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1.
J Alzheimers Dis ; 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31594223

RESUMO

Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer's disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis (p < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aß positive MCI cases from Aß negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aß positive SCD and control cases from Aß negative controls. These findings suggest that in prodromal stages of AD, such as in Aß positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aß positive SCD and control cases.

2.
Transl Psychiatry ; 9(1): 250, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591382

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing huge emotional and economic burden to our societies. An effective therapy has not been implicated yet, which is in part also due to the fact that pathological changes occur years before clinical symptoms manifest. Thus, there is a great need for the development of a translatable biomarker. Recent evidence highlights microRNAs as candidate biomarkers. In this study, we use next-generation sequencing to study the small noncoding RNAome (sncRNAome) in exosomes derived from human cerebrospinal fluid (CSF). We show that the sncRNAome from CSF-derived exosomes is dominated not only by microRNAs (miRNAs) but also by PIWI-interacting RNAs (piRNAs). We define a combined signature consisting of three miRNAs and three piRNAs that are suitable to detect AD with an AUC of 0.83 in a replication cohort and furthermore predict the conversion of mild-cognitive impaired (MCI) patients to AD dementia with an AUC of 0.86 for the piRNA signature. When combining the smallRNA signature with pTau and Aß 42/40 ratio the AUC reaches 0.98. Our study reports a novel exosomal small noncoding RNA signature to detect AD pathology and provides the first evidence that in addition to miRNAs, piRNAs should also be considered as a candidate biomarker for AD.

3.
J Neurosci ; 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31541019

RESUMO

Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTL). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC) have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance and levels of total and phosphorylated tau as well as Aß42/40 ratio in cerebrospinal fluid (CSF). We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus and both, increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.SIGNIFICANCE STATEMENTSubregions in the human medial temporal lobe (MTL) are critically involved in episodic memory and at the same time affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related functional magnetic resonance imaging in combination with measures of tau pathology in cerebrospinal fluid, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.

4.
Neuroimage Clin ; 24: 101994, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31505368

RESUMO

OBJECTIVE: The three recognized variants of primary progressive aphasia (PPA) are associated with different loci of degeneration-left posterior perisylvian in logopenic variant (lvPPA), left frontal operculum in non-fluent variant (nfvPPA), and left rostroventral-temporal in semantic variant (svPPA). Meanwhile, it has become apparent that patients with lvPPA, in which Alzheimer pathology is the norm, frequently have more extensive language deficits-namely semantic and grammatical problems-than is captured in the strict diagnostic recommendations for this variant. We hypothesized that this may be because the degeneration in AD-related PPA typically extends beyond the left posterior perisylvian region. METHODS: Magnetic resonance images from 25 PPA patients (9AD-related PPA, 10 svPPA, 6 nfvPPA) and a healthy control cohort were used to calculate cortical thickness in three regions of interest (ROIs). The three ROIs being the left-hemispheric loci of maximal reported degeneration for each of the three variants of PPA. RESULTS: Consistent with past studies, the most severe cortical thinning was in the posterior perisylvian ROI in AD-related PPA; the ventral temporal ROI in svPPA; and the frontal opercular ROI in nfvPPA. Significant cortical thinning in AD-related PPA, however, was evident in all three ROIs. In contrast, thinning in svPPA and nfvPPA was largely restricted to their known peak loci of degeneration. CONCLUSIONS: Although cortical degeneration in AD-related PPA is maximal in the left posterior perisylvian region, it extends more diffusely throughout the left hemisphere language network offering a plausible explanation for why the linguistic profile of lvPPA so often includes additional semantic and grammatic deficits.

5.
Hum Mutat ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464095

RESUMO

Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.

6.
Alzheimers Res Ther ; 11(1): 66, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366409

RESUMO

BACKGROUND: Subjective cognitive decline (SCD) has been proposed as a pre-MCI at-risk condition of Alzheimer's disease (AD). Current research is focusing on a refined assessment of specific SCD features associated with increased risk for AD, as proposed in the SCD-plus criteria. We developed a structured interview (SCD-I) for the assessment of these features and tested their relationship with AD biomarkers. METHODS: We analyzed data of 205 cognitively normal participants of the DELCODE study (mean age = 68.9 years; 52% female) with available CSF AD biomarkers (Aß-42, p-Tau181, Aß-42/Tau ratio, total Tau). For each of five cognitive domains (including memory, language, attention, planning, others), a study physician asked participants about the following SCD-plus features: the presence of subjective decline, associated worries, onset of SCD, feeling of worse performance than others of the same age group, and informant confirmation. We compared AD biomarkers of subjects endorsing each of these questions with those who did not, controlling for age. SCD was also quantified by two summary scores: the number of fulfilled SCD-plus features, and the number of domains with experienced decline. Covariate-adjusted linear regression analyses were used to test whether these SCD scores predicted abnormality in AD biomarkers. RESULTS: Lower Aß-42 levels were associated with a reported decline in memory and language abilities, and with the following SCD-plus features: onset of subjective decline within 5 years, confirmation of cognitive decline by an informant, and decline-related worries. Furthermore, both quantitative SCD scores were associated with lower Aß42 and lower Aß42/Tau ratio, but not with total Tau or p-Tau181. CONCLUSIONS: Findings support the usefulness of a criterion-based interview approach to assess and quantify SCD in the context of AD and validate the current SCD-plus features as predictors of AD pathology. While some features seem to be more closely associated with AD biomarkers than others, aggregated scores over several SCD-plus features or SCD domains may be the best predictors of AD pathology.

7.
EMBO J ; 38(17): e100481, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31304985

RESUMO

Regulation of adult neural stem cell (NSC) number is critical for lifelong neurogenesis. Here, we identified a post-transcriptional control mechanism, centered around the microRNA 204 (miR-204), to control the maintenance of quiescent (q)NSCs. miR-204 regulates a spectrum of transcripts involved in cell cycle regulation, neuronal migration, and differentiation in qNSCs. Importantly, inhibition of miR-204 function reduced the number of qNSCs in the subependymal zone (SEZ) by inducing pre-mature activation and differentiation of NSCs without changing their neurogenic potential. Strikingly, we identified the choroid plexus of the mouse lateral ventricle as the major source of miR-204 that is released into the cerebrospinal fluid to control number of NSCs within the SEZ. Taken together, our results describe a novel mechanism to maintain adult somatic stem cells by a niche-specific miRNA repressing activation and differentiation of stem cells.

8.
Nervenarzt ; 90(9): 891-897, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31332452

RESUMO

Alzheimer's disease is histopathologically characterized by aggregation of two proteins, namely amyloid-beta peptide and tau protein. Whereas former intervention trials focused particularly on the amyloid pathology, recent therapeutic approaches are directed against the tau pathology. This article summarizes recent progress in anti-tau therapies, especially therapies based on anti-tau immunization and antisense oligonucleotides (ASO).


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Humanos , Imunoterapia , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
9.
J Neurol ; 266(10): 2465-2474, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31227891

RESUMO

INTRODUCTION: Subjective cognitive decline (SCD) can represent a preclinical stage of Alzheimer's disease. Diffusion tensor imaging (DTI) could aid an early diagnosis, yet only few monocentric DTI studies in SCD have been conducted, reporting heterogeneous results. We investigated microstructural changes in SCD in a larger, multicentric cohort. METHODS: 271 participants with SCD, mild cognitive impairment (MCI) or Alzheimer's dementia (AD) and healthy controls (CON) were included, recruited prospectively at nine centers of the observational DELCODE study. DTI was acquired using identical protocols. Using voxel-based analyses, we investigated fractional anisotropy (FA), mean diffusivity (MD) and mode (MO) in the white matter (WM). Discrimination accuracy was determined by cross-validated elastic-net penalized regression. Center effects were explored using variance analyses. RESULTS: MO and FA were lower in SCD compared to CON in several anterior and posterior WM regions, including the anterior corona radiata, superior and inferior longitudinal fasciculus, cingulum and splenium of the corpus callosum (p < 0.01, uncorrected). MD was higher in the superior and inferior longitudinal fasciculus, cingulum and superior corona radiata (p < 0.01, uncorrected). The cross-validated accuracy for discriminating SCD from CON was 67% (p < 0.01). As expected, the AD and MCI groups had higher MD and lower FA and MO in extensive regions, including the corpus callosum and temporal brain regions. Within these regions, center accounted for 3-15% of the variance. CONCLUSIONS: DTI revealed subtle WM alterations in SCD that were intermediate between those in MCI and CON and may be useful to detect individuals with an increased risk for AD in clinical studies.

10.
Cortex ; 117: 33-40, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30927559

RESUMO

Alien limb phenomenon is a rare syndrome associated with a feeling of non-belonging and disowning toward one's limb. In contrast, anarchic limb phenomenon leads to involuntary but goal-directed movements. Alien/anarchic limb phenomena are frequent in corticobasal syndrome (CBS), an atypical parkinsonian syndrome characterized by rigidity, akinesia, dystonia, cortical sensory deficit, and apraxia. The structure-function relationship of alien/anarchic limb was investigated in multi-centric structural magnetic resonance imaging (MRI) data. Whole-group and single-subject comparisons were made in 25 CBS and eight CBS-alien/anarchic limb patients versus controls. Support vector machine was used to see if CBS with and without alien/anarchic limb could be distinguished by structural MRI patterns. Whole-group comparison of CBS versus controls revealed asymmetric frontotemporal atrophy. CBS with alien/anarchic limb syndrome versus controls showed frontoparietal atrophy including the supplementary motor area contralateral to the side of the affected limb. Exploratory analysis identified frontotemporal regions encompassing the pre-/and postcentral gyrus as compromised in CBS with alien limb syndrome. Classification of CBS patients yielded accuracies of 79%. CBS-alien/anarchic limb syndrome was differentiated from CBS patients with an accuracy of 81%. Predictive differences were found in the cingulate gyrus spreading to frontomedian cortex, postcentral gyrus, and temporoparietoocipital regions. We present the first MRI-based group analysis on CBS-alien/anarchic limb. Results pave the way for individual clinical syndrome prediction and allow understanding the underlying neurocognitive architecture.

11.
J Neurosci ; 39(19): 3752-3769, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30796158

RESUMO

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. Parkinson's disease is a movement disorder with characteristic motor features that arise due to the loss of dopaminergic neurons from the substantia nigra. Although symptomatic treatment by the dopamine precursor levodopa and dopamine agonists can improve motor symptoms, no disease-modifying therapy exists yet. Here, we show that Emapunil (AC-5216, XBD-173), a synthetic ligand of the translocator protein 18, ameliorates degeneration of dopaminergic neurons, preserves striatal dopamine metabolism, and prevents motor dysfunction in female mice treated with the MPTP, as a model of parkinsonism. We found that Emapunil modulates the inositol requiring kinase 1α (IRE α)/X-box binding protein 1 (XBP1) unfolded protein response pathway and induces a shift from pro-inflammatory toward anti-inflammatory microglia activation. Previously, Emapunil was shown to cross the blood-brain barrier and to be safe and well tolerated in a Phase II clinical trial. Therefore, our data suggest that Emapunil may be a promising approach in the treatment of Parkinson's disease.SIGNIFICANCE STATEMENT Our study reveals a beneficial effect of Emapunil on dopaminergic neuron survival, dopamine metabolism, and motor phenotype in the MPTP mouse model of parkinsonism. In addition, our work uncovers molecular networks which mediate neuroprotective effects of Emapunil, including microglial activation state and unfolded protein response pathways. These findings not only contribute to our understanding of biological mechanisms of translocator protein 18 (TSPO) function but also indicate that translocator protein 18 may be a promising therapeutic target. We thus propose to further validate Emapunil in other Parkinson's disease mouse models and subsequently in clinical trials to treat Parkinson's disease.

12.
J Neurol ; 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30506397

RESUMO

The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson's syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30421149

RESUMO

Alzheimer's disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30224549

RESUMO

OBJECTIVE: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers. METHODS: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA. RESULTS: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05). CONCLUSION: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.

15.
Neurology ; 91(15): e1390-e1401, 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30209235

RESUMO

OBJECTIVE: To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). METHODS: Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. RESULTS: At baseline, serum NfL level correlated with CSF NfL (bvFTD r = 0.706, p < 0.0001; AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p <0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006; [follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001; 95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001; [follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. CONCLUSIONS: As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.

16.
J Alzheimers Dis ; 64(3): 801-813, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29914027

RESUMO

BACKGROUND: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer's disease (AD). OBJECTIVE: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. METHODS: We determined rs-fMRI functional connectivity based on Pearson's correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. RESULTS: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. CONCLUSION: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.

17.
J Neurochem ; 147(3): 291-309, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29804302

RESUMO

In the last decades, lysosomes and mitochondria were considered distinct and physically separated organelles involved in different cellular functions. While lysosomes were thought to exclusively be the rubbish dump of the cell involved in the degradation of proteins and other cell compartments, mitochondria were considered solely involved in the oxidation of energy substrate to get ATP, together with other minor duties. Nowadays, our view of these organelles is profoundly changed since studies demonstrated that mitochondria and lysosome are mutually functional, maintaining proper cell homeostasis. Furthermore, the onset of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, lysosomal storage disorders, and amyotrophic lateral sclerosis) is tightly linked to mutations in mitochondrial and lysosomal regulators. In this context, mitochondrial dysfunction leads to lysosomal impairment and buildup of autophagy by-products, whereas lysosomal imperfections trigger functional and morphological mitochondrial defects. Here, we provide an updated overview covering recent findings about mitochondria and lysosomal interaction in physiology and pathophysiology, focusing the attention on the molecular mechanism that control their interdependence.

18.
Mycologia ; 110(2): 401-418, 2018 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29792783

RESUMO

A multigene phylogenetic analysis of Genabea, Myrmecocystis, and related genera in Pyronemataceae was conducted to establish genetically supported generic limits. The nuc rDNA 28S gene, translation elongation factor 1-α gene (TEF1), and RNA polymerase II second-largest subunit gene (RPB2) significantly supported the monophyly of several distinct genera of hypogeous Pyronemataceae. The genetic identity of Genabea fragilis is established, and the new species Genabea hyalospora, G. urbana, Myrmecocystis mediterranea, and M. microspora are proposed to accommodate undescribed lineages. Two rare species, M. sphaerospora and M. spinospora, are tentatively identified based on collections that are morphologically similar to the original descriptions. The genus Genea was found to be monophyletic, except for G. cazaresii, which is nested among epigeous species of Humaria. The new combination Humaria cazaresii is proposed to accommodate this species.

19.
Mol Plant ; 11(7): 955-969, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29734002

RESUMO

The transition metal manganese (Mn) is indispensable for photoautotrophic growth since photosystem II (PSII) employs an inorganic Mn4CaO5 cluster for water splitting. Here, we show that the Arabidopsis membrane protein CHLOROPLAST MANGANESE TRANSPORTER1 (CMT1) is involved in chloroplast Mn homeostasis. CMT1 is the closest homolog of the previously characterized thylakoid Mn transporter PHOTOSYNTHESIS-AFFECTED MUTANT71 (PAM71). In contrast to PAM71, CMT1 resides at the chloroplast envelope and is ubiquitously expressed. Nonetheless, like PAM71, the expression of CMT1 can also alleviate the Mn-sensitive phenotype of yeast mutant Δpmr1. The cmt1 mutant is severely suppressed in growth, chloroplast ultrastructure, and PSII activity owing to a decrease in the amounts of pigments and thylakoid membrane proteins. The importance of CMT1 for chloroplast Mn homeostasis is demonstrated by the significant reduction in chloroplast Mn concentrations in cmt1-1, which exhibited reduced Mn binding in PSII complexes. Moreover, CMT1 expression is downregulated in Mn-surplus conditions. The pam71 cmt1-1double mutant resembles the cmt1-1 single mutant rather than pam71 in most respects. Taken together, our results suggest that CMT1 mediates Mn2+ uptake into the chloroplast stroma, and that CMT1 and PAM71 function sequentially in Mn delivery to PSII across the chloroplast envelope and the thylakoid membrane.

20.
Alzheimers Res Ther ; 10(1): 41, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695300

RESUMO

BACKGROUND: With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. METHODS: We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. RESULTS: Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures. CONCLUSION: Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.

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