Publications by authors named "Lucilla Parnetti"

205 Publications

Amyloid-β: a potential link between epilepsy and cognitive decline.

Nat Rev Neurol 2021 Jun 11. Epub 2021 Jun 11.

Neurology Clinic, Department of Medicine and Surgery, University of Perugia - S. Maria della Misericordia Hospital, Perugia, Italy.

People with epilepsy - in particular, late-onset epilepsy of unknown aetiology - have an elevated risk of dementia, and seizures have been detected in the early stages of Alzheimer disease (AD), supporting the concept of an epileptic AD prodrome. However, the relationship between epilepsy and cognitive decline remains controversial, with substantial uncertainties about whether epilepsy drives cognitive decline or vice versa, and whether shared pathways underlie both conditions. Here, we review evidence that amyloid-β (Aβ) forms part of a shared pathway between epilepsy and cognitive decline, particularly in the context of AD. People with epilepsy show an increased burden of Aβ pathology in the brain, and Aβ-mediated epileptogenic alterations have been demonstrated in experimental studies, with evidence suggesting that Aβ pathology might already be pro-epileptogenic at the soluble stage, long before plaque deposition. We discuss the hypothesis that Aβ mediates - or is at least a major determinant of - a continuum spanning epilepsy and cognitive decline. Serial cognitive testing and assessment of Aβ levels might be worthwhile to stratify the risk of developing dementia in people with late-onset epilepsy. If seizures are a clinical harbinger of dementia, people with late-onset epilepsy could be an ideal group in which to implement preventive or therapeutic strategies to slow cognitive decline.
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http://dx.doi.org/10.1038/s41582-021-00505-9DOI Listing
June 2021

Tracing Neurological Diseases in the Presymptomatic Phase: Insights From Neurofilament Light Chain.

Front Neurosci 2021 24;15:672954. Epub 2021 May 24.

Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

The identification of neurological diseases in their presymptomatic phase will be a fundamental aim in the coming years. This step is necessary both to optimize early diagnostics and to verify the effectiveness of experimental disease modifying drugs in the early stages of diseases. Among the biomarkers that can detect neurological diseases already in their preclinical phase, neurofilament light chain (NfL) has given the most promising results. Recently, its measurement in serum has enabled the identification of neurodegeneration in diseases such as multiple sclerosis (MS) and Alzheimer's disease (AD) up to 6-10 years before the onset of symptoms. Similar results have been obtained in conditions such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), up to 2 years before clinical onset. Study of the longitudinal dynamics of serum NfL has also revealed interesting aspects of the pathophysiology of these diseases in the preclinical phase. This review sought to discuss these very recent findings on serum NfL in the presymptomatic phase of neurological diseases.
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http://dx.doi.org/10.3389/fnins.2021.672954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180886PMC
May 2021

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Nat Commun 2021 06 7;12(1):3417. Epub 2021 Jun 7.

Servei de Neurologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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http://dx.doi.org/10.1038/s41467-021-22491-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184987PMC
June 2021

The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer's Disease, Parkinson's Disease and Multiple Sclerosis.

Int J Mol Sci 2021 May 7;22(9). Epub 2021 May 7.

Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.
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http://dx.doi.org/10.3390/ijms22094958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125719PMC
May 2021

Small-expanded allele spinocerebellar ataxia 17: imaging and phenotypic variability.

Neurol Sci 2021 May 24. Epub 2021 May 24.

Neurology Department, Perugia General Hospital and Perugia University, Perugia, Italy.

Spinocerebellar ataxia 17 (SCA17) is a rare genetic cause of adult-onset ataxia caused by an abnormal expansion of the CAG/CAA sequence in the TATA-box Binding Protein (TBP) gene. A number of repeats higher than 49 are full penetrance-expanded. The range between 41 and 49 repeats is characterized by decreased penetrance, and it is usually referred to as "small." Here, we describe two patients with the SCA17 phenotype and with 43 and 44 CAG repeats in the TBP gene, and review all the previously reported cases of SCA17 with a small range of expansions. We focus on both clinical features and imaging findings, which, in the case of small-expanded alleles, can resemble those of atypical parkinsonisms. Thus, we suggest to consider the small-expanded allele SCA17 as a possible diagnosis in patients with adult-onset ataxia, even when both clinical and imaging characteristics are suggestive for other non-genetic neurodegenerative diseases.
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http://dx.doi.org/10.1007/s10072-021-05313-zDOI Listing
May 2021

Cerebrospinal fluid hemoglobin levels as markers of blood contamination: relevance for α-synuclein measurement.

Clin Chem Lab Med 2021 May 6. Epub 2021 May 6.

Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

Objectives: Cerebrospinal fluid α-synuclein (CSF α-syn) represents a possible biomarker in Parkinson's disease (PD) diagnosis. CSF blood contamination can introduce a bias in α-syn measurement. To date, CSF samples with a red blood cells (RBC) count >50 RBC × 10/L or haemoglobin (Hb) concentration >200 μg/L are excluded from biomarker studies. However, investigations for defining reliable cut-off values are missing.

Methods: We evaluated the effect of blood contamination on CSF α-syn measurement by a systematic approach in a cohort of 42 patients with different neurological conditions who underwent lumbar puncture (LP) for diagnostic reasons. CSF samples were spiked with whole blood and serially diluted to 800, 400, 200, 100, 75, 50, 25, 5, 0 RBC × 10/L. CSF α-syn and Hb levels were measured by ELISA.

Results: In neat CSF, the average concentration of α-syn was 1,936 ± 636 ng/L. This value increased gradually in spiked CSF samples, up to 4,817 ± 1,456 ng/L (+149% α-syn variation) in samples with 800 RBC × 10/L.We established different cut-offs for discriminating samples with α-syn level above 5, 10, and 20% variation, corresponding to a Hb (RBC) concentration of 1,569 μg/L (37 RBC × 10/L), 2,082 μg/L (62 RBC × 10/L), and 3,118 μg/L (87 RBC × 10/L), respectively.

Conclusions: Our data show the high impact of CSF blood contamination on CSF α-syn levels, highlighting the measurement of Hb concentration as mandatory when assessing CSF α-syn. The thresholds we calculated are useful to classify CSF samples for blood contamination, considering as reliable only those showing a Hb concentration <1,569 μg/L.
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http://dx.doi.org/10.1515/cclm-2020-1521DOI Listing
May 2021

Neuro-Immune Cross-Talk in the Striatum: From Basal Ganglia Physiology to Circuit Dysfunction.

Front Immunol 2021 19;12:644294. Epub 2021 Apr 19.

Section of Neurology, Department of Medicine and Surgery, Università degli Studi di Perugia, Perugia, Italy.

The basal ganglia network is represented by an interconnected group of subcortical nuclei traditionally thought to play a crucial role in motor learning and movement execution. During the last decades, knowledge about basal ganglia physiology significantly evolved and this network is now considered as a key regulator of important cognitive and emotional processes. Accordingly, the disruption of basal ganglia network dynamics represents a crucial pathogenic factor in many neurological and psychiatric disorders. The striatum is the input station of the circuit. Thanks to the synaptic properties of striatal medium spiny neurons (MSNs) and their ability to express synaptic plasticity, the striatum exerts a fundamental integrative and filtering role in the basal ganglia network, influencing the functional output of the whole circuit. Although it is currently established that the immune system is able to regulate neuronal transmission and plasticity in specific cortical areas, the role played by immune molecules and immune/glial cells in the modulation of intra-striatal connections and basal ganglia activity still needs to be clarified. In this manuscript, we review the available evidence of immune-based regulation of synaptic activity in the striatum, also discussing how an abnormal immune activation in this region could be involved in the pathogenesis of inflammatory and degenerative central nervous system (CNS) diseases.
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http://dx.doi.org/10.3389/fimmu.2021.644294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091963PMC
April 2021

Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Section of Neurology, Department of Medicine and Surgery, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer's disease, fronto-temporal dementia, Parkinson's disease, Huntington's disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.
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http://dx.doi.org/10.3390/ijms22094440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123079PMC
April 2021

Machine Learning Driven Profiling of Cerebrospinal Fluid Core Biomarkers in Alzheimer's Disease and Other Neurological Disorders.

Front Neurosci 2021 31;15:647783. Epub 2021 Mar 31.

Neurology 5/Neuropathology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.

Amyloid-beta (Aβ) 42/40 ratio, tau phosphorylated at threonine-181 (p-tau), and total-tau (t-tau) are considered core biomarkers for the diagnosis of Alzheimer's disease (AD). The use of fully automated biomarker assays has been shown to reduce the intra- and inter-laboratory variability, which is a critical factor when defining cut-off values. The calculation of cut-off values is often influenced by the composition of AD and control groups. Indeed, the clinically defined AD group may include patients affected by other forms of dementia, while the control group is often very heterogeneous due to the inclusion of subjects diagnosed with other neurological diseases (OND). In this context, unsupervised machine learning approaches may overcome these issues providing unbiased cut-off values and data-driven patient stratification according to the sole distribution of biomarkers. In this work, we took advantage of the reproducibility of automated determination of the CSF core AD biomarkers to compare two large cohorts of patients diagnosed with different neurological disorders and enrolled in two centers with established expertise in AD biomarkers. We applied an unsupervised Gaussian mixture model clustering algorithm and found that our large series of patients could be classified in six clusters according to their CSF biomarker profile, some presenting a typical AD-like profile and some a non-AD profile. By considering the frequencies of clinically defined OND and AD subjects in clusters, we subsequently computed cluster-based cut-off values for Aβ42/Aβ40, p-tau, and t-tau. This approach promises to be useful for large-scale biomarker studies aimed at providing efficient biochemical phenotyping of neurological diseases.
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http://dx.doi.org/10.3389/fnins.2021.647783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044304PMC
March 2021

Novel noninvasive biomarkers of prodromal Alzheimer disease: The role of optical coherence tomography and optical coherence tomography-angiography.

Eur J Neurol 2021 Jul 30;28(7):2185-2191. Epub 2021 Apr 30.

Section of Neurology, Laboratory of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.

Background And Purpose: A reduction of retinal thickness and an alteration of retinal perfusion have been found in Alzheimer disease (AD). Nowadays, retinal layers and retinal perfusion can be evaluated by means of noninvasive imaging techniques, namely, optical coherence tomography (OCT) and OCT-angiography (OCT-A). Here, we have compared the retinal thickness and the perfusion index, measured by means of OCT and OCT-A, in patients with mild cognitive impairment due to AD (MCI-AD) and in age- and sex-matched cognitively healthy controls.

Methods: Twenty-four MCI-AD patients and 13 control subjects were enrolled. MCI-AD patients underwent lumbar puncture; all of them showed a cerebrospinal fluid (CSF) profile compatible with AD. OCT was used for evaluating retinal volumes and thicknesses, whereas with OCT-A we measured fractal dimension (FD), vascular perfusion density (VPD), and vessel length density (VLD) of superficial capillary plexus (SCP), intermediate capillary plexus (ICP), deep capillary plexus (DCP), and choriocapillaris. The comparisons between groups were made after adjustment for age, diabetes, and hypertension.

Results: A significant reduction of SCP-VLD (p = 0.012), ICP-VPD (p = 0.015), ICP-VLD (p = 0.004), DCP-VPD (p = 0.012), and DCP-VLD (p = 0.009) was found in MCI-AD patients compared to controls. Conversely, FD was higher in MCI-AD than in controls (p = 0.044). CSF Aβ42/total tau negatively correlated with FD (r = -0.51, p = 0.010).

Conclusions: OCT-A might have a potential role in detecting new noninvasive biomarkers for early AD detection. Retinal VPD might identify amyloid angiopathy-related chronic injury, and FD could show early vessel recruitment as a compensative mechanism at disease onset. Further studies will be needed to confirm these findings.
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http://dx.doi.org/10.1111/ene.14871DOI Listing
July 2021

High performance liquid chromatography determination of L-glutamate, L-glutamine and glycine content in brain, cerebrospinal fluid and blood serum of patients affected by Alzheimer's disease.

Amino Acids 2021 Mar 22;53(3):435-449. Epub 2021 Feb 22.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy.

Altered glutamatergic neurotransmission is thought to play a crucial role in the progression of Alzheimer's disease (AD). Accordingly, the identification of peculiar biochemical patterns reflecting AD-related synaptopathy in blood and cerebrospinal fluid (CSF) could have relevant diagnostic and prognostic implications. In this study, we measured by High-Performance Liquid Chromatography the amount of glutamate, glutamine and glycine in post-mortem brain samples of AD patients, as well as in CSF and blood serum of drug-free subjects encompassing the whole AD clinical spectrum (pre-clinical AD, n = 18, mild cognitive impairment-AD, n = 29, dementia AD, n = 30). Interestingly, we found that glutamate and glycine levels, as well as total tau protein content, were significantly reduced in the superior frontal gyrus of patients with AD, compared with non-demented controls. No significant change was also found in glutamate, glutamine and glycine CSF concentrations between AD patients and neurological controls. Remarkably, serum glutamate levels were significantly higher in patients affected by early AD phases compared to controls, and were negatively correlated with CSF total tau levels. Conversely, serum glutamine concentration was significantly increased in AD patients, with a negative correlation with MMSE performances. Finally, we reported a significant correlation between serum L-glutamate concentrations and CDR score in female but not in male cohort of AD subjects. Overall, our results suggest that serum glutamate and glutamine levels in AD patients could vary across disease stages, potentially reflecting the progressive alteration of glutamatergic signaling during neurodegenerative processes.
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http://dx.doi.org/10.1007/s00726-021-02943-7DOI Listing
March 2021

A/T/(N) Profile in Cerebrospinal Fluid of Parkinson's Disease with/without Cognitive Impairment and Dementia with Lewy Bodies.

Diagnostics (Basel) 2020 Nov 26;10(12). Epub 2020 Nov 26.

Laboratory of Clinical Neurochemistry, Section of Neurology, Department of Medicine, University of Perugia, 06132 Perugia (PG), Italy.

Neuropathological investigations report that in synucleinopathies with dementia, namely Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB), the histopathological hallmarks of Alzheimer's Disease (AD), in particular amyloid plaques, are frequently observed. In this study, we investigated the cerebrospinal fluid (CSF) AD biomarkers in different clinical phenotypes of synucleinopathies. CSF Aβ42/Aβ40 ratio, phosphorylated tau and total tau were measured as markers of amyloidosis (A), tauopathy (T) and neurodegeneration (N) respectively, in 98 PD (48 with mild cognitive impairment, PD-MCI; 50 cognitively unimpaired, PD-nMCI), 14 PDD and 15 DLB patients, and 48 neurological controls (CTRL). In our study, CSF AD biomarkers did not significantly differ between CTRL, PD-MCI and PD-nMCI patients. In PD-nMCI and PD-MCI groups, A-/T-/N- profile was the most represented. Prevalence of A+ was similar in PD-nMCI and PD-MCI (10% and 13%, respectively), being higher in PDD (64%) and in DLB (73%). DLB showed the lowest values of Aβ42/Aβ40 ratio. Higher total tau at baseline predicted a worse neuropsychological outcome after one year in PD-MCI. A+/T+, i.e., AD-like CSF profile, was most frequent in the DLB group (40% vs. 29% in PDD).
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http://dx.doi.org/10.3390/diagnostics10121015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760640PMC
November 2020

White Matter Hyperintensities Are No Major Confounder for Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

J Alzheimers Dis 2021 ;79(1):163-175

Department of Geriatrics, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer's disease (AD). However, CSF biomarker levels can be affected by confounding factors.

Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels.

Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis.

Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group.

Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.
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http://dx.doi.org/10.3233/JAD-200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902951PMC
January 2021

Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: A European multi-site 3T study.

Magn Reson Imaging 2021 02 19;76:108-115. Epub 2020 Nov 19.

IRCCS SDN, Naples, Italy.

Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was -0.22[IQR = 0.50] for LGA-SPM8, -0.12[0.57] for LGA-SPM12, -0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies.
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http://dx.doi.org/10.1016/j.mri.2020.11.008DOI Listing
February 2021

CSF and Blood Biomarkers in Neuroinflammatory and Neurodegenerative Diseases: Implications for Treatment.

Trends Pharmacol Sci 2020 12 27;41(12):1023-1037. Epub 2020 Oct 27.

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy. Electronic address:

Neuroinflammatory and neurodegenerative diseases are characterized by the interplay of a number of molecular pathways that can be assessed through biofluids, especially cerebrospinal fluid and blood. Accordingly, the definition and classification of these disorders will move from clinical and pathological to biological criteria. The consequences of this biomarker-based diagnostic and prognostic approach are highly relevant to the field of drug development. Indeed, in view of the availability of disease-modifying drugs, fluid biomarkers offer a unique opportunity for improving the quality and applicability of results from clinical trials. Herein, we discuss the benefits of using fluid biomarkers for patient stratification, target engagement, and outcome assessment, as well as the most recent developments in neuroinflammatory and neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.tips.2020.09.011DOI Listing
December 2020

Unraveling Pathophysiological Mechanisms of Parkinson's Disease: Contribution of CSF Biomarkers.

Biomark Insights 2020 12;15:1177271920964077. Epub 2020 Oct 12.

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow for early and more precise diagnosis and provide information about prognosis. Developments in analytical chemistry allow for the detection of a large number of molecules in cerebrospinal fluid (CSF), which are known to be associated with the pathogenesis of PD. Given the pathophysiology of PD, CSF α-synuclein species have the strongest rationale for use, also providing encouraging preliminary results in terms of early diagnosis. In the field of classical Alzheimer's disease (AD) biomarkers, low CSF Aβ levels have shown a robust prognostic value in terms of development of cognitive impairment. Other CSF biomarkers including lysosomal enzymes, neurofilament light chain, markers of neuroinflammation and oxidative stress, although promising, have not proved to be reliable for diagnostic and prognostic purposes yet. Overall, the implementation of CSF biomarkers may give a substantial contribution to the optimal use of disease-modifying drugs.
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http://dx.doi.org/10.1177/1177271920964077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555566PMC
October 2020

Abnormalities of resting-state EEG in patients with prodromal and overt dementia with Lewy bodies: Relation to clinical symptoms.

Clin Neurophysiol 2020 11 23;131(11):2716-2731. Epub 2020 Sep 23.

Department of Neurology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

Objective: Here we tested if cortical sources of resting state electroencephalographic (rsEEG) rhythms may differ in sub-groups of patients with prodromal and overt dementia with Lewy bodies (DLB) as a function of relevant clinical symptoms.

Methods: We extracted clinical, demographic and rsEEG datasets in matched DLB patients (N = 60) and control Alzheimer's disease (AD, N = 60) and healthy elderly (Nold, N = 60) seniors from our international database. The eLORETA freeware was used to estimate cortical rsEEG sources.

Results: As compared to the Nold group, the DLB and AD groups generally exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). As compared to the DLB "controls", the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower central alpha source activities (p < 0.005); (2) greater cognitive deficits exhibited higher parietal and central theta source activities as well as higher central, parietal, and occipital alpha source activities (p < 0.01); (3) visual hallucinations pointed to greater parietal delta source activities (p < 0.005).

Conclusions: Relevant clinical features were associated with abnormalities in spatial and frequency features of rsEEG source activities in DLB patients.

Significance: Those features may be used as neurophysiological surrogate endpoints of clinical symptoms in DLB patients in future cross-validation prospective studies.
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http://dx.doi.org/10.1016/j.clinph.2020.09.004DOI Listing
November 2020

Measurement of CSF core Alzheimer disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

Alzheimers Res Ther 2020 09 29;12(1):121. Epub 2020 Sep 29.

Laboratory of Clinical Neurochemistry, Section of Neurology, University of Perugia, Piazzale Lucio Severi 1/8, 06132, Perugia, PG, Italy.

Background: Cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau), and total-tau (t-tau) represent core biomarkers of Alzheimer disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work.

Methods: Fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after 1-month deep freezing (- 80 °C). As an automated platform, we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes.

Results: In fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%), and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42. These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau. Nevertheless, the Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples.

Conclusions: Small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cutoffs for fresh and frozen samples are required, larger, multi-center investigations are needed.
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http://dx.doi.org/10.1186/s13195-020-00689-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526419PMC
September 2020

Changes of olfactory tract in Parkinson's disease: a DTI tractography study.

Neuroradiology 2021 Feb 11;63(2):235-242. Epub 2020 Sep 11.

Movement Disorders Center, Neurology Department, Perugia General Hospital and University of Perugia, S. Maria della Misericordia Hospital, Perugia, Italy.

Purpose: Impaired olfactory function is one of the main features of Parkinson's disease. However, how peripheral olfactory structures are involved remains unclear. Using diffusion tensor imaging fiber tracking, we investigated for MRI microstructural changes in the parkinsonian peripheral olfactory system and particularly the olfactory tract, in order to seek a better understanding of the structural alternations underlying hyposmia in Parkinson's disease.

Methods: All patients were assessed utilizing by the Italian Olfactory Identification Test for olfactory function and the Unified Parkinson's Disease Rating Scale-III part as well as Hoehn and Yahr rating scale for motor disability. Imaging was performed on a 3 T Clinical MR scanner. MRI data pre-processing was carried out by DTIPrep, diffusion tensor imaging reconstruction, and fiber tracking using Diffusion Toolkit and tractography analysis by TrackVis. The following parameters were used for groupwise comparison: fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and tract volume.

Results: Overall 23 patients with Parkinson's disease (mean age 63.6 ± 9.3 years, UPDRS-III 24.5 ± 12.3, H&Y 1.9 ± 0.5) and 18 controls (mean age 56.3 ± 13.7 years) were recruited. All patients had been diagnosed hyposmic. Diffusion tensor imaging analysis of the olfactory tract showed significant fractional anisotropy, and tract volume decreases for the Parkinson's disease group compared with controls (P < 0.05). Fractional anisotropy and age, in the control group, were significant for multiple correlations (r = - 0.36, P < 0.05, Spearman's rank correlation).

Conclusions: Fiber tracking diffusion tensor imaging analysis of olfactory tract was feasible, and it could be helpful for characterizing hyposmia in Parkinson's disease.
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http://dx.doi.org/10.1007/s00234-020-02551-4DOI Listing
February 2021

Cerebrospinal fluid and serum d-serine concentrations are unaltered across the whole clinical spectrum of Alzheimer's disease.

Biochim Biophys Acta Proteins Proteom 2020 12 5;1868(12):140537. Epub 2020 Sep 5.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy. Electronic address:

The diagnosis of Alzheimer's disease (AD) relies on the presence of amyloidosis and tauopathy, as reflected in cerebrospinal fluid (CSF), independently from the clinical stage. Recently, CSF d-serine has been proposed as a possible new AD biomarker, reflecting dysfunctional activation of neuronal glutamatergic N-methyl-d-aspartate receptor (NMDAR). In this study, we measured blood serum and CSF concentration of two NMDAR modulators, such as d-serine and d-aspartate, in a cohort of drug-free subjects encompassing the whole AD clinical spectrum. In addition, we also analyzed d-serine levels in a cohort of post-mortem AD and control cortex samples. We reported unaltered serum and CSF concentrations of d-serine and d-aspartate in AD patients both during the AD progression and compared to non-demented controls. Accordingly, no correlation was detected between serum or CSF d-serine content and mini-mental state examination or Clinical Dementia Rating. Similarly, cortical d-serine levels were also unaltered in post-mortem samples of AD patients. Overall, our results failed to confirm previous findings indicating the CSF d-serine as a novel biomarker for AD.
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http://dx.doi.org/10.1016/j.bbapap.2020.140537DOI Listing
December 2020

Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study.

PLoS Med 2020 08 20;17(8):e1003289. Epub 2020 Aug 20.

Department of Biochemistry and Molecular Biology, Lariboisière Hospital, APHP, Paris, France.

Background: The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.

Methods And Findings: This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.

Conclusions: In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.
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http://dx.doi.org/10.1371/journal.pmed.1003289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446786PMC
August 2020

Cognitive impairment in multiple sclerosis: lessons from cerebrospinal fluid biomarkers.

Neural Regen Res 2021 Jan;16(1):36-42

Section of Neurology, Department of Medicine, University of Perugia, Perugia, Italy.

Cognitive impairment is a common clinical manifestation of multiple sclerosis, but its pathophysiology is not completely understood. White and grey matter injury together with synaptic dysfunction do play a role. The measurement of biomarkers in the cerebrospinal fluid and the study of their association with cognitive impairment may provide interesting in vivo evidence of the biological mechanisms underlying multiple sclerosis-related cognitive impairment. So far, only a few studies on this topic have been published, giving interesting results that deserve further investigation. Cerebrospinal fluid biomarkers of different pathophysiological mechanisms seem to reflect different neuropsychological patterns of cognitive deficits in multiple sclerosis. The aim of this review is to discuss the studies that have correlated cerebrospinal fluid markers of immune, glial and neuronal pathology with cognitive impairment in multiple sclerosis. Although preliminary, these findings suggest that cerebrospinal fluid biomarkers show some correlation with cognitive performance in multiple sclerosis, thus providing interesting insights into the mechanisms underlying the involvement of specific cognitive domains.
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http://dx.doi.org/10.4103/1673-5374.286949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818856PMC
January 2021

Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.

Neuroimage 2020 09 13;218:116932. Epub 2020 May 13.

CRMBM-CEMEREM, UMR 7339, Aix-Marseille University, CNRS, Marseille, France.

Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults.

Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session.

Results: Significant MRI site and vendor effects (p ​< ​.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p ​< ​1.39E-36). In particular, volumes larger than 200 ​mm (for amygdalar nuclei) and 300 ​mm (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε ​< ​5% and DICE ​> ​0.80).

Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116932DOI Listing
September 2020

Late-Onset Epilepsy With Unknown Etiology: A Pilot Study on Neuropsychological Profile, Cerebrospinal Fluid Biomarkers, and Quantitative EEG Characteristics.

Front Neurol 2020 15;11:199. Epub 2020 Apr 15.

Neurology Clinic, University of Perugia-S. Maria della Misericordia Hospital, Perugia, Italy.

Despite the fact that epilepsy has been associated with cognitive decline, neuropsychological, neurobiological, and neurophysiological features in patients with late-onset epilepsy of unknown etiology (LOEU) are still unknown. This cross-sectional study aims to investigate the neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD), and resting-state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU-MCI) and with normal cognition (LOEU-CN), compared to non-epileptic MCI (NE-MCI) and cognitively normal (CN) controls. Consecutive patients in two clinical Units diagnosed with LOEU-CN (19), LOEU-MCI (27), and NE-MCI (21) were enrolled, and compared to age and sex-matched cognitively normal subjects CN (11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho-tau and total tau, classified through A/T/(N) system). Recordings of resting-state eyes-closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed. Most LOEU patients had an MCI status at seizure onset (59%). Patients with LOEU-MCI performed significantly worse on measures of global cognition, visuo-spatial abilities, and executive functions compared to NE-MCI patients ( < 0.05). Regarding MCI subtypes, multiple-domain MCI was 3-fold more frequent in LOEU-MCI than in NE-MCI patients (OR 3.14, 95%CI 0.93-10.58, = 0.06). CSF Aβ42 levels were lower in the LOEU-MCI compared with the LOEU-CN group. Finally, parietal and occipital sources of alpha (8-12 Hz) rhythms were less active in the LOEU-MCI than in the NE-MCI and CN groups, while the opposite was true for frontal and temporal cortical delta sources. MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU-MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross-validate our findings and test the predictive value of CSF and EEG variables.
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http://dx.doi.org/10.3389/fneur.2020.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174783PMC
April 2020

Impulse Control Disorders and Levodopa-Induced Dyskinesias in Parkinson's Disease: Pulsatile versus Continuous Dopaminergic Stimulation.

J Parkinsons Dis 2020 ;10(3):927-934

Movement Disorders Center, Neurology Department, Perugia General Hospital and University of Perugia, Perugia, Italy.

Background: Dopaminergic medications in Parkinson's disease (PD) are usually associated with the development of both levodopa-induced dyskinesias (LID) and impulse control and repetitive behavior disorders (ICRB).

Objective: To assess the prevalence and the severity of ICRB in a cohort of moderate and advanced PD patients and to investigate the potential interplay between ICRB, LID and dopaminergic therapies.

Methods: 117 PD patients were consecutively recruited. LID were assessed by using the Rush Dyskinesia Rating Scale (RDRS). ICRB were tested by means of Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease Rating Scale (QUIP-RS).

Results: 55 patients were affected by LID. Among them, 37 were treated only by oral therapy, OT (LID/OT), while 18 were on treatment with jejunal levodopa infusion, JLI (LID/JLI). 62 patients were not affected by LID (NLID) and all of them were on therapy only with oral drugs. The overall prevalence of clinically significant ICRB was 34% (95% CI = 26% to 43%) and the mean value (±SD) of QUIP-RS total score was 5.4±8.5. Prevalence of clinically significant ICRB, as well as severity of ICRB, was higher in patients with LID compared to NLID patients (p = 0.016 and p < 0.001, respectively). When considering LID/JLI, LID/OT and NLID groups, QUIP-RS total score was significantly higher in LID/OT patients compared to LID/JLI (10.4±11.8 vs. 4.9±6.0, p = 0.019) and NLID (10.4±11.8 vs. 2.5±4.8, p < 0.001) groups.

Conclusion: PD patients with LID show ICRB more frequently and more severely than patients without LID. Among LID patients, those treated by JLI showed a lower severity of ICRB than those on OT, suggesting a potential protective effect of JLI on ICRB.
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http://dx.doi.org/10.3233/JPD-191833DOI Listing
January 2020

Abnormal cortical neural synchronization mechanisms in quiet wakefulness are related to motor deficits, cognitive symptoms, and visual hallucinations in Parkinson's disease patients: an electroencephalographic study.

Neurobiol Aging 2020 07 12;91:88-111. Epub 2020 Mar 12.

Department of Biophysics, International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.

Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.02.029DOI Listing
July 2020

Molecular profiling in Parkinsonian syndromes: CSF biomarkers.

Clin Chim Acta 2020 Jul 4;506:55-66. Epub 2020 Mar 4.

Section of Neurology, Department of Medicine, University of Perugia, Italy; Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Italy.

An accurate and early diagnosis of degenerative parkinsonian syndromes is a major need for their correct and timely therapeutic management. The current diagnostic criteria are mostly based on clinical features and molecular imaging. However, diagnostic doubts often persist especially in the early stages of diseases when signs are slight, ambiguous and overlapping among different syndromes. Molecular imaging may not be altered in the early stages of diseases, also failing to discriminate among different syndromes. Cerebrospinal fluid (CSF) represents an ideal source of biomarkers reflecting different pathways of neuropathological changes taking place in the brain and preceding the clinical onset. The aim of this review is to provide un update on CSF biomarkers in parkinsonian disorders, discussing in detail their association with neuropathological correlates. Their potential contribution in differential diagnosis and prognostic assessment of different parkinsonian syndromes is also discussed. Before entering the clinical use both for diagnostic and prognostic purposes, these CSF biomarkers need to be thoroughly assessed in terms of pre-analytical and analytical variability, as well as to clinical validation in independent cohorts.
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http://dx.doi.org/10.1016/j.cca.2020.03.002DOI Listing
July 2020

Fingerprinting Alzheimer's Disease by H Nuclear Magnetic Resonance Spectroscopy of Cerebrospinal Fluid.

J Proteome Res 2020 04 12;19(4):1696-1705. Epub 2020 Mar 12.

Laboratory of Clinical Neurochemistry, Department of Medicine, Section of Neurology, University of Perugia, Perugia 06123, Italy.

In this study, we sought for a cerebrospinal fluid (CSF) metabolomic fingerprint in Alzheimer's disease (AD) patients characterized, according to the clinical picture and CSF AD core biomarkers (Aβ, p-tau, and t-tau), both at pre-dementia (mild cognitive impairment due to AD, MCI-AD) and dementia stages (ADdem) and in a group of patients with a normal CSF biomarker profile (non-AD) using untargeted H nuclear magnetic resonance (NMR) spectroscopy-based metabolomics. This is a retrospective study based on two independent cohorts: a Dutch cohort, which comprises 20 ADdem, 20 MCI-AD, and 20 non-AD patients, and an Italian cohort, constituted by 14 ADdem and 12 non-AD patients. H NMR CSF spectra were analyzed using OPLS-DA. Metabolomic fingerprinting in the Dutch cohort provides a significant discrimination (86.1% accuracy) between ADdem and non-AD. MCI-AD patients show a good discrimination with respect to ADdem (70.0% accuracy) but only slight differences when compared with non-AD (59.6% accuracy). Acetate, valine, and 3-hydroxyisovalerate result to be altered in ADdem patients. Valine correlates with cognitive decline at follow-up ( = 0.53, = 0.0011). The discrimination between ADdem and non-AD was confirmed in the Italian cohort. The CSF metabolomic fingerprinting shows a signature characteristic of ADdem patients with respect to MCI-AD and non-AD patients.
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http://dx.doi.org/10.1021/acs.jproteome.9b00850DOI Listing
April 2020

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson's Disease.

J Clin Med 2020 Feb 21;9(2). Epub 2020 Feb 21.

Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti, 06123 Perugia, Italy.

Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson's disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded α-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson's disease.
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http://dx.doi.org/10.3390/jcm9020594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073989PMC
February 2020
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