Development and evaluation of one-step RT-qPCR TaqMan multiplex panels applied to six viruses occurring in lily and tulip bulbs.

One-step RT-qPCR TaqMan assays have been developed for six plant viruses with considerable economic impact in the growing of tulip and lily bulbs: lily mottle virus, lily symptomless virus, lily virus X, Plantago asiatica mosaic virus, tulip breaking virus and tulip virus X. To enhance efficacy and cost-efficiency these assays were combined into multiplex panels. Four different multiplex panels were designed, each consisting of three virus assays and an adapted assay for the housekeeping gene nad5 of lilies and tulips, that acts as an internal amplification control. To eliminate false negative results due to variation in the viral genome sequences, for each target virus two assays were developed on distinct conserved genomic regions. Specificity, PCR efficiency and compatibility of primers and probes were tested using gBlock constructions. Diagnostic samples were used to evaluate the strategy. High Throughput Sequencing of a set of the diagnostic samples, further verified the presence or absence of the viruses in the RNA samples and sequence variations in the target genes. This interchangeable multiplex panel strategy may be a valuable tool for the detection of viruses in certification, surveys and virus diagnostics.

Minocycline for sporadic and hereditary cerebral amyloid angiopathy (BATMAN): study protocol for a placebo-controlled randomized double-blind trial.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. METHODS: The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. DISCUSSION: The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT05680389. Registered on January 11, 2023.

Neurofilament light chain: A novel blood biomarker in patients with ataxia telangiectasia.

AIM: Neurofilament light chain (NfL) is recognized as a blood biomarker in several neurodegenerative disorders, but its possible relevance in Ataxia Telangiectasia (A-T) has not been examined. The aim of this study was to investigate the biomarker potential of blood NfL concentrations in patients with A-T. METHOD: Blood (serum/plasma) NfL concentrations were measured in a Dutch and an American cohort of patients with A-T and compared to control values. Additionally, correlations between NfL concentrations and disease phenotype (classic versus variant A-T) were studied. RESULTS: In total 40 (23 Dutch and 17 American) patients with A-T (32 patients with classic A-T and 7 patients with variant A-T) and 17 age- and gender-matched (to the American cohort) healthy controls were included in this study. Blood (serum/plasma) NfL concentrations in patients with classic A-T and age ≤ 12 years were elevated compared to age matched controls. Patients with classic A-T > 12 years also had higher blood (serum/plasma) NfL concentrations (here: compared to age-dependent reference values found in the literature). Patients with classic A-T had higher blood (serum/plasma) NfL concentrations than patients with the variant phenotype. CONCLUSION: Blood (serum/plasma) NfL concentrations are elevated in patients with classic A-T and appear to correlate with the disease phenotype (classic versus variant). Therefore, blood (serum/plasma) NfL may be a promising biomarker in A-T.

Downregulation of synapse-associated protein expression and loss of homeostatic microglial control in cerebrospinal fluid of infectious patients with delirium and patients with Alzheimer's disease.

Delirium is a complex and multifactorial condition associated with long-term cognitive decline. Due to the strong links between systemic inflammation, delirium and dementia we hypothesized that responses within the brain in patients who develop delirium could show biochemical overlap with patients with Alzheimer's disease (AD). In this observational study we analyzed protein expression signatures in cerebrospinal fluid (CSF) from 15 patients with infectious delirium and compared these to 29 patients with AD, 30 infectious patients without delirium and 15 non-infectious controls free of neurological disease. A proximity extension assay was performed measuring a total of 184 inflammatory and neurology-related proteins. Eight inflammatory proteins (4%), including the key neuron-microglia communication marker CX3CL1 (fractalkine), were significantly upregulated in both delirium and AD, compared to infectious patients without delirium. Likewise, 23 proteins (13%) showed downregulation in both delirium and AD, relative to infectious patients without delirium, which interestingly included CD200R1, another neuron-microglia communication marker, as well as a cluster of proteins related to synapse formation and function. Synaptopathy is an early event in AD and correlates strongly with cognitive dysfunction. These results were partially mediated by aging, which is an important predisposing risk factor among many others for both conditions. Within this study we report the first in vivo human evidence suggesting that synapse pathology and loss of homeostatic microglial control is involved in the pathophysiology of both infectious delirium and AD and thus may provide a link for the association between infections, delirium and long-term cognitive decline.

Adult macrophage activation syndrome-haemophagocytic lymphohistiocytosis: 'of plasma exchange and immunosuppressive escalation strategies' - a single centre reflection.

OBJECTIVE: In the context of systemic autoimmunity, that is systemic lupus erythematosus (SLE) or adult-onset Still's disease (AOSD), secondary haemophagocytic lymphohistiocytosis (HLH; also referred to as macrophage activation syndrome (MAS) or more recently MAS-HLH) is a rare and potentially life-threatening complication. Pathophysiological hallmarks are aberrant macrophage and T cell hyperactivation and a systemic cytokine flare, which generate a sepsis-like, tissue-damaging, cytopenic phenotype. Unfortunately, for adult MAS-HLH we lack standardized treatment protocols that go beyond high-dose corticosteroids. Consequently, outcome data are scarce on steroid refractory cases. Aside from protocols based on treatment with calcineurin inhibitors, etoposide, cyclophosphamide and anti-IL-1, favourable outcomes have been reported with the use of intravenous immunoglobulin (IvIG) and plasma exchange (PE). METHODS: Here we report a retrospective series of steroid refractory MAS-HLH, the associated therapeutic regimes and outcomes. RESULTS: In this single-centre experience, 6/8 steroid refractory patients survived (median follow-up: 54.4 (interquartile range: 23.3-113.3) weeks). All were initially treated with PE, which induced partial response in 5/8 patients. Yet, all patients required escalation of immunosuppressive therapies. One case of MAS-HLH in new-onset AOSD had to be escalated to etoposide, whereas most SLE-associated MAS-HLH patients responded well to cyclophosphamide. Relapses occurred in 2/8 cases. CONCLUSION: Together, early use of PE is at most a supportive measure, not a promising monotherapy of adult MAS-HLH. In refractory cases, conventional cytoreductive therapies (i.e. cyclophosphamide and etoposide) constitute potent and reliable rescue approaches, whereas IvIG, anti-thymoglobulin, and biologic agents appear to be less effective.

Creation of a new genus in the family Secoviridae substantiated by sequence variation of newly identified strawberry latent ringspot virus isolates.

To obtain insight into the sequence diversity of strawberry latent ringspot virus (SLRSV), isolates from collections and diagnostic samples were sequenced by high-throughput sequencing. For five SLRSV isolates, the complete genome sequences were determined, and for 18 other isolates nearly complete genome sequences were determined. The sequence data were analysed in relation to sequences of SLRSV and related virus isolates available in the NCBI GenBank database. The genome sequences were annotated, and sequences of the protease-polymerase (Pro-Pol) region and coat proteins (CPs) (large and small CP together) were used for phylogenetic analysis. The amino acid sequences of the Pro-Pol region were very similar, whereas the nucleotide sequences of this region were more variable. The amino acid sequences of the CPs were less similar, which was corroborated by the results of a serological comparison performed using antisera raised against different isolates of SLRSV. Based on these results, we propose that SLRSV and related unassigned viruses be assigned to a new genus within the family Secoviridae, named "Stralarivirus". Based on the phylogenetic analysis, this genus should include at least three viruses, i.e., SLRSV-A, SLRSV-B and lychnis mottle virus. The newly generated sequence data provide a basis for designing molecular tests to screen for SLRSV.

Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy.

AIMS: We investigated the potential of apolipoprotein D (apoD) as cerebrospinal fluid (CSF) biomarker for cerebral amyloid angiopathy (CAA) after confirmation of its association with CAA pathology in human brain tissue. METHODS: The association of apoD with CAA pathology was analysed in human occipital lobe tissue of CAA (n = 9), Alzheimer's disease (AD) (n = 11) and healthy control cases (n = 11). ApoD levels were quantified in an age- and sex-matched CSF cohort of CAA patients (n = 31), AD patients (n = 27) and non-neurological controls (n = 67). The effects of confounding factors (age, sex, serum levels) on apoD levels were studied using CSF of non-neurological controls (age range 16-85 years), and paired CSF and serum samples. RESULTS: ApoD was strongly associated with amyloid deposits in vessels, but not with parenchymal plaques in human brain tissue. CSF apoD levels correlated with age and were higher in men than women in subjects >50 years. The apoD CSF/serum ratio correlated with the albumin ratio. When controlling for confounding factors, CSF apoD levels were significantly lower in CAA patients compared with controls and compared with AD patients (P = 0.0008). CONCLUSIONS: Our data show that apoD is specifically associated with CAA pathology and may be a CSF biomarker for CAA, but clinical application is complicated due to dependency on age, sex and blood-CSF barrier integrity. Well-controlled follow-up studies are required to determine whether apoD can be used as reliable biomarker for CAA.

The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease.

BACKGROUND: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease. METHODS/DESIGN: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions. DISCUSSION: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach. TRIAL REGISTRATION: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT.

Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed prospectively the safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo major histocompatibility complex-Streptamer-isolated CMV epitope-specific donor T cells. Forty-four allo-HSCT patients receiving a T-cell-replete (D+ repl; n=28) or T-cell-depleted (D+ depl; n=16) graft from a CMV-seropositive donor were screened for CMV-specific T-cell immunity. Eight D+ depl recipients received adoptive T-cell therapy from their stem cell donor. CMV epitope-specific T cells were well supported and became detectable in all treated patients. Complete and partial virological response rates were 62.5% and 25%, respectively. Owing to longsome third-party donor (TPD) identification, only 8 of the 57 CMV patients transplanted from CMV-seronegative donors (D-) received antigen-specific T cells from partially human leukocyte antigen (HLA)-matched TPDs. In all but one, TPD-derived CMV-specific T cells remained undetectable. In summary, adoptive transfer correlated with functional virus-specific T-cell reconstitution in D+ depl patients. Suboptimal HLA match may counteract expansion of TPD-derived virus-specific T cells in D- patients.

Soluble TLR2 and 4 concentrations in cerebrospinal fluid in HIV/SIV-related neuropathological conditions.

HIV in the central nervous system (CNS) mainly infects microglial cells which are known to express toll-like receptors (TLRs). This paper aimed to study the role of soluble TLR2 (sTLR2), sTLR4, and other inflammatory markers in cerebrospinal fluid (CSF) in HIV/Simian immunodeficiency virus (SIV)-related neurological sequelae. We determined sTLR2 and sTLR4 levels in CSF and serum/plasma of SIV-infected rhesus macaques with and without neurological sequelae, as well as in HIV-infected patients with and without cognitive impairments and Alzheimer's disease (AD) patients and matched controls. CSF cytokines and chemokines levels were analyzed in macaques as markers of neuroinflammation, while neopterin and S100B CSF concentrations were measured in HIV-infected patients as microglial and astrocyte marker, respectively. We found detectable levels of sTLR2 and sTLR4 in CSF of macaques and humans. Furthermore, CSF sTLR2 and sTLR4 concentrations were higher in SIV-infected macaques with neurological sequelae compared to those without neurological complications (p = 0.0003 and p = 0.0006, respectively). CSF IL-8 and monocyte chemoattractant protein-1 (MCP-1) levels were elevated in macaques with neurological sequelae, and a positive correlation was found between CSF levels of sTLR2/4 and IL-8 and MCP-1. Also in humans, elevated CSF sTLR4 levels were found in HIV-infected patients with cognitive impairments compared to HIV-infected patients with normal cognition (p = 0.019). Unlike CSF S100B levels, neopterin correlated positively with sTLR2 and sTLR4. No difference was found in plasma and CSF sTLR2 and sTLR4 levels between AD patients and control subjects (p = 0.26). In conclusion, CSF sTLR2 and sTLR4 may play a role in HIV/SIV-related neuroinflammation and subsequent neuropathology.

Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey.

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.

Amyloid beta-42 (Aß-42), neprilysin and cytokine levels. A pilot study in patients with HIV related cognitive impairments.

HIV-associated dementia (HAD) is associated with amyloid-beta (Aß) deposition. This study measured CSF and plasma amyloid beta-42 (Aß-42), neprilysin (NEP) and cytokine levels in HIV-related cognitive impairments (HCI), HIV normal cognitive functioning (NF) and non-HIV controls. Our data showed a trend towards detectable plasma Aß-42 levels more frequently in HCI (67%), when compared to NF (29%) and controls (10%). We showed elevated IL-8 levels in CSF of HCI compared to NF, although not significant values. The data from this pilot study indicates that CSF IL-8 and plasma Aß-42 may be interesting biomarkers for the presence of HCI.

Susceptibility-weighted imaging improves the diagnostic accuracy of 3T brain MRI in the work-up of parkinsonism.

BACKGROUND AND PURPOSE: The differentiation between Parkinson disease and atypical parkinsonian syndromes can be challenging in clinical practice, especially in early disease stages. Brain MR imaging can help to increase certainty about the diagnosis. Our goal was to evaluate the added value of SWI in relation to conventional 3T brain MR imaging for the diagnostic work-up of early-stage parkinsonism. MATERIALS AND METHODS: This was a prospective observational cohort study of 65 patients presenting with parkinsonism but with an uncertain initial clinical diagnosis. At baseline, 3T brain MR imaging with conventional and SWI sequences was performed. After clinical follow-up, probable diagnoses could be made in 56 patients, 38 patients diagnosed with Parkinson disease and 18 patients diagnosed with atypical parkinsonian syndromes, including 12 patients diagnosed with multiple system atrophy-parkinsonian form. In addition, 13 healthy controls were evaluated with SWI. Abnormal findings on conventional brain MR imaging were grouped into disease-specific scores. SWI was analyzed by a region-of-interest method of different brain structures. One-way ANOVA was performed to analyze group differences. Receiver operating characteristic analyses were performed to evaluate the diagnostic accuracy of conventional brain MR imaging separately and combined with SWI. RESULTS: Disease-specific scores of conventional brain MR imaging had a high specificity for atypical parkinsonian syndromes (80%-90%), but sensitivity was limited (50%-80%). The mean SWI signal intensity of the putamen was significantly lower for multiple system atrophy-parkinsonian form than for Parkinson disease and controls (P < .001). The presence of severe dorsal putaminal hypointensity improved the accuracy of brain MR imaging: The area under the curve was increased from 0.75 to 0.83 for identifying multiple system atrophy-parkinsonian form, and it was increased from 0.76 to 0.82 for identifying atypical parkinsonian syndromes as a group. CONCLUSIONS: SWI improves the diagnostic accuracy of 3T brain MR imaging in the work-up of parkinsonism by identifying severe putaminal hypointensity as a sign indicative of multiple system atrophy-parkinsonian form.

Ancillary investigations to diagnose parkinsonism: a prospective clinical study.

Various ancillary investigations can assist clinicians in the differential diagnosis of patients with parkinsonism. It is unknown which test offers greatest diagnostic value in clinical practice. We included 156 consecutive patients with parkinsonism, but with an initially uncertain diagnosis. At baseline, all patients underwent extensive clinical testing and the following ancillary investigations: brain magnetic resonance imaging (MRI); (123)I-iodobenzamide single photon-emission computed tomography (IBZM-SPECT); analysis of cerebrospinal fluid (CSF); and anal sphincter electromyography (EMG). The final diagnosis was established after 3-year follow-up by two movement disorder specialists, according to international consensus criteria. We determined the diagnostic value by comparing the baseline clinical parameters and ancillary studies with the final diagnosis. Out of a potential 138 parameters, univariate analysis identified 35 parameters that discriminated Parkinson's disease (PD, n = 62) and atypical parkinsonism (AP, n = 94), with AUC of 0.55-0.81. Stepwise logistic regression showed that the combination of tandem gait, axial UPDRS subscore, slow saccadic eye movements and dysphagia yielded an AUC of 0.93, adjusted for optimism. The combination of tandem gait and axial UDPRS subscore yielded an AUC of 0.90. None of the ancillary investigations alone or in combination with clinical testing improved this clinically based diagnostic accuracy, not even in a subgroup of patients with the greatest diagnostic uncertainty at baseline. Our study demonstrates that a comprehensive set of clinical tests provides good accuracy to differentiate PD from AP. Our results also suggest that routine MRI, IBZM-SPECT, CSF analysis and anal sphincter EMG do not improve this diagnostic accuracy. Future work should evaluate the possible diagnostic value of more advanced diagnostic tests.

Structural biomarkers in the cerebrospinal fluid within 24 h after a traumatic spinal cord injury: a descriptive analysis of 16 subjects.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: To characterize the cerebrospinal fluid (CSF) concentrations of glial fibrillary acidic protein, neuron specific enolase (NSE), S-100ß, tau and neurofilament heavy chain (NFH) within 24 h of an acute traumatic spinal cord injury (SCI), and to correlate these concentrations with the baseline severity of neurologic impairment as graded by the American Spinal Injury Association impairment scale (AIS). METHODS: A lumbar puncture was performed to obtain CSF from 16 acute traumatic SCI patients within 24 h post injury. Neurological examinations were performed within 24 h of injury and again at 6 or 12 months post injury. The correlations between the CSF concentrations and initial AIS were calculated by using Pearson correlation coefficients. In addition, an independent Student's t-test was used to test for differences in CSF concentrations between patients of different AIS grades. RESULTS: The CSF NSE concentrations were significantly correlated with the baseline neurologic impairment being either 'motor complete' (AIS A, B) or 'motor incomplete' (AIS C, D) (r=0.520, P<0.05). The mean S-100ß concentration in motor complete patients was significantly higher compared with motor incomplete patients; 377.2 µg l(-1) (s.d.±523 µg l(-1)) vs 57.1 µg l(-1) (s.d.±56 µg l(-1)) (P<0.05), respectively. Lastly, the mean NFH concentration in motor complete patients was significantly higher compared with motor incomplete patient, 11 813 ng l(-1) (s.d.±16 195 ng l(-1)) vs 1446.8 ng l(-1) (s.d.±1533 ng l(-1)), (P<0.05), respectively. CONCLUSION: In this study we identified differences in the structural CSF biomarkers NSE, S-100ß and NFH between motor complete and motor incomplete SCI patients. Our data showed no clear differences in any of the protein concentrations between the different AIS grades.

GLUT1 deficiency syndrome into adulthood: a follow-up study.

GLUT1 deficiency syndrome (GLUT1DS) is a treatable neurometabolic disorder in which glucose transport into the brain is disturbed. Besides the classic phenotype of intellectual disability, epilepsy, and movement disorders, other phenotypes are increasingly recognized. These include, for example, idiopathic generalized epilepsy and paroxysmal exercise-induced dyskinesia. Since the disorder has only been recognized for two decades and is mostly diagnosed in children, little is known about the disease course. Our purpose was to investigate the disease course of GLUT1DS patients with the classic, complex phenotype from infancy into adulthood. We performed a systematic literature review as well as a cohort study, including GLUT1DS patients aged 18 years and older. The literature search yielded a total of 91 adult GLUT1DS patients, of which 33 patients (one-third) had a complex phenotype. The cohort study included seven GLUT1DS patients with a complex phenotype who were prospectively followed up in our clinic from childhood into adulthood. Our results show that epilepsy is a prominent feature during childhood in classic GLUT1DS patients. During adolescence, however, epilepsy diminishes or even disappears, but new paroxysmal movement disorders, especially paroxysmal exercise-induced dyskinesia, either appear or worsen if already present in childhood. Intellectual disability was not systematically assessed, but cognitive functions appeared to be stabile throughout life. Like children, adolescents may benefit from a ketogenic diet or variants thereof.

Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment.

BACKGROUND: Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid ß(1-42) protein (Aß42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. RESULTS: Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aß42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aß42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aß42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. CONCLUSIONS: In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

Age and diagnostic performance of Alzheimer disease CSF biomarkers.

OBJECTIVES: Core CSF changes in Alzheimer disease (AD) are decreased amyloid ß(1-42), increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly. METHODS: We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43-89 years) and 304 controls (67, 44-91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43-89 years) followed for at least 2 years, or until dementia diagnosis. RESULTS: The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages. CONCLUSION: Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.

CSF α-synuclein does not differentiate between parkinsonian disorders.

Differentiating between Parkinson's disease (PD) and atypical Parkinsonism (AP) is clinically relevant but challenging. A timely and correct diagnosis might result in better targeted treatment strategies, adequate patient counseling, and early recognition of disease-specific complications. We aimed to investigate whether cerebrospinal fluid (CSF) concentrations of α-synuclein are of additional diagnostic value. We examined 142 consecutive patients with parkinsonism, mean disease duration 39.7 mo (Parkinson's disease (PD), n = 58; MSA, n = 47; dementia with Lewy bodies (DLB), n = 3; VaP, n = 22; progressive supranuclear palsy (PSP), n = 10; CBD, n = 2). Gold standard was the clinical diagnosis established after 2 years of clinical follow-up. CSF concentrations of α-synuclein, blood pigments and the erythrocyte count were determined. No differences between CSF α-synuclein concentrations of patients with PD with the reference values from our laboratory were observed. We neither found significant differences between patients with PD and AP nor between AP subgroups. Adjustment for age, disease severity or presence of erythrocytes or blood pigments in CSF did not alter these results. Our results imply that CSF α-synuclein is currently unsuitable as biomarker to differentiate between PD and AP.