Publications by authors named "Thibaud Lebouvier"

52 Publications

LeSCoD: a new clinical scale for the detection of Lewy body disease in neurocognitive disorders.

J Neurol 2021 Apr 8. Epub 2021 Apr 8.

Centre Mémoire Ressource et Recherche (CMRR), Department of Neurology, CHU Nantes, 44093, Nantes, France.

Background: Dementia with Lewy bodies remains underdiagnosed in clinical practice mainly because of the low sensitivity of existing diagnostic criteria and a strong overlap with Alzheimer's pathology that can mask the Lewy phenotype.

Objective: The objective of this study was therefore to develop and validate a new clinical scale designed to detect signs of Lewy body disease, called LeSCoD for Lewy body Screening scale in Cognitive Disorders.

Methods: 128 patients who fulfilled the clinical criteria of dementia with Lewy bodies (DLB; n = 32), Alzheimer's disease (AD; n = 77) or both (n = 19) was prospectively enrolled. F-DOPA PET imaging and/or CSF biomarkers were available in some patients. LeSCoD scale was systematically administered and the potential correlation with F-DOPA PET imaging was evaluated in a subgroup of patients.

Results: LeSCoD scale showed robust internal and external validity. We determined a cut-off of 10 above which the sensitivity and specificity for Lewy body disease diagnosis were 86% and 95%, respectively. The LeSCoD scale correlated with striatal dopamine uptake in F-DOPA PET.

Conclusion: LeSCoD scale is a simple and reliable tool for the evaluation of Lewy body disease in routine clinical practice, with a higher sensitivity and specificity than the existing criteria. It might be an alternative to the use of dopamine-specific imaging.
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http://dx.doi.org/10.1007/s00415-021-10539-0DOI Listing
April 2021

The infantile myofibromatosis NOTCH3 L1519P mutation leads to hyperactivated ligand-independent Notch signaling and increased PDGFRB expression.

Dis Model Mech 2021 Jan 28. Epub 2021 Jan 28.

Department of Neurobiology, Care Science and Society, Karolinska Institutet, Sweden

Infantile myofibromatosis (IMF) is a benign tumor form characterized by the development of nonmetastatic tumors in skin, bone, muscle and sometimes viscera. Autosomal dominant forms of IMF are caused by mutations in the gene, but a family carrying a L1519P mutation in the gene has also recently been identified. In this report, we address the molecular consequences of the NOTCH3 mutation and the relationship between the NOTCH and PDGFRB signaling in IMF. The NOTCH3 receptor generates enhanced downstream signaling in a ligand-independent manner. Despite the enhanced signaling, the NOTCH3 receptor is absent from the cell surface and instead accumulates in the endoplasmic reticulum. Furthermore, the localization of the NOTCH3 receptor in the bipartite, heterodimeric state is altered, combined with avid secretion of the mutated extracellular domain from the cell. Chloroquine treatment strongly reduces the amount of secreted NOTCH3 extracellular domain and decreases signaling. Finally, NOTCH3 upregulates PDGFRB expression in fibroblasts, supporting a functional link between Notch and PDGF dysregulation in IMF. Collectively, our data define a NOTCH3-PDGFRB axis in IMF, where an IMF-mutated NOTCH3 receptor elevates PDGFRB expression. The functional characterization of a ligand-independent gain-of-function NOTCH3 mutation is important for Notch therapy considerations for IMF, including strategies aimed at altering lysosome function.
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http://dx.doi.org/10.1242/dmm.046300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927659PMC
January 2021

Characteristics and progression of patients with frontotemporal dementia in a regional memory clinic network.

Alzheimers Res Ther 2021 01 8;13(1):19. Epub 2021 Jan 8.

Univ. Lille, Inserm, CHU Lille, Lille Neuroscience & Cognition, CNRMAJ, LiCEND, DistAlz, F-59000, Lille, France.

Background: Due to heterogeneous clinical presentation, difficult differential diagnosis with Alzheimer's disease (AD) and psychiatric disorders, and evolving clinical criteria, the epidemiology and natural history of frontotemporal lobar degeneration (FTD) remain elusive. In order to better characterize FTD patients, we relied on the database of a regional memory clinic network with standardized diagnostic procedures and chose AD patients as a comparator.

Methods: Patients that were first referred to our network between January 2010 and December 2016 and whose last clinical diagnosis was degenerative or vascular dementia were included. Comparisons were conducted between FTD and AD as well as between the different FTD syndromes, divided into language variants (lvFTD), behavioral variant (bvFTD), and FTD with primarily motor symptoms (mFTD). Cognitive progression was estimated with the yearly decline in Mini Mental State Examination (MMSE).

Results: Among the patients that were referred to our network in the 6-year time span, 690 were ultimately diagnosed with FTD and 18,831 with AD. Patients with FTD syndromes represented 2.6% of all-cause dementias. The age-standardized incidence was 2.90 per 100,000 person-year and incidence peaked between 75 and 79 years. Compared to AD, patients with FTD syndromes had a longer referral delay and delay to diagnosis. Patients with FTD syndromes had a higher MMSE score than AD at first referral while their progression was similar. mFTD patients had the shortest survival while survival in bvFTD, lvFTD, and AD did not significantly differ. FTD patients, especially those with the behavioral variant, received more antidepressants, anxiolytics, and antipsychotics than AD patients.

Conclusions: FTD syndromes differ with AD in characteristics at baseline, progression rate, and treatment. Despite a broad use of the new diagnostic criteria in an organized memory clinic network, FTD syndromes are longer to diagnose and account for a low proportion of dementia cases, suggesting persistent underdiagnosis. Congruent with recent publications, the late peak of incidence warns against considering FTD as being exclusively a young-onset dementia.
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http://dx.doi.org/10.1186/s13195-020-00753-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796569PMC
January 2021

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey.

Int J Geriatr Psychiatry 2021 02 16;36(2):324-333. Epub 2020 Sep 16.

Servicio de geriatria, Hospital Universitario Ramon y Cajal, Madrid, Spain.

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI.

Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI.

Results: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI.

Conclusions: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.
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http://dx.doi.org/10.1002/gps.5427DOI Listing
February 2021

Twenty-year trends in patient referrals throughout the creation and development of a regional memory clinic network.

Alzheimers Dement (N Y) 2020 26;6(1):e12048. Epub 2020 Aug 26.

Inserm CHU Lille Lille Neurosciences & Cognition UMR-S1172 Degenerative and Vascular Cognitive Disorders Univ. Lille Lille France.

Introduction: Memory clinics (MCs) are the main model for dementia diagnosis and care. Following the development of a MC network in Northern France, our objectives were to assess its impact on patient characteristics over 20 years.

Methods: The characteristics of new consultants were studied from 1997 to 2016.

Results: New consultants increased from 774 per year in 1997 to 26258 per year in 2016, as the number of MCs increased from 12 to 29. Over time, patients were progressively older and less educated, and more were living alone. A greater proportion of patients were referred by specialists. Referral delay and home-to-MC distance kept decreasing. The oldest patients were referred at a progressively less-severe stage. The proportion of young patients kept increasing in the tertiary referral center.

Discussions: The development of a region-wide MC network led to increased referral of vulnerable patients and differentiation of the tertiary referral center over time.
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http://dx.doi.org/10.1002/trc2.12048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449245PMC
August 2020

Does amnesia specifically predict Alzheimer's pathology? A neuropathological study.

Neurobiol Aging 2020 11 20;95:123-130. Epub 2020 Jul 20.

Univ Lille, Lille Neuroscience & Cognition (Inserm UMRS1172) Degenerative and Vascular Cognitive Disorders, CHU Lille, Laboratory of Excellence Distalz (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease), Lille, France.

Amnesia is a key component of Alzheimer's disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients' histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.011DOI Listing
November 2020

Antihypertensive agents in Alzheimer's disease: beyond vascular protection.

Expert Rev Neurother 2020 02 27;20(2):175-187. Epub 2019 Dec 27.

Inserm, CHU Lille, University of Lille, Lille, France.

: Midlife hypertension has been consistently linked with increased risk of cognitive decline and Alzheimer's disease (AD). Observational studies and randomized trials show that the use of antihypertensive therapy is associated with a lesser incidence or prevalence of cognitive impairment and dementia. However, whether antihypertensive agents specifically target the pathological process of AD remains elusive.: This review of literature provides an update on the clinical and preclinical arguments supporting anti-AD properties of antihypertensive drugs. The authors focused on validated all classes of antihypertensive treatments such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), β-blockers, diuretics, neprilysin inhibitors, and other agents. Three main mechanisms can be advocated: action on the concurrent vascular pathology, action on the vascular component of Alzheimer's pathophysiology, and action on nonvascular targets.: In 2019, while there is no doubt that hypertension should be treated in primary prevention of vascular disease and in secondary prevention of stroke and mixed dementia, the place of antihypertensive agents in the secondary prevention of 'pure' AD remains an outstanding question.
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http://dx.doi.org/10.1080/14737175.2020.1708195DOI Listing
February 2020

The gut in Parkinson's disease: Bottom-up, top-down, or neither?

Neurogastroenterol Motil 2020 01;32(1):e13777

DistAlz, Licend, CHU Lille, INSERM URM_S1172, University Lille, Lille, France.

The gut-brain axis is a hot topic in Parkinson's disease. In an attempt to decipher its role in the disease pathogenesis, several animal models have been developed. Most of these models tried to reproduce Braak's hypothesis by showing that the pathological process could spread from the gut to the brain (bottom-up scenario). Interestingly, others groups showed that a top-down scenario could also occur and that 6-hydroxydopamine-induced nigrostriatal denervation was sufficient to induce significant changes in the gastrointestinal tract. Aside from this toxic approach, the article by O'Donovan and colleagues in this edition of Neurogastroenterology and Motility showed that bilateral nigral injection of adeno-associated virus (AAV)-alpha-synuclein in rats was accompanied by changes in the enteric nervous system and the gut microbiota, which occurred without any apparent brain-to-gut spread of human injected alpha-synuclein. Some changes observed in the gastrointestinal tract of animals injected with AAV-alpha-synuclein were in line with previous observations in Parkinson's disease patients, including increased expression of glial markers, swollen tyrosine hydroxylase-positive varicosities in the submucosal plexus, and decreases in Faecalibacterium and Lachnospiraceae. These findings suggest that, in addition to gut-brain pathways, the brain-to-gut communication may also be involved in Parkinson's disease pathophysiology. In this mini-review, we describe the strengths and limitations of the existing studies on the gut-brain axis in experimental models of parkinsonism and discuss an alternative hypothesis in which the central and enteric nervous system would evolve separately during disease progression.
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http://dx.doi.org/10.1111/nmo.13777DOI Listing
January 2020

Astrocyte-microglial association and matrix composition are common events in the natural history of primary familial brain calcification.

Brain Pathol 2020 05 10;30(3):446-464. Epub 2019 Oct 10.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Primary familial brain calcification (PFBC) is an age-dependent and rare neurodegenerative disorder characterized by microvascular calcium phosphate deposits in the deep brain regions. Known genetic causes of PFBC include loss-of-function mutations in genes involved in either of three processes-platelet-derived growth factor (PDGF) signaling, phosphate homeostasis or protein glycosylation-with unclear molecular links. To provide insight into the pathogenesis of PFBC, we analyzed murine models of PFBC for the first two of these processes in Pdgfb and Slc20a2 mice with regard to the structure, molecular composition, development and distribution of perivascular calcified nodules. Analyses by transmission electron microscopy and immunofluorescence revealed that calcified nodules in both of these models have a multilayered ultrastructure and occur in direct contact with reactive astrocytes and microglia. However, whereas nodules in Pdgfb mice were large, solitary and smooth surfaced, the nodules in Slc20a2 mice were multi-lobulated and occurred in clusters. The regional distribution of nodules also differed between the two models. Proteomic analysis and immunofluorescence stainings revealed a common molecular composition of the nodules in the two models, involving proteins implicated in bone homeostasis, but also proteins not previously linked to tissue mineralization. While the brain vasculature of Pdgfb mice has been reported to display reduced pericyte coverage and abnormal permeability, we found that Slc20a2 mice have a normal pericyte coverage and no overtly increased permeability. Thus, lack of pericytes and increase in permeability of the blood-brain barrier are likely not the causal triggers for PFBC pathogenesis. Instead, gene expression and spatial correlations suggest that astrocytes are intimately linked to the calcification process in PFBC.
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http://dx.doi.org/10.1111/bpa.12787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317599PMC
May 2020

Benzodiazepine use and brain amyloid load in nondemented older individuals: a florbetapir PET study in the Multidomain Alzheimer Preventive Trial cohort.

Neurobiol Aging 2019 12 14;84:61-69. Epub 2019 Aug 14.

UMR 1253, iBrain, Université de Tours, Inserm, Tours, France; CHU de Tours, Tours, France.

It remains unclear whether benzodiazepines (BZDs) constitute a risk factor for Alzheimer's disease (AD). In this study, we investigated associations between chronic use of BZDs and brain amyloid load, a hallmark of AD, in 268 nondemented older individuals. F-florbetapir positron emission tomography scans were performed to assess amyloid load as measured by standardized uptake value ratios, which were compared between chronic BZD users and nonusers using adjusted multiple linear regressions. Short- versus long-acting BZDs were also considered in the analyses. Standardized uptake value ratios were significantly lower in BZD users (n = 47) than in nonusers (n = 221), independent of multiple adjustments. The effect was stronger for short-acting BZDs than for long-acting BZDs. This is the first large clinical study showing a reduced brain amyloid load in chronic BZD users, especially with short-acting BZDs. Our results do not support the view of BZD use as a risk factor for AD and instead support the involvement of pharmacological mechanisms related to neuronal hyperactivity, neuroinflammation, and sleep quality as potential targets for blocking amyloid accumulation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.008DOI Listing
December 2019

Idiopathic Normal-Pressure Hydrocephalus: Diagnostic Accuracy of Automated Sulcal Morphometry in Patients With Ventriculomegaly.

Neurosurgery 2019 10;85(4):E747-E755

Department of Neuroradiology, Hôpital Henri Mondor, Créteil, France.

Background: Idiopathic normal-pressure hydrocephalus (iNPH) is a treatable cause of gait and cognitive impairment. iNPH should be differentiated from ventriculomegaly secondary to brain atrophy to choose the best therapeutic option (ventriculoperitoneal shunt vs medical management).

Objective: To determine the diagnostic accuracy of automated sulcal morphometry to differentiate patients with iNPH from patients with ventriculomegaly of neurodegenerative origin.

Methods: Thirty-eight consecutive patients with iNPH (shunt responsive n = 31, nonresponsive n = 7), 35 with vascular cognitive disorder, and 25 age- and sex-matched healthy controls were prospectively included and underwent cognitive evaluation and 3T brain magnetic resonance imaging. Sulcal opening of 10 sulci of interest was retrospectively measured using an automated surface-based approach from the 3-dimensional T1-weighted images. Receiver-operating characteristic curve analyses determined the best parameter to identify iNPH patients.

Results: The best parameter to discriminate shunt-responsive iNPH from patients with vascular cognitive disorder and healthy controls was the ratio between calcarine sulcus and cingulate sulcus opening with an area under the curve of 0.94 (95% CI: 0.89, 0.99). A cut-off value of 0.95 provided the highest sensitivity (96.8%) and specificity (83.3%).

Conclusion: This preliminary study showed that automated sulcal morphometry may help the neurosurgeon to identify iNPH patients and to exclude other causes of ventriculomegaly.
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http://dx.doi.org/10.1093/neuros/nyz121DOI Listing
October 2019

Is endoscopic third ventriculostomy safe and efficient in the treatment of obstructive chronic hydrocephalus in adults? A prospective clinical and MRI study.

Acta Neurochir (Wien) 2019 07 8;161(7):1353-1360. Epub 2019 May 8.

Department of Neurology, Lille University Hospital (CHU Lille), University of Lille, Lille, France.

Background: In case of suspected normal pressure hydrocephalus, MRI is performed systematically and can sometimes highlight an obstruction of the flow pathways of the CSF (aqueductal stenosis or other downstream obstruction). It seems legitimate for these patients to ask the question of a treatment with endoscopic third ventriculostomy (ETV), even if the late decompensation of an obstruction may suggest an association with a CSF resorption disorder. The aim of this study was to evaluate clinical and radiological evolution after ETV in a group of elderly patients with an obstructive chronic hydrocephalus (OCH).

Methods: ETV was performed in 15 patients with OCH between 2012 and 2017. Morphometric (callosal angle, ventricular surface, third ventricular width, and Evans' index) and velocimetric parameters (stroke volume of the aqueductal (SVa) CSF) parameters were measured prior and after surgery with brain MRI. The clinical score (mini-mental status examination (MMSE) and the modified Larsson's score, evaluating walking, autonomy, and incontinence) were performed pre- and postoperatively.

Results: SVa was less than 15 μL/R-R in 12 out of the 15 patients; in the other three cases, the obstruction was located at a distance from the middle part of the aqueduct. Fourteen out of 15 patients were significantly improved: mean Larsson's score decreased from 3.8 to 0.6 (P ≤ 0.01) and mean MMSE increased from 25.7 to 28 (P = 0.084). Evans' index and ventricular area decreased postoperatively and the callosal angle increased (P ≤ 0.01). The mean follow-up lasted 17.9 months. No postoperative complications were observed.

Conclusion: ETV seems to be a safe and efficient alternative to shunt for chronic hydrocephalus with obstruction; the clinical improvement is usual and ventricular size decreases slightly.
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http://dx.doi.org/10.1007/s00701-019-03932-2DOI Listing
July 2019

Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype.

Brain 2019 06;142(6):1573-1586

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Primary familial brain calcification (PFBC) is a rare neurogenetic disorder with diverse neuropsychiatric expression. Mutations in four genes cause autosomal dominant PFBC: SLC20A2, XPR1, PDGFB and PDGFRB. Recently, biallelic mutations in the MYORG gene have been reported to cause PFBC with an autosomal recessive pattern of inheritance. We screened MYORG in 29 unrelated probands negatively screened for the autosomal dominant PFBC genes and identified 11 families with a biallelic rare or novel predicted damaging variant. We studied the clinical and radiological features of 16 patients of these 11 families and compared them to that of 102 autosomal dominant PFBC patients carrying a mutation in one of the four known autosomal dominant PFBC genes. We found that MYORG patients exhibited a high clinical penetrance with a median age of onset of 52 years (range: 21-62) with motor impairment at the forefront. In particular, dysarthria was the presenting sign in 11/16 patients. In contrast to patients with autosomal dominant PFBC, 12/15 (80%) symptomatic patients eventually presented at least four of the following five symptoms: dysarthria, cerebellar syndrome, gait disorder of any origin, akinetic-hypertonic syndrome and pyramidal signs. In addition to the most severe clinical pattern, MYORG patients exhibited the most severe pattern of calcifications as compared to the patients from the four autosomal dominant PFBC gene categories. Strikingly, 12/15 presented with brainstem calcifications in addition to extensive calcifications in other brain areas (lenticular nuclei, thalamus, cerebellar hemispheres, vermis, ±cortex). Among them, eight patients exhibited pontine calcifications, which were observed in none of the autosomal dominant PFBC patients and hence appeared to be highly specific. Finally, all patients exhibited cerebellar atrophy with diverse degrees of severity on CT scans. We confirmed the existence of cerebellar atrophy by performing MRI voxel-based morphometry analyses of MYORG patients with autosomal dominant PFBC mutation carriers as a comparison group. Of note, in three families, the father carried small pallido-dentate calcifications while carrying the mutation at the heterozygous state, suggesting a putative phenotypic expression in some heterozygous carriers. In conclusion, we confirm that MYORG is a novel major PFBC causative gene and that the phenotype associated with such mutations may be recognized based on pedigree, clinical and radiological features.
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http://dx.doi.org/10.1093/brain/awz095DOI Listing
June 2019

Frontotemporal dementia is the leading cause of "true" A-/T+ profiles defined with Aβ ratio.

Alzheimers Dement (Amst) 2019 Dec 15;11:161-169. Epub 2019 Feb 15.

University of Lille, Inserm U1172, CHU Lille, DISTALZ, Lille, France.

Introduction: Patients with positive tauopathy but negative Aβ (A-T+) in the cerebrospinal fluid (CSF) represent a diagnostic challenge. The Aβ ratio supersedes Aβ and reintegrates "false" A-T+ patients into the Alzheimer's disease spectrum. However, the biomarker and clinical characteristics of "true" and "false" A-T+ patients remain elusive.

Methods: Among the 509 T+N+ patients extracted from the databases of three memory clinics, we analyzed T+N+ patients with normal Aβ and compared "false" A-T+ with abnormal Aβ ratio and "true" A-T+ patients with normal Aβ ratio, before CSF analysis and at follow-up.

Results: 24.9% of T+N+ patients had normal Aβ levels. Among them, 42.7% were "true" A-T+. "True" A-T+ had lower CSF tau than "false" A-T+ patients. 48.0% of "true" A-T+ patients were diagnosed with frontotemporal lobar degeneration before CSF analysis and 64.0% at follow-up, as compared with 6% in the "false" A-T+ group ( < .0001).

Discussion: Frontotemporal lobar degeneration is probably the main cause of "true" A-T+ profiles.
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http://dx.doi.org/10.1016/j.dadm.2019.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378630PMC
December 2019

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Brain 2018 10;141(10):2895-2907

Neurodegenerative Brain Diseases, Center of Molecular Neurology, VIB, Antwerp, Belgium.

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/brain/awy238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158742PMC
October 2018

Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types.

Sci Data 2018 08 21;5:180160. Epub 2018 Aug 21.

Integrated Cardio Metabolic Centre, Department of Medicine Huddinge, Karolinska Institutet, Blickagången 6, SE-141 57 Huddinge, Sweden.

Vascular diseases are major causes of death, yet our understanding of the cellular constituents of blood vessels, including how differences in their gene expression profiles create diversity in vascular structure and function, is limited. In this paper, we describe a single-cell RNA sequencing (scRNA-seq) dataset that defines vascular and vessel-associated cell types and subtypes in mouse brain and lung. The dataset contains 3,436 single cell transcriptomes from mouse brain, which formed 15 distinct clusters corresponding to cell (sub)types, and another 1,504 single cell transcriptomes from mouse lung, which formed 17 cell clusters. In order to allow user-friendly access to our data, we constructed a searchable database (http://betsholtzlab.org/VascularSingleCells/database.html). Our dataset constitutes a comprehensive molecular atlas of vascular and vessel-associated cell types in the mouse brain and lung, and as such provides a strong foundation for future studies of vascular development and diseases.
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http://dx.doi.org/10.1038/sdata.2018.160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103262PMC
August 2018

Author Correction: A molecular atlas of cell types and zonation in the brain vasculature.

Nature 2018 08;560(7716):E3

Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Blickagången 6, SE-141 57, Huddinge, Sweden.

In Fig. 1b of this Article, 'Csf1r' was misspelt 'Csfr1'. In addition, in Extended Data Fig. 11b, owing to an error during figure formatting, the genes listed in the first column shifted down three rows below the first gene on the list, causing a mismatch between the gene names and their characteristics. These errors have been corrected online, and the original Extended Data Fig. 11b is provided as Supplementary Information to the accompanying Amendment.
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http://dx.doi.org/10.1038/s41586-018-0232-xDOI Listing
August 2018

Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study.

J Alzheimers Dis 2018 ;63(4):1317-1323

University of Lille, Inserm U1171, CHU, DISTALZ, Lille, France.

Background: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD).

Objective: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD.

Methods: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data.

Results: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2±3.5 years) than in patients without LP (7±1.7 years) or with amygdala LP (8±2.8 years; p < 0.01). There was no significant difference in cognitive profiles.

Conclusion: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis.
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http://dx.doi.org/10.3233/JAD-170914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218122PMC
June 2019

A molecular atlas of cell types and zonation in the brain vasculature.

Nature 2018 02 14;554(7693):475-480. Epub 2018 Feb 14.

Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre (KI/AZ ICMC), Blickagången 6, SE-141 57 Huddinge, Sweden.

Cerebrovascular disease is the third most common cause of death in developed countries, but our understanding of the cells that compose the cerebral vasculature is limited. Here, using vascular single-cell transcriptomics, we provide molecular definitions for the principal types of blood vascular and vessel-associated cells in the adult mouse brain. We uncover the transcriptional basis of the gradual phenotypic change (zonation) along the arteriovenous axis and reveal unexpected cell type differences: a seamless continuum for endothelial cells versus a punctuated continuum for mural cells. We also provide insight into pericyte organotypicity and define a population of perivascular fibroblast-like cells that are present on all vessel types except capillaries. Our work illustrates the power of single-cell transcriptomics to decode the higher organizational principles of a tissue and may provide the initial chapter in a molecular encyclopaedia of the mammalian vasculature.
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http://dx.doi.org/10.1038/nature25739DOI Listing
February 2018

Update on tauopathies.

Curr Opin Neurol 2017 Dec;30(6):589-598

University Lille, Inserm, CHU-Lille, Memory and Resources Research Centre, Lille, France.

Purpose Of Review: The purpose of this review is to provide an update on the role of tau beyond the stabilization of microtubules and on the clinical, pathological, diagnostic and therapeutic aspects of tauopathies.

Recent Findings: Beyond its function as a microtubule-associated tau protein, tau is also involved in gene regulation, signal transduction and metabolism. Experimental models allow for the development of new diagnostic and therapeutic tools. Tauopathies encompass different disorders that may manifest with various clinical syndromes. Differential diagnosis with other proteinopathies is still challenging. Cerebrospinal fluid biomarkers and radiotracers were extensively studied in the last year. Although diagnostic accuracy remains deceiving in non-Alzheimer's disease tauopathies, positron emission tomography tau tracers could be used to monitor disease progression.

Summary: Despite the advent of novel therapeutic approaches and the increasing number of clinical trials in tauopathies, accurate clinical diagnosis is still an unmet need and better tau biomarkers are still desperately needed. Although primary taupathies are rare and heterogeneous disorders, their combined prevalence and the importance of tau disorder in Alzheimer's disease and secondary tauopathies makes research on tauopathy a priority - because it could benefit many patients.
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http://dx.doi.org/10.1097/WCO.0000000000000502DOI Listing
December 2017

Biochemical analysis of α-synuclein extracted from control and Parkinson's disease colonic biopsies.

Neurosci Lett 2017 02 23;641:81-86. Epub 2017 Jan 23.

Inserm, U913, Nantes F-44035, France; Nantes University, Nantes F-44035, France; CHU Nantes, Department of Neurology, Nantes F-44093, France. Electronic address:

Lewy bodies and neurites, the pathological hallmarks found in the brain of Parkinson's disease (PD) patients, are primarily composed of aggregated and hyperphosphorylated alpha-synuclein. The observation that alpha-synuclein inclusions are also found in the gut of the vast majority of parkinsonian patients has led to an increasing number of studies aimed at developing diagnostic procedures based on the detection of pathological alpha-synuclein in gastrointestinal biopsies. The previous studies, which have all used immunohistochemistry for the detection of alpha-synuclein, have provided conflicting results. In the current survey, we used a different approach by analyzing the immunoreactivity pattern of alpha-synuclein separated by one- and two-dimensional electrophoresis, in colonic biopsies from PD subjects and healthy individuals. We did not observe any differences between controls and PD in the expression levels, phosphorylation or aggregation status of alpha-synuclein. Overall, our study suggests that the two biochemical methods tested here are not adequate for the prediction of PD using gastrointestinal biopsies. Further studies, using other biochemical approaches, are warranted to test whether there exists specific forms of pathological alpha-synuclein that distinguish PD from control subjects.
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http://dx.doi.org/10.1016/j.neulet.2017.01.050DOI Listing
February 2017

Analysis of the brain mural cell transcriptome.

Sci Rep 2016 10 11;6:35108. Epub 2016 Oct 11.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Pericytes, the mural cells of blood microvessels, regulate microvascular development and function and have been implicated in many brain diseases. However, due to a paucity of defining markers, pericyte identification and functional characterization remain ambiguous and data interpretation problematic. In mice carrying two transgenic reporters, Pdgfrb-eGFP and NG2-DsRed, we found that double-positive cells were vascular mural cells, while the single reporters marked additional, but non-overlapping, neuroglial cells. Double-positive cells were isolated by fluorescence-activated cell sorting (FACS) and analyzed by RNA sequencing. To reveal defining patterns of mural cell transcripts, we compared the RNA sequencing data with data from four previously published studies. The meta-analysis provided a conservative catalogue of 260 brain mural cell-enriched gene transcripts. We validated pericyte-specific expression of two novel markers, vitronectin (Vtn) and interferon-induced transmembrane protein 1 (Ifitm1), using fluorescent in situ hybridization and immunohistochemistry. We further analyzed signaling pathways and interaction networks of the pericyte-enriched genes in silico. This work provides novel insight into the molecular composition of brain mural cells. The reported gene catalogue facilitates identification of brain pericytes by providing numerous new candidate marker genes and is a rich source for new hypotheses for future studies of brain mural cell physiology and pathophysiology.
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http://dx.doi.org/10.1038/srep35108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5057134PMC
October 2016

A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia.

Neurology 2016 May 6;86(18):1729-35. Epub 2016 Apr 6.

From Université de la Sorbonne UPMC Paris 06 UMR S 1127 (E.H., M.V., V.B., C.H., D.G., A. Méneret, S. Dupont, E.A., J.-C.C., E.R.), Inserm U 1127, CIC-1422, CNRS UMR 7225, Institut du Cerveau et de la Moëlle, Paris; Département des Maladies du Système Nerveux (E.H., M.V., C.H., B.D., C.B., D.G., J.-C.C., E.R.), Département de Biostatistiques, Unité de Recherche Clinique (N.C., A.B., A. Mallet), Pharmacie (F.C.-B.), Département de Pharmacologie (N.Z.), Département de Génétique, UF de Neurogénétique Moléculaire et Cellulaire (F.C.), and Département d'Epilepsie et de Réhabilitation (S. Dupont), Hôpital Pitié-Salpêtrière, AP-HP; Unité de Neurophysiologie (E.H., E.A.), Département DéPAS, Hôpital Saint-Antoine, AP-HP, Paris; Hospices Civils de Lyon (S.T.), Hôpital Neurologique Pierre Wertheimer; Université Lyon 1 (S.T.); CNRS (S.T.), Centre de Neurosciences Cognitives, UMR 5229, Bron; Département de Neurologie (C.T.), Hôpital de Hautepierre, CHU Strasbourg; Fédération de Médecine translationnelle de Strasbourg (FMTS) (C.T.), Strasbourg, France; Département de Neurologie (G.G.), Hôpital Brugmann, Bruxelles, Belgium; Département de Neurologie (S.Drapier), Hôpital Pontchaillou, CHU Rennes; EA-4712 "Comportement et Noyaux Gris Centraux" (S. Drapier), Université de Rennes 1; Département de Neurologie et Pathologies du Movement (E.M.) and Département de Neurologie (T.L.), CHU de Lille; INSERM UMR-S 1172 (E.M.), Lille; Département de Neurologie (A.D.D.M.), Hôpital Maison Blanche, CHU de Reims; Centre Memoire de Ressources et de Recherche (CMRR) (T.L.), Lille; ESPCI Paris Tech (A.-P.L.), PSL Research University; and Département de Neurologie et Pathologie du Movement (J.-P.A.), Pôle Neurosciences Cliniques, INT-CNRS/AMU Aix-Marseille, France.

Objective: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia.

Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co-primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression-Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects.

Results: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] -5 [-9.25 to -1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] -2 [-2.58 to -2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] -3 [-8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] -1 [-1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated.

Conclusions: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia.

Classification Of Evidence: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia.
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http://dx.doi.org/10.1212/WNL.0000000000002631DOI Listing
May 2016

Functional Characterization of Germline Mutations in PDGFB and PDGFRB in Primary Familial Brain Calcification.

PLoS One 2015 23;10(11):e0143407. Epub 2015 Nov 23.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 75185, Sweden.

Primary Familial Brain Calcification (PFBC), a neurodegenerative disease characterized by progressive pericapillary calcifications, has recently been linked to heterozygous mutations in PDGFB and PDGFRB genes. Here, we functionally analyzed several of these mutations in vitro. All six analyzed PDGFB mutations led to complete loss of PDGF-B function either through abolished protein synthesis or through defective binding and/or stimulation of PDGF-Rβ. The three analyzed PDGFRB mutations had more diverse consequences. Whereas PDGF-Rβ autophosphorylation was almost totally abolished in the PDGFRB L658P mutation, the two sporadic PDGFRB mutations R987W and E1071V caused reductions in protein levels and specific changes in the intensity and kinetics of PLCγ activation, respectively. Since at least some of the PDGFB mutations were predicted to act through haploinsufficiency, we explored the consequences of reduced Pdgfb or Pdgfrb transcript and protein levels in mice. Heterozygous Pdgfb or Pdgfrb knockouts, as well as double Pdgfb+/-;Pdgfrb+/- mice did not develop brain calcification, nor did Pdgfrbredeye/redeye mice, which show a 90% reduction of PDGFRβ protein levels. In contrast, Pdgfbret/ret mice, which have altered tissue distribution of PDGF-B protein due to loss of a proteoglycan binding motif, developed brain calcifications. We also determined pericyte coverage in calcification-prone and non-calcification-prone brain regions in Pdgfbret/ret mice. Surprisingly and contrary to our hypothesis, we found that the calcification-prone brain regions in Pdgfbret/ret mice model had a higher pericyte coverage and a more intact blood-brain barrier (BBB) compared to non-calcification-prone brain regions. While our findings provide clear evidence that loss-of-function mutations in PDGFB or PDGFRB cause PFBC, they also demonstrate species differences in the threshold levels of PDGF-B/PDGF-Rβ signaling that protect against small-vessel calcification in the brain. They further implicate region-specific susceptibility factor(s) in PFBC pathogenesis that are distinct from pericyte and BBB deficiency.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143407PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658112PMC
June 2016

Gpr116 Receptor Regulates Distinctive Functions in Pneumocytes and Vascular Endothelium.

PLoS One 2015 22;10(9):e0137949. Epub 2015 Sep 22.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.

Despite its known expression in both the vascular endothelium and the lung epithelium, until recently the physiological role of the adhesion receptor Gpr116/ADGRF5 has remained elusive. We generated a new mouse model of constitutive Gpr116 inactivation, with a large genetic deletion encompassing exon 4 to exon 21 of the Gpr116 gene. This model allowed us to confirm recent results defining Gpr116 as necessary regulator of surfactant homeostasis. The loss of Gpr116 provokes an early accumulation of surfactant in the lungs, followed by a massive infiltration of macrophages, and eventually progresses into an emphysema-like pathology. Further analysis of this knockout model revealed cerebral vascular leakage, beginning at around 1.5 months of age. Additionally, endothelial-specific deletion of Gpr116 resulted in a significant increase of the brain vascular leakage. Mice devoid of Gpr116 developed an anatomically normal and largely functional vascular network, surprisingly exhibited an attenuated pathological retinal vascular response in a model of oxygen-induced retinopathy. These data suggest that Gpr116 modulates endothelial properties, a previously unappreciated function despite the pan-vascular expression of this receptor. Our results support the key pulmonary function of Gpr116 and describe a new role in the central nervous system vasculature.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137949PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579087PMC
May 2016

An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients.

J Alzheimers Dis 2015 ;45(4):1061-76

AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, Innovative Medicines, AstraZeneca R&D, Sweden Department Clinical Neuroscience, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.

Alzheimer's disease (AD) is the most common form of dementia, with no disease-modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181, and with the two ratios t-tau/Aβ1-42 and p-tau181/Aβ1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF biomarker p-tau181/Aβ1-42 ratio with consideration of APOE ε4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome-wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181/Aβ1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients.
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http://dx.doi.org/10.3233/JAD-142118DOI Listing
March 2016

Appraisal of the dopaminergic and noradrenergic innervation of the submucosal plexus in PD.

J Parkinsons Dis 2014 ;4(4):571-6

Inserm U913, Nantes, France University Nantes, Nantes, France CHU Nantes, Department of Neurology, Nantes, France Inserm CIC 00-04, Nantes, France.

Background: The principal components of the enteric nervous system (ENS) are two neuronal networks, the myenteric and submucosal plexus (SMP), which are primarily involved in the regulation of gastrointestinal (GI) motility and secretion, respectively. These two plexus are made up of intrinsic neurons receiving input from the extrinsic sympathetic and parasympathetic innervation of the gut. Both the intrinsic and extrinsic innervations of the gut are affected by Lewy pathology in Parkinson's disease (PD). A recent autopsy survey indicated that there was no global or dopaminergic loss in the myenteric plexus in PD but the SMP was not examined.

Objective: The aim of the present work was to compare the relative abundance of dopaminergic and noradrenergic neurons in colonic biopsies between PD patients and control individuals.

Methods: Colonic biopsies were taken during the course of a colonoscopy in 35 PD patients and 10 control subjects. Density of dopaminergic neurons and expression of the dopaminergic and noradrenergic markers were analyzed by tyrosine hydroxylase (TH) immunofluorescence and Western blot using anti-dopamine transporter (DAT) and anti-dopamine beta-hydroxylase (DBH), respectively.

Results: No significant differences were observed in the density of dopaminergic neurons and in the expression levels of dopaminergic and noradrenergic markers in colonic biopsies from PD patients as compared to controls.

Conclusion: Our results indicate that there is no evidence of dopaminergic and noradrenergic neuronal loss in the SMP in PD, thereby suggesting that neuropathology in submucosal neurons is unlikely to be a causative factor for GI dysfunction in PD.
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http://dx.doi.org/10.3233/JPD-140422DOI Listing
August 2015

Apathy as a feature of prodromal Alzheimer's disease: an FDG-PET ADNI study.

Int J Geriatr Psychiatry 2015 May 20;30(5):470-7. Epub 2014 Jun 20.

Alzheimer's Disease Clinical Research Centre, Gérontopôle, Toulouse University Hospital, Toulouse, France.

Objective: The goal of this study is to evaluate brain metabolism in mild cognitive impairment (MCI) patients with and without apathy (as determined by the Neuropsychiatric Inventory Questionnaire).

Methods: Baseline data from 65 MCI participants (11 with apathy and 54 without) from the Alzheimer's Disease (AD) Neuroimaging Initiative study were analyzed. All participants underwent a comprehensive cognitive and neuropsychiatric assessment, volumetric MRI and measures of cerebral glucose metabolism applying (18)F-fluorodeoxyglucose positron emission tomography at baseline. The presence of apathy at baseline was determined by the Neuropsychiatric Inventory Questionnaire.

Results: There was no difference between apathy and apathy-free MCI patients regarding cognitive assessment and neuropsychiatric measures when apathy-specific items were removed. Cerebrovascular disease load and cerebral atrophy were equivalent in both groups. Compared with the apathy-free MCI patients, MCI patients with apathy had significantly decreased metabolism in the posterior cingulate cortex.

Conclusion: The presence of apathy in MCI patients is associated with AD-specific pattern of brain metabolic defect. These results could suggest that apathy belongs to the spectrum of prodromal AD symptoms.
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http://dx.doi.org/10.1002/gps.4161DOI Listing
May 2015

[Frontal variant of frontotemporal dementia].

Geriatr Psychol Neuropsychiatr Vieil 2014 Mar;12(1):63-73

Centre mémoire ressources et recherche, Hôpital Laennec, CHU de Nantes, France ; Labo EMC, EA3082, Université Lyon 2, Bron, France.

The behavioral variant of frontotemporal dementia (bvFTD), characterized by early behavioral disorders, is a rare disease (about 5.000 cases in France). Diagnostic criteria have been revised in 2011 and propose three levels of diagnostic probability. However, it still could be difficult to discriminate FTD from other cerebral affections or psychiatric diseases. Genetic and molecular research has greatly expanded during the past fifteen years. About ten mutations have been discovered, bringing to describe particular phenotypes. To date, there is no curative treatment. Memantine had aroused some hope but is now abandoned. Inhibitors of serotonine recapture often permit to temporarily reduce behavioral troubles. But the caregiver's burden is high. The evolution of the bvFTD is faster than that of AD, particularly when associated with motor neuron disease (15% of cases). The therapeutic hope relies today on potential disease modifying drugs which could ensue from genetic discoveries.
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http://dx.doi.org/10.1684/pnv.2014.0451DOI Listing
March 2014

Peripheral autonomic nervous system involvement in Gaucher-related parkinsonism.

J Parkinsons Dis 2014 ;4(1):29-32

Inserm, U913, Nantes, France Inserm, CIC-04, Nantes, France University Nantes, Nantes, France CHU Nantes, Department of Neurology, Nantes, France.

The pathological process affects the peripheral autonomic nervous system in the vast majority of sporadic PD patients. Recent reports have shown that patients with a familial form of the disease caused by mutation of the gene encoding LRRK2 and alpha-synuclein also display autonomic abnormalities, especially cardiac sympathetic denervation. In the present report, we have studied the involvement of the peripheral autonomic system in a patient with Gaucher disease-associated parkinsonism. Using colonic biopsies and quantitative 123I-MIBG scintigraphy respectively, we show that both Lewy pathology and cardiac denervation were present in this case of Gaucher-associated Parkinsonism. We discuss the consequence of these findings on the pathophysiology of the disease.
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http://dx.doi.org/10.3233/JPD-130333DOI Listing
October 2014