Synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), and dementiawith Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.
In the ankle strategy, the body moves around the ankle as an inverted pendulum. This type of movement is usually adequate to account for small degrees of postural
disturbance or sway, particularly when standing on a firm surface. Alternatively, the hip strategy involves an exertion of torque (or bend) at the hips and is employed when the CoM must be relocated quickly or to a larger degree. The hip strategy is commonly used when the support surface is variable or ankle torque is ineffective. When the disturbance is large and the CoM travels outside the limits of stability, a step or a reach must occur to prevent a fall. Selecting a movement largely depends on the individual’s expectations and experience and in general, those at a lower risk of falling employ the ankle strategy, with those at higher risks of falling (i.e. the elderly) employing hip and stepping strategies more frequently (F. B. Horak, 2006). These strategies may be anticipatory, voluntary or compensatory. Automatic postural reactions (APRs) represent responses to sensory (visual, vestibular and somatosensory) input, which signal postural disturbances in relation to movement. Anticipatory postural adjustments (APAs) occur prior to the initiation of voluntary movements and serve to counteract the disturbance that movement will impose on balance (Kim et al., 2013).
the U.K. PD Brain Bank criteria for idiopathic PD (21). Inclusion criteria were idiopathic PD of at least 5-year duration, total Unified Parkinson’s Disease Rating Scale (UPDRS) level in off-condition of 20/180 or greater, Hoehn and Yahr disease stage 1 or greater, and UPDRS motor scale im- provement to L-DOPA challenge test of 30% or greater. PD patients with deep brain stimulation, rest tremor (. 3 on one subitem of UPDRS), levodopa-in- duced dyskinesia in “on” state (motion incompatible with MR spectroscopic examination), and dementia (as as- sessed according to the fourth edition of the Diagnostic and Statistical Man- ual of Mental Disorders criteria) were not recruited. Healthy volunteers were recruited from healthy volunteers’ list owned and maintained by the Clini- cal Investigation Centre of Clermont- Ferrand. For each group, subjects who presented with brain disease, had MR imaging contraindications, or were on any medication that could interact with brain neurotransmitters (anti- depressants, neuroleptics) were not recruited. All recruited participants had normal panel blood tests, exclud- ing liver failure. At this stage of the study, no subject was excluded as the patients were carefully selected by a specialized medical doctor during the inclusion visit.
described severe motor fluctuations and LID that were not improved by optimal antiparkinsonian medication. Selection criteria for surgery were: an excellent response to levodopa, tested during an acute levodopa challenge; no postural instability during the best ‘‘on’’ period; no dementia (Mini Mental Scale .24, Mattis scale .130/144); and normal magnetic resonance imaging. Exclusion criteria for surgery were: psychosis, neoplasia and severe depression. For the specific tool of this study, exclusion criteria were diabetes and thyroid disease. All women were post-menopausal. The study protocol was approved by the regional medical school ethics committee. It was performed according to the principles set out in the declara- tion of Helsinki and complied with French legisla- tion (the Huriet law).
Patients from the study
From January 2001 to June 2009, 824 cerebrospinal fluid specimens and 16 brain biopsies from patients without a previous diagnosis of Whipple’s disease were analysed using PCR for T. whipplei in our laboratory in Marseille, France, which is a reference centre for T. whipplei diag- nosis in our country. All samples were collected as part of routine clinical management, and they were sent to our laboratory for the detection of all microorganisms potentially responsible for encephalitis. Our diagnostic criteria for T. whipplei encephalitis required at least two positive PCR assays targeting 2 different sequences on 2 different cerebrospinal fluid specimens, performed as previously reported, or positive PCR assays on brain biopsies [16,17] and negative results PAS staining of gastric and small-bowel specimens, plus an absence of meningitis, myelitis, and other organ involvement. Our study is in compliance with the Helsinki declaration. The local ethics committee from IFR 48 (Marseille, France) approved this study. Written informed consent was obtained from the patient for the use of information in this case report and any accompanying images.
a variety of immune-response genes, including inflammatory cytokines 4 . It is therefore plausible to assume that
TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the SNpc. The best characterized TLR transduction pathway is that of TLR4 which functions extracellularly in conjunc- tion with CD14 and MD-2, the so-called lipopolysaccharide (LPS) recognition complex, which signals down- stream through the myeloid differentiation factor 88 (MyD88) pathway. Accordingly, as first demonstration in the central nervous system (CNS), the only cellular population stained positive for TLR4 in the brain parenchyma of adult rats were microglia 5 . Recent data also indicate that TLR4 is up-regulated by MPTP treatment in a mouse
discrepancies between the single study that suggested an association between the MC1R p.R160W variant and the current study could be explained by the different populations used. It is possible, for example, that in different populations, other genetic or environmental factors exist that differentially modify the association of MC1R with PD. However, if this variant is hypothesized to be the functional variant that increases the risk for PD, by affecting the function of the melanocortin 1 receptor, it should have relatively similar effects in each population. Further support for the lack of association of MC1R with PD is provided by the meta-OR previously reported for this variant (OR=0.98, 95% CI 0.89-1.07, p=0.62) in the International PD Genomic Consortium data,(Dong, et al., 2014) and the lack of signal in this locus in the PDGene database (www.pdgene.org). Although we cannot decisively rule out that this variant has a minor role in PD susceptibility that can only be detected in a much larger meta-analysis, the current data suggest that the MC1R gene, and specifically the p.R160W variant, are probably not associated with PD, or have a very small effect. A previous observation from a cohort of 272 PD patients and 1185 controls, which suggested that the p.R151C variant is associated with PD,(Gao, et al., 2009b) was also not supported by our results.
MATERIALS AND METHODS
The subjects were 25 residents of the general ward (mean age; 84.9 + 9.1 years) and 11 residents of the dementia ward (mean age; 87.5 + 12.8 years) at our facility during the period from Septem- ber 2011 to May 2012. The subjects and their families had written informed consent to participate in the study. Elderly residents withdementia are ranked into five levels (I, II, III, IV, and M) according to their needs, which includes ADL, physical and psychological condition, and those whose degrees of independence in everyday life (Japanese Ministry of Health, Labour and Welfare, 1993) are judged to be at level III or above are admitted to a dementia ward recognized under the care insurance system. Level III is defined as: “Since they have symptoms, behaviors and difficulties in under- standing that make them difficult to live in their everyday life, they need care.”
119. Rees, K., Stowe, R., Patel, S., Ives, N., Breen, K., Ben-Shlomo, Y., and Clarke, C.E. (2011). Anti- hypertensive drugs as disease-modifying agents for Parkinson’s disease: evidence from observational studies and clinical trials. Cochrane Database Syst. Rev. CD008535.
120. Ries, V, Cheng, H.C., Baohan, A., Kareva, T., Oo, T.F., Rzhetskaya, M., Bland, R.J., During, M.J., Kholodilov, N., and Burke, R.E. (2009). Regulation of the postnatal development of dopamine neurons of the substantia nigra in vivo by Akt/protein kinase B. J Neurochem. 110, 23–33.
depends on the subjective dendograms cutoff, our findings however revealed clearly distinguishable patterns with three poles: the hippocampus, the posterior association areas, and the frontal cortex.
In the hippocampus, the presence of abnormally phosphorylated tau proteins that aggregate to form neurofibrillary tangles (NFT), may be one of the processes underlying severe atrophy and moderate hypometabolism in spite of low Aβ burden. Indeed, neurodegeneration seems to be closely related to tau pathology: progression of both gray matter atrophy (Whitwell et al., 2008) and hypoperfusion (Bradley et al., 2002) through the brain seems to follow NFT spreading as evaluated with Braak staging. In addition, neuronal loss has been shown to correlate with local counts of NFT in different brain areas such as the entorhinal cortex (Gómez-Isla et al., 1996) and superior temporal sulcus (Gómez-Isla et al., 1997). Consequently, as NFT first appear and remain predominant in medial temporal structures as the disease pathology progresses (Braak and Braak, 1991; Delacourte et al., 1999), it is likely that NFT, rather than Aβ deposition, are responsible for hippocampal atrophy and hypometabolism. However, the possibility of a distant effect of Aβ on the hippocampus cannot be ruled out, especially because the brain structures to which the hippocampus projects the most, i.e. the retrosplenial cortex and medial and orbital prefrontal cortex (Aggleton, 2011) are also those showing the highest Aβ load (Figure 2, right).
We asked whether the GL, as an estimation of refined carbohydrate consumption, was associated with the risk of dementia during the 11.4 years of follow-up (Table 2). We did not find any direct association between dementia and the daily GL or GL value of breakfast, lunch, afternoon snack, and dinner. However, the interaction between afternoon-snack GL and APOE-ε4 carrier status was significantly associated with the dementia risk. APOE-ε4 carrier status was also associated with the dementia risk. After adjustments for Mediterranean-diet-like score and physical activity (Model 2), the interaction remained significant. Significant covariates were APOE-ε4 carrier status, age, T2D and history of head trauma as risk factors and living in Montpellier as protective factor (Fig. 3). Multiple imputations (Model 3) did not change these results showing that the risk of dementia was higher in APOE-ε4 carriers who consumed afternoon snacks with high GL value. To quantify this association, we stratified by APOE-ε4 (Supplementary Figure 1, Supplementary Figure 2). In APOE-ε4 carriers, hazard ratio for a 10-point increase in the GL value per day was 2.06 [1.07-4.0]. Finally, in categorical analyses the interaction between the higher tercile of the afternoon-snack GL and APOE-ε4 carrier status was significantly associated with the dementia risk (Supplementary Table 3). Kaplan-Meyer survival curves clearly illustrated it (Supplementary Figure 3).
DA cell loss did not result in significant impairment of motor parameters in MPTP/probenecid- treated mice. This is a known limitation of rodent MPTP models of PD, probably because DA cell loss and accompanying striatal DA depletion is insufficient to induce a behavioural phenotype. Others have reported deficits in the grid test and the open field test in MPTP/probenecid-treated mice  but levels of striatal DA depletion achieved in these studies were far greater than those reported here. Of interest, however, both apamin and bee venom stimulated the locomotor activity in mice intoxicated with MPTP/probenecid, indicating that in this experimental situation, both treatments probably had the capacity to stimulate DA release , possibly by a mechanism involving SK channel blockade. Hyperactivity observed in the open field assay might also be related to an increase in adrenergic/ noradrenergic release induced by. SK channels are present centrally on locus coeruleus neurons  and peripherally on the adrenal gland and their blockade can cause an increase in adrenergic tone .
The association between high triglycerides level at baseline and risk of incident dementia is an original finding. Few studies have focused on hypertriglyceridemia and its relations to dementia. A transversal study made known the potential relations between elevated triglyceride levels and poorer cognitive function in patients with diabetes (21). A similar association was found in a longitudinal study with a long-term follow-up: in the Honolulu-Asia Aging Study, an 1 SD increase in triglycerides levels during mid-life increased the risk of dementia 25 years later (9). In our study, high triglycerides level was only associated with incident vascular dementia (even if there were only 40 cases) but not with AD. Whether moderate hypertriglyceridemia is an independent risk factor for cardiovascular disease remains a debated question but a metanalysis of thousands of patients followed up for more than 10 yr showed that a triglycerides elevation of 1 mmol/L increased the risk of cardiovascular disease, independently of HDL-cholesterol (22). However, the precise mechanisms, especially in the brain, by which hypertriglyceridemia might increase dementia risk still have to be elucidated. Few studies have examined the relations between HDL-cholesterol and incidence of dementia, most focusing on total cholesterol or LDL- cholesterol with conflicting results (23).
The suggested operation of the dual ACh/GABA co- transmission is illustrated in a schematic diagram (Supplemen- tary Fig. 15 ). Cholinergic interneurons directly innervate various types of GABAergic interneurons 5 , 34 and SPNs dendritic shafts or spines 8 , 9 , raising the possibility of similar connections of CGINs. Similar to CINs, CGINs are autonomous pacemakers capable of maintaining spike activity in the absence of synaptic inputs 7 . In control conditions, interplay between dopamine innervation and intrinsic membrane properties, restrict ongoing activity, allowing the generation of behaviorally relevant oscillations and the pause response to sensory cues 2 , 35 , 36 . Whether the pause response is generated by the cortex or the thalamus as suggested by Surmeier and colleagues 1 cannot be ascertained at present, but our results are in full accord with this study in stressing the crucial role of CGINs in the synchronization of striatal networks in relation to sensory integration. Present results suggest that a balance between cholinergic excitation and GABAergic inhibition has an impor- tant role in this operation with intracellular chloride level in CGINs being a determinant factor.
One of the main roles seems to be its involvement in the trafficking of synaptic vesicles and in the regulation of vesicle exocytosis and synaptic vesicle-mediated release of neurotransmitter. α-syn is mainly located at presynaptic terminals and it is associated with the distal reserve pool of synaptic vesicles (H. J. Lee et al. 2011; Bellani et al. 2010; Lautenschläger et al. 2018; Lashuel et al. 2013; Scott and Roy 2012). More specifically, monomeric α-syn plays an important role in the docking, priming and fusion steps of vesicle fusion and exocytosis probably by interacting and serving as a non-classical chaperone that facilitate SNARE (soluble N‐ethylmaleimide-sensitive factor attachment protein receptor) complexes assembly (Jacqueline Burré et al. 2010; Jacqueline Burré 2015; Lashuel et al. 2013; Huang et al. 2019). Endocytosis is directly related to exocytosis, and both are critical for the maintenance of presynaptic structural integrity. In the process of endocytosis, α-syn mediates membrane curvature and is also involved in the process of receptor internalization in order to regulate DAT homeostasis and N-methyl-D-aspartate receptor (NMDA) receptor through clathrin-mediated endocytosis (Kisos, Ben-Gedalya, and Sharon 2014; Cheng et al. 2011; Huang et al. 2019). In addition, α-syn also enhances microtubule formation and axonal transport through interactions with tubulin (Koprich, Kalia, and Brotchie 2017; Cartelli et al. 2016; Alim et al. 2004). Those possible different functions of α-syn may be due to its conformational flexibility allowing the protein to adopt different forms when it interacts with biological membranes, other proteins or protein complexes (Lashuel et al. 2013).
population. Hence, an early diagnosis of dementia is still a great challenge to prevent insecurity and health worsening in aged people living at home.
Generally, dementia is diagnosed in gathering clues of pathological changes in people life. To assess those changes, physicians use neurological examination, neuropsychological testing, and brain imaging technologies. Finally, diagnosis of possible dementia is asserted by comparing evidences, added to an autonomy decline. This autonomy decline is frequently assessed by Activities of Daily Living interviews  in which impairments are known to be related to cognitive decline caused by dementia .
rares (respectivement 45% et 20% des patients) de même que les troubles de résonance (10% des patients), l’absence de toute anomalie ne concernant que 11% des patients. Ces données ont suggéré une progression « caudo-rostrale » des troubles du conduit vocal au cours de la maladie, débutant au niveau laryngé pour atteindre ensuite la partie postérieure de la constriction linguo-palatine, puis sa partie antérieure et enfin la constriction bilabiale. Une autre étude plus récente (Ho et al 1998) a été conduite chez 200 patients parkinsoniens évalués avec leur traitement anti-parkinsonien habituel dans une tâche de conversation spontanée. L’analyse perceptive a montré l’absence de toute anomalie chez 26% des patients. Parmi les 74% montrant des anomalies de sévérité variable, la dysphonie prédominait d’autant plus que l’atteinte globale de la communication parlée était moins sévère (94% dans le groupe d’atteinte légère, 72% dans le groupe d’atteinte modérée, 46% dans le groupe d’atteinte sévère et 14% dans le groupe d’atteinte extrême). Les troubles de l’articulation et du débit n’apparaissaient qu’à partir du groupe d’atteinte modérée et prenaient progressivement une importance croissante allant de pair avec la sévérité globale des troubles de parole. Ces résultats confirment le caractère précoce de la dysphonie au cours de la maladie de Parkinson : toutefois, la progression de la maladie s’exprime ensuite davantage par les troubles de l’articulation et du débit, lesquels perturbent l’intelligibilité de façon plus nette.
The study included individuals who received genetic coun- seling in the Neurogenetics Unit of Piti´e-Salpˆetri`ere Univer- sity Hospital (Paris) for being at risk of carrying the mutation known in their family to be responsible for ALS, FTD, or ALS/FTD between 2008 and June 2019. We compared the data obtained with those of the population requesting PT for HD during the same period. This department has gained, over more than 27 years, a vast experience in delivering genetic counseling to subjects at risk of harboring mutations leading to late-onset dominantly inherited neurodegenerative dis- eases, such as HD, dementias, and prion diseases. At-risk in- dividuals request, on their own initiative, genetic counseling in our clinic. They have been informed about their genetic risk by their aﬀected family member or the neurologist of the aﬀected relative. Genetic counseling takes place in a multi- disciplinary framework, comprised of at least a neurologist, geneticist, and psychologist. Interviews are structured as previously reported. 22 Brieﬂy, at-risk individuals receive from the neurologist/geneticist, before testing, oral and written information about the disease, the genetic risk of trans- mission, therapeutic implications, and limitations of testing. They are then given time to reﬂect and make their decision, during which they are supported by at least 1 interview with a
2.3.1. Lexical features
This group is the primary group of linguistic features used to detect and discriminate different cognitive impairments. Multiple studies reported that patients with AD have the ratio of pronouns to full noun phrases higher than the control group [30, 10, 31]. Other features like TTR, Moving-Average Type-Token Ratio (MATTR), open:closed word ratio, verb rates, vocabulary size, average word length and syntactic complexity were also have been studied and found to be predictors of cognitive impairments, but not all of them were markers of AD. For example, a reduced vocabulary size can suggest a form of Primary Progressive Aphasia, and we have seen it in the Picnic corpus. Non-words and out-of-vocabulary words are indicators of disfluency. However, they can be a symptom of other types of dementia as well.
maybe triggered primarily by the disconnections
between the different ROIs within this network, as observed in the group comparisons. The negative correl- ation between fluctuation scores and functional connect- ivity between the SN and DMN is striking because it involves the RPFC of the SN and the MPFC of the DMN, a pair of ROIs showing a hyperconnectivity (but with a different lateralization) in DLB patients compared to healthy subjects, which we interpreted as a compensa- tion process. In agreement with this hypothesis, greater fluctuations in DLB patients may thus be linked to a fail- ure of this compensation. Second, these findings tend to confirm the involvement of thalamic functional distur- bances in the etiology of fluctuations in DLB patients, as suggested by previous studies [ 10 , 18 ]. The thalamus has strong functional connections with cortical nodes of the SN, especially the anterior insula hub, and participates with it in a large-scale network integrating interoceptive inputs with cognitive inputs from other networks and generating viscero-autonomic, emotional, and cognitive processes in response to salient stimuli [ 67 , 68 ]. More- over, the functional and structural connectivity of the thalamus with the DMN [ 69 , 70 ] and the frontoparietal regions [ 71 ] was shown to be crucial for consciousness. The negative correlation between thalamic functional connectivity and fluctuation scores in the DLB group therefore seems concordant with the clinical characteris- tics of this symptom. Furthermore, this correlation could also be consistent with the results of our VBM analysis showing a negative correlation between fluctuation scores and gray matter volume in several cholinergic re- gions. Indeed, as mentioned by Peraza et al. [ 72 ], loss of cholinergic function may impair the ability of the cholin- ergic system to inhibit intracortical short-range func- tional connections, which is the mechanism by which the brain can enhance thalamocortical interactions in re- sponse to external stimuli [ 73 , 74 ]. It is thus possible that both phenomena may contribute to the occurrence of fluctuations in DLB patients. Alternatively, thalamic functional disturbances could also be a consequence of cholinergic function deficits.