A combination of total tau and neurofilaments discriminates between neurodegenerative and primary psychiatric disorders.

BACKGROUND AND PURPOSE: Neuropsychiatric symptoms are commonly observed in neurodegenerative diseases. No biomarker is currently available to diagnose psychiatric conditions. As a consequence, the distinction between psychiatric and neurodegenerative disorders can be challenging in daily practice. METHODS: This retrospective study included a cohort of 64 primary psychiatric patients (PSY) and 162 patients suffering from various neurodegenerative disorders (NDG). Total tau (t-Tau), phosphorylated tau (p-Tau), Aß1-42 peptide (Aß1-42) and neurofilament light chain protein (NfL) were analysed in cerebrospinal fluid. The discrimination between PSY and NDG patients was assessed using both individual and combined analysis of cerebrospinal fluid markers. RESULTS: Cerebrospinal fluid t-Tau and NfL exhibited the best diagnostic performances: they were able to discriminate between PSY and each subgroup of NDG patients. t-Tau had the highest sensitivity (93.8%) but a poor specificity (67.3%). Indeed, some NDG subgroups exhibited low t-Tau levels comparable to PSY patients. A sequential combination t-Tau + NfL improved the characterization of patients, especially in these particular subgroups, increasing specificity up to 89.6% without modification of sensitivity. Finally, this combination of markers led to a high classification rate of 90.7% for the whole cohort of patients. CONCLUSION: The sequential combination t-Tau + NfL enables the biological detection of neurodegeneration in patients with psychiatric features. This association of markers seems to be a promising strategy for a differential diagnosis in clinical practice between primary psychiatric conditions and neurodegenerative disorders, thus improving medical care of patients.

[Diagnostic profile of young-onset dementia before 65 years. Experience of a French Memory Referral Center]. / Les pathologies démentielles avant 65 ans. Expérience de la file active d'une consultation mémoire neurologique.

OBJECTIVE: The aim of the study was to compare the profiles of patients with young (age≤65 years) and late (age>65 years) onset of dementia in a memory clinic of a Memory Referral Center in Lyons (France), for the year 2008. METHODS: A total of 746 demented patients were evaluated using clinical, neuropsychological and imaging information. For each patient, diagnoses of the dementing disorder used clinical criteria at the first visit. We examined the distribution of patients diagnosis and differences in sex and education between the young-onset dementia (YOD) and the late-onset dementia (LOD) groups. RESULTS: From a total of 746 registered demented patients (300 men, 446 women), there were 91 patients (12.2%) with YOD (from 36.5 to 65 years) and 655 patients with LOD (from 66 to 92 years). Among the 91 YOD patients, the most frequent causes were Mild Cognitive Impairment (MCI) (18.7%), then Alzheimer's disease (AD), frontotemporal dementia and posterior cortical atrophy (14.3% each), followed by progressive aphasia (11.0%), dementia with Lewy bodies (DLD) (9.9%), semantic dementia (8.8%), other causes (3.3%), vascular dementia (2.2%), undetermined dementia (2.2%), AD+cerebrovascular disease (1.1%). Among the 655 LOD patients, AD was the most frequent cause of dementia (57.4%). Referred cases by a specialist doctor were 50.5% in the YOD group and 12.7% in the LOD group (P<0.0001). In the ACP group, 68.4% patients began before 65 years. CONCLUSION: The number of YOD in our memory clinic was four-fold the number of expected patients in France. The characteristics of the Referral Center explain the high frequency of rare dementia such as progressive aphasia (5.2% of overall number), semantic dementia (3.6%) and posterior cortical atrophy (2.5%).

[The 5-word test in 37 depressed patients compared with 36 normal controls and 35 patients with mild Alzheimer's disease]. / Évaluation de la mémoire au moyen du Test des 5 mots chez 37 dépressifs comparés à 36 témoins et 35 patients ayant une forme légère de maladie d'Alzheimer.

OBJECTIVES: Patients with major depression (MD) express frequent memory complaints leading to consultations in memory clinics. The 5-word test (5WT) is a verbal memory test with semantic cueing, which has shown its sensitivity and its specificity in identifying patients with Alzheimer's disease (AD). Our objective was to evaluate memory performances of aged patients with MD compared with controls and AD patients. METHODS: Characteristics of the 5WT were investigated in a sample of 37 patients with MD (66.8±7.5 years) compared with 36 normal controls (67.3±6.8 years) and 35 mild AD patients (67.5±6.1 years). RESULTS: Duration of depression was 15.3±11.5 years. Memory complaints of MD patients were ancient (4.6±5.5 years) and severe (McNair memory questionnaire=47.6±20.7). The Total score of MD patients did not differ from controls but was greater than those of AD patients. Learning and Memory scores of MD patients were significantly lower than those of controls and significantly greater than those of AD patients. Forgetting rate between Learning and Memory scores was more important in AD (72.4%) than in controls (2.8%) and MD (13.6%). No intrusions were recorded in controls, three MD patients each made one intrusion, whereas 80% of AD patients made between one to six intrusions (mainly during cued delayed recall). Receiver operating characteristic curves determined the most significant cut-off scores of the Total score. It appeared easy to discriminate AD patients from controls (cut-off=9, sensitivity=94.3%, specificity=100%) or MD patients (cut-off=8, sensitivity=88.5%, specificity=89.2%) whereas it was more difficult to discriminate MD patients from controls (cut-off=10, specificity=88.9%, sensitivity=37.8%). DISCUSSION: MD patients had significant difficulties with the 5WT as compared to controls, without being of the magnitude of those observed in AD patients. CONCLUSION: The 5WT allows a reliable evaluation of memory in MD patients. The presence of true memory deficits with the 5WT could not be ascribed to depression but to other pathological conditions. Consequently, further memory testing should be conducted.

CSF biomarkers in posterior cortical atrophy.

OBJECTIVE: To describe CSF biomarker profiles in posterior cortical atrophy (PCA), which induces high-order visual deficits often associated with Alzheimer disease (AD) pathology, and relate these findings to clinical and neuropsychological assessment. METHODS: This prospective observational study included 22 patients with PCA who underwent CSF biomarker analysis of total tau (t-tau), phosphorylated tau on amino acid 181 (p-tau181), and amyloid ß (Aß(42)). At group level, the CSF profiles of patients with PCA were compared to those of patients with typical AD and patients with other dementia (OD). Individually, the clinical presentation of patients with PCA was correlated to their CSF profile to assess the predictability of clinical features for diagnosis of underlying AD pathology. RESULTS: At group level, the PCA biomarker profile was not different from that of the AD group, but very different from that of the OD group (p < 0.001). More than 90% of patients with PCA had CSF profiles consistent with AD. All patients with PCA with either isolated higher-order visual deficit (n = 8) or visual deficit associated with memory impairment (n = 11) had CSF profiles consistent with AD. Only one of the 3 patients with PCA with asymmetric motor signs fulfilled biological CSF criteria for AD. CONCLUSIONS: PCA syndrome is usually associated with CSF biomarkers suggestive of AD, as shown by previous neuropathologic studies. This does not apply in case of motor signs suggesting associated corticobasal syndrome. CSF biomarkers help to discriminate AD from non-AD processes associated with this condition.

[Q-ACP: a questionnaire for evaluating visual and gestural complaints in patients with posterior cortical atrophy]. / Q-ACP: un questionnaire d'évaluation des plaintes visuelles et gestuelles des patients ayant une atrophie corticale postérieure.

INTRODUCTION: Posterior cortical atrophy (PCA) is a clinical neurodegenerative syndrome associated with atrophy in parieto-occipital cortices, and characterized by prominent disorders of higher visual processing, affecting both dorsal and ventral streams. METHODS: We used a questionnaire (Q-ACP) specifically designed to assess visual and praxis dysfunctions in PCA. The Q-ACP contains 32 items (combined in 12 domains) aimed at describing everyday deficiencies that patients or caregivers notice about visual and gestural domains. It was administered to 34 patients with PCA (MMSE = 20.0 ± 5.1) which were compared with 17 patients with Alzheimer's disease (AD) (MMSE = 23.4 ± 1.9) and 31 normal controls (MMSE = 28.9 ± 1.1). RESULTS: Q-ACP of PCA patients (18.4 ± 5.3) was significantly greater than those of AD patients (2.7 ± 2.0) or normal controls (0.97 ± 1.6), and revealed disproportionate deficits on questions of visuospatial ability. Q-ACP was comparable in right (18.5 ± 4.3) and left (18.2 ± 6.8) PCA patients (p = 0.88). There was a negative correlation between MMSE and Q-ACP in PCA patients (r = -0.36; p = 0.045), but not in AD patients (r = -0.21; p = 0.42). When only the 22 PCA patients with MMSE equal or greater than 20 were considered, their Q-ACP score (17.2 ± 5.3) remained significantly greater than those of AD patients and normal controls (p = 0.0001). Controls had difficulties for only 12 of the 32 questions, and AD patients for 20 questions, whereas each of the 32 questions could be abnormal in the PCA group. The less often reported difficulties by PCA patients were for more easily reading small than big letters (14.7 %) whereas the most frequently impaired questions were for spatial and apractic agraphia (88.2 % for each question). Of the 12 domains of Q-ACP, all were impaired in PCA patients, 11 in AD patients and seven in controls. CONCLUSION: Q-ACP is a useful tool for assessing visual and praxis everyday difficulties of patients with PCA. These difficulties are rarely observed in normal aged controls or patients with mild AD.

[The five-word test in three age-groups of mild Alzheimer's disease (60, 70 and 80 year-old patients): Utility of the Total Score, Total Weighted Score, Learning Score and Memory Score]. / Le Test des cinq mots dans les formes légères de maladie d'Alzheimer : comparaison du score total, du Score Total Pondéré, du Score d'apprentissage et du Score de mémoire dans trois classes d'âge (60 ans, 70 ans, 80 ans).

INTRODUCTION: The five-word test (5WT) is a serial verbal memory test with semantic cuing. It is proposed to rapidly evaluate memory of aging people and has previously shown its sensitivity and its specificity in identifying patients with AD. It measures the efficacy of free and cued recalls during a procedure of immediate and delayed recalls. METHODS: The 5WT was compared in a group of 202 normal subjects and a group of 302 mild AD patients (MMS of 20 or more) aged from 60 to 92 years, in three age classes (60 years, 70 years, 80 years). Nine scores were measured (Total Score, Total Weighted Score, Free Immediate Recall, Learning Score=total of Immediate Recalls, Free Delayed Recall, Memory Score=total of Delayed Recalls, Forgetting Rate, Percentage of Immediate Cuing, Percentage of Delayed Cuing) as well as the presence of intrusions. For each age class, Receiver Operating Characteristic curves determined the most significant cut-off scores. RESULTS: For each score of the 5WT, AD patients differed significantly from controls. The cut-off scores were not the same according to age. For the Total Score, the cut-off scores were 10 (60 years), 9 (70 years) and 8 (80 years), whereas the cut-off scores of the Total Weighted Score were 17 (60 years), 16 (70 years) and 14 (80 years). As suggested by Cowppli-Bony et al. (2005), the Total Weighted Score (which gives a higher coefficient to free recalls) was better than the Total Score for discriminating mild AD. The 5WT is useful to discriminate normal controls and mild AD patients. Normal aged subjects displayed good encoding, efficient stocking and consolidation (few forgetting, efficient cued recall), intrusions were rare. Mild AD patients were characterized by weak encoding of words and severe deficit for stocking and consolidation (important forgetting, impaired cued recall), they made numerous intrusions. This psychometric profile is characteristic of the amnestic hippocampal syndrome found in AD. CONCLUSION: The 5WT is a simple and reliable test for investigating memory in elderly people above 60 years old. According to age, different cut-offs are needed for the Total Score and the Total Weighted Score, the latter appearing more discriminating than the Total Score for the diagnosis of mild AD. It is also interesting to evaluate the presence of intrusions. Lastly, it is important to consider the forgetting rate (between Learning and Memory Scores) in order to confirm the presence of a hippocampal amnesia.

[Validation of the Rapid BAttery of Denomination (BARD) in 382 controls and 1004 patients of a memory clinic]. / Validation de la batterie rapide de dénomination (BARD) chez 382 témoins et 1004 patients d'une consultation mémoire.

INTRODUCTION: The Rapid BAttery of Denomination (BARD) is a short 10-item naming test derived from the 60-item Boston Naming Test. It is easily performed in less than 15 seconds by normal controls independently of age, gender and education (Croisile, 2005,2007,2008). Our aim was to evaluate the BARD in various conditions seen in a memory clinic. PATIENTS AND METHODS: The BARD was used in 382 normal subjects (165 men and 217 women, aged from 20 to 97 years) and 1004 patients attending a memory clinic. Three groups of 505 patients with Alzheimer's disease (AD) were compared: mild patients (n=402), moderate patients (n=84) and moderately severe patients (n=19). The BARD was also used in 499 patients with a Mini Mental Status (MMSE)>or=20: 173 patients with amnestic Mild Cognitive Impairment (aMCI), 56 patients with frontotemporal dementia (FTD), 41 patients with Lewy Body dementia (LBD), 36 patients with nonfluent primary progressive aphasia (NFPPA), 27 patients with semantic dementia (SD), 16 patients with posterior cortical atrophy (PCA), 150 patients with anxiety or depression (ADD). RESULTS: The performance of the patients was not affected by age, gender or education. aMCI had a score of 9.97+/-0.18, ADD a score of 9.97+/-0.2. A mild anomia was observed in three groups: mild AD (9.78+/-0.5), FTD (9.79+/-0.65) et LBD (9.98+/-0.16). A more pronounced anomia was present in moderate AD (9.10+/-1.06), moderately severe AD (8.05+/-1.27), PCA (8.12+/-3.28) and NFPPA (8.44+/-1.61). The anomia was severe in SD (5.85+/-2.46). The 10 items were perfectly named by 98 % of ADD, 96.53 % of aMCI, 82.09 % of mild AD, 87.5 % of FTD patients, 97.56 % of LBD patients, 68.75 % of PCA patients, but only 45.24 % moderate AD, 5.26 % of moderately severe AD, 27.78 % of NFPPA, and 3.7 % of SD. In the patients with MMS>or=20, Anova showed that the BARD scores of the ADD, aMCI, mild AD, FTD and LBD groups were significantly greater than the BARD scores of NFPPA, SD and PCA. PCA and NFPPA groups did not differ for BARD scores whereas they were significantly better than SD. A ROC curve comparing the 822 mild anomic patients (AD, FTD, LBD, aMCI, ADD) with the 79 more anomic patients (NFPPA, SD, PCA) showed that for a BARD score of 10, sensitivity was 72.2 %, specificity was 89.2 %, and 87.7 % of the patients were correctly classified. CONCLUSION: The BARD is a quick and useful tool for identifying naming disorders in a memory clinic. In patients with MMSE>or=20, making one error at the BARD is highly abnormal and significantly characteristic of cognitive disorders: the more frequent the errors are, the more probable is the presence of a visual agnosia (PCA), an aphasia (NFPPA), or a semantic disorder (SD).

Double dissociation in neural correlates of visual working memory: a PET study.

Using positron emission tomography (PET), we investigated the organisation of spatial versus object-based visual working memory in 11 normal human subjects. The paradigm involved a conditional colour-response association task embedded within two visual working memory tasks. The subject had to remember a position (spatial) or shape (object-based) and then use this to recover the colour of the matching element for the conditional association. Activation of the nucleus accumbens and the anterior cingulate cortex was observed during the conditional associative task, indicating a possible role of these limbic structures in associative memory. When the 2 memory tasks were contrasted, we observed activation of 2 distinct cortical networks: (1) The spatial task activated a dorsal stream network distributed in the right hemisphere in the parieto-occipital cortex and the dorsal prefrontal cortex, and (2) The non spatial task activated a ventral stream network distributed in the left hemisphere in the temporo- occipital cortex, the ventral prefrontal cortex and the striatum. These results support the existence of a domain-specific dissociation with dorsal and ventral cortical systems involved respectively in spatial and non spatial working memory functions.

Dissociable effects of dopaminergic therapy on spatial versus non-spatial working memory in Parkinson's disease.

There is now evidence for definite and early cognitive deficits in Parkinson's disease (PD), involving, in particular, executive functions and working memory. However, the distinction between visuo-spatial and non-spatial working memory deficits and the impact of dopamine on these deficits are still open to debate. The aim of this study was therefore to investigate cognitive and motor performance in PD patients in two conditional associative learning tasks requiring either spatial or non-spatial visual working memory. The subject had to point to visual targets according to the visual characteristics of memorised visual cues (colour, position and form). To assess the effect of L-dopa therapy, PD patients were studied over two consecutive days: one ON/OFF group of nine PD patients with treatment (ON condition) on the first day and without treatment (OFF condition) on the second day; and another OFF/ON group of nine PD patients tested on reverse. The PD groups were compared to a control group of nine age-matched healthy subjects. Our main data demonstrate that: (1) in PD patients with OFF treatment, the response time of manual pointing is increased mainly in the non-spatial working memory task; and (2) in PD patients with ON treatment, either the response time is normal (on the first day) or is increased in both visuo-spatial and non-spatial tasks. We suggest that this dissociation between spatial versus non-spatial working memory deficits in non-medicated PD might be related to compensatory mechanisms that occur following fronto-striatal dysfunction.

The timing of antiparkinsonian treatment reduction after subthalamic nucleus stimulation.

The objective of this work was to precisely analyse the reduction of the antiparkinsonian treatment in 18 consecutive patients with Parkinson's disease (PD) operated on for bilateral subthalamic nucleus (STN) stimulation, first after 1 month of follow-up, then at 1 year postoperatively. Trihexyphenidyle, selegiline, entacapone, apomorphine and lisuride could be withdrawn shortly after starting STN electrical stimulation. The levodopa mean daily dose was reduced by 57% at 1 month after surgery and remained stable at 1 year. The mean ropinirole and bromocriptine daily dose decrements after surgery corresponded to 54 and 63%, respectively, at 1 month and to 77 and 40% at 1 year. At 12 months postoperatively, one third of the patients no longer received any antiparkinsonian drugs and the others were on monotherapy of either levodopa or dopamine agonists or received a combined treatment of a dopaminergic agonist and levodopa. In conclusion, STN stimulation allows a major reduction and simplification of antiparkinsonian treatment which can usually be achieved during the early postoperative period.

Subthalamic nucleus stimulation in Parkinson's disease: clinical evaluation of 18 patients.

The aim of the present study was to assess the efficacy and safety of chronic subthalamic nucleus deep-brain stimulation (STN-DBS) in patients with Parkinson's disease (PD). 18 consecutive severely affected PD patients were included (mean age, SD: 56.9+/-6 years; mean disease duration: 13.5+/-4.4 years). All the patients were evaluated clinically before and 6 months after the surgical procedure using the Unified Parkinson's Disease Rating Scale (UPDRS). Additionally, a 12 months follow-up was available in 14 patients. The target coordinates were determined by ventriculography under stereotactic conditions, followed by electrophysiology and intraoperative stimulation. After surgery, continuous monopolar stimulation was applied bilaterally in 17 patients at 2.9+/-0.4 V through 1 (n = 31) or 2 contacts (n = 3). One patient had bilateral bipolar stimulation. The mean frequency of stimulation was 140+/-16 Hz and pulse width 68+/-13 micros. Off medication, the UPDRS part III score (max = 108) was reduced by 55 % during on stimulation (score before surgery: 44.9+/-13.4 vs at 6 months: 20.2+/-10; p < 0.001). In the on medication state, no difference was noted between the preoperative and the postoperative off stimulation conditions (scores were respectively: 17.9+/-9.2 and 23+/-12.6). The severity of motor fluctuations and dyskinesias assessed by UPDRS IV was reduced by 76 % at 6 months (scores were respectively: 10.3+/-3 and 2.5+/-3; p < 0.001). Off medication, the UPDRS II or ADL score was reduced by 52.8 % during on stimulation (26.9+/-6.5 preop versus 12.7+/-7 at 6 months). The daily dose of antiparkinsonian treatment was diminished by 65.5 % (levodopa equivalent dose -- mg/D -- was 1045 +/- 435 before surgery and 360 +/- 377 at 6 months; p < 0.01). These results remained stable at 12 months for the 14 patients studied. Side effects comprised lower limb phlebitis (n = 2), pulmonary embolism (n = 1), depression (n = 6), dysarthria and freezing (n = 1), sialorrhea and drooling (n = 1), postural imbalance (n = 1), transient paresthesias and dyskinesias. This study confirms the great value of subthalamic nucleus stimulation in the treatment of intractable PD. Some adverse events such as depression may be taken into account in the inclusion criteria and also in the post-operative outcome.