairment, epilepsy) and Mild Cognitive Impairment (10%). Normal subjects were present in 8.1% of the SRP. DISCUSSION: As compared to non-SRP, SRP are younger, more demented (64,4%) and more prone to have non-AD dementia (69,9%). However, AD represented the most frequent diagnosis (19.4% of SRP). CONCLUSION: SRP are an important part of the activity of an Academic Memory Clinic in Lyon. As compared to GPs, young and demented patients are more likely to be sent in a specialized referral center by specialist doctors.

Subthalamic nucleus stimulation selectively improves motor and visual memory performance in Parkinson's disease.

Although the treatment of Parkinson's disease via subthalamic stimulation yields remarkable improvements in motor symptoms, its effects on memory function are less clear. In this context, we previously demonstrated dissociable effects of levodopa therapy on parkinsonian performance in spatial and nonspatial visual working memory. Here we used the same protocol with an additional, purely motor task to investigate visual memory and motor performance in 2 groups of patients with Parkinson's disease with or without subthalamic stimulation. In each stimulation condition, subjects performed a simple motor task and 3 successive cognitive tasks: 1 conditional color-response association task and 2 visual (spatial and nonspatial) working memory tasks. The Parkinson's groups were compared with a control group of age-matched healthy subjects. Our principal results demonstrated that (1) in the motor task, stimulated patients were significantly improved with respect to nonstimulated patients and did not differ significantly from healthy controls, and (2) in the cognitive tasks, stimulated patients were significantly improved with respect to nonstimulated patients, but both remained significantly impaired when compared with healthy controls. These results demonstrate selective effects of subthalamic stimulation on parkinsonian disorders of motor and visual memory functions, with clear motor improvement for stimulated patients and a partial improvement for their visual memory processing.

[The 5-word test in 85 patients with generalized anxiety disorder]. / Le test des 5 mots chez 85 patients ayant un trouble anxieux généralisé

OBJECTIVES: Patients with generalized anxiety disorder (GAD) expressed frequent memory complaints leading to consultations in memory clinics. The 5-word test (5WT) is a serial verbal memory test with semantic cuing. It is proposed to rapidly evaluate memory of people with memory complaints. It has previously shown its sensitivity and its specificity in identifying patients with Alzheimer's disease (AD). The objective was to evaluate memory performances of patients with GAD. METHODS: Characteristics of the 5WT were investigated in a sample of 85 patients with GAD compared with 183 normal controls aged from 40 to 70 years. RESULTS: For each score of the 5WT, GAD patients significantly differed from controls. Forgetting rate was twice more important in GAD patients than in controls. However, for any score of the 5WT, Receiver Operating Characteristic (ROC) curves found no significant cut-off scores combining reliable sensitivity, specificity and correct classification of the subjects. DISCUSSION: In spite of ancient and severe mnestic complaints, GAD patients have significant difficulties with the 5WT as compared to controls without being of the magnitude of those observed in AD patients. CONCLUSION: The 5WT is an easy and rapid test allowing a reliable evaluation of memory in GAD patients. Results could usually confort patients. The presence of true memory deficits with the 5WT could not be ascribed to anxiety but to other pathological conditions. Consequently, further memory testing should be done.

Bilateral subthalamic nucleus stimulation in advanced Parkinson's disease: three years follow-up.

OBJECTIVE: To assess the long-term efficacy and safety of chronic bilateral stimulation of the subthalamic nucleus (STN) in patients with advanced Parkinson's disease (PD). METHODS: 36 consecutive patients with idiopathic Parkinson's disease treated with bilateral stimulation of the STN were studied. Parkinsonian status was assessed preoperatively and at 1 and 3 years postoperatively using the Unified Parkinson's Disease Rating Scale (UPDRS) and neuropsychological evaluation in on and off-medication / on and off stimulation conditions. RESULTS: At 3 years follow-up, STN stimulation reduced the UPDRS motor score by 54.2 % compared to baseline in the off-medication conditions. Tremor, rigidity, bradykinesia, postural stability, and gait improved by 72.2 %, 62.4 %, 56.8 %, 40.5 % and 45.3 %, respectively. UPDRS part II scores were reduced by 41.4 %. The overall dopaminergic drugs dose was reduced by 48.6 % after surgery and four patients were no longer taking antiparkinsonian medication at three years. However, axial dopa-unresponsive signs worsened in some patients. The most frequent transient adverse event consisted in mood disorders in 23 patients. CONCLUSIONS: Our data demonstrate that: 1) bilateral STN stimulation is relatively safe, improves the motor symptoms and drug-related motor complications of PD, and reduces the daily dosage of medication; 2) this benefit is sustained over time despite the occurrence of axial doparesistant signs in some patients.

Role of dopaminergic treatment in dopamine receptor down-regulation in advanced Parkinson disease: a positron emission tomographic study.

BACKGROUND: In patients with advanced Parkinson disease (PD) who are undergoing long-term treatment with a dopaminergic medication, a down-regulation of striatal dopamine D2 receptor expression has been demonstrated and interpreted as a consequence of either the disease itself or dopaminergic drug administration. OBJECTIVE: To compare, using positron emission tomography, the striatal binding of raclopride carbon C 11, a dopamine D2 receptor ligand, in PD patients who completely discontinued dopaminergic therapy (off drug) with that in PD patients who continued receiving dopaminergic therapy (on drug) after undergoing subthalamic nucleus stimulation. MAIN OUTCOME MEASURES: The positron emission tomographic data were acquired in off-stimulation and, for 12 hours, off-medication conditions. Five off-drug PD patients, 7 on-drug PD patients, and 8 healthy subjects participated. RESULTS: In off-drug PD patients, the putaminal raclopride C 11 binding was 24% higher than in on-drug PD patients. The same tendency was noted for the caudate nucleus, but was not significant (P=.07). Compared with control subjects, the putaminal raclopride C 11 binding was increased by 21% in off-drug and was normal in on-drug PD patients. Compared with controls, the caudate raclopride C 11 binding was reduced by 23% in on-drug and was normal in off-drug PD patients. Further analysis using statistical parametric mapping showed a significant increase of binding bilaterally in the caudate nucleus and putamen in off-drug compared with on-drug PD patients (P=.002 at cluster level). CONCLUSIONS: The down-regulation of dopamine D2 receptors probably relates to the long-term and intermittent administration of dopaminergic treatments rather than to disease progression. This phenomenon is reversed by the complete withdrawal of dopaminergic drugs. Furthermore, an up-regulation of putaminal dopamine D2 receptors is demonstrated in late-stage PD after dopaminergic drug withdrawal.