Publications by authors named "Andrea Sturchio"

22 Publications

  • Page 1 of 1

Soluble Amyloid-β Consumption in Alzheimer's Disease.

J Alzheimers Dis 2021 Jun 12. Epub 2021 Jun 12.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden.

Brain proteins function in their soluble, native conformation and cease to function when transformed into insoluble aggregates, also known as amyloids. Biophysically, the soluble-to-insoluble phase transformation represents a process of polymerization, similar to crystallization, dependent on such extrinsic factors as concentration, pH, and a nucleation surface. The resulting cross-β conformation of the insoluble amyloid is markedly stable, making it an unlikely source of toxicity. The spread of brain amyloidosis can be fully explained by mechanisms of spontaneous or catalyzed polymerization and phase transformation instead of active replication, which is an enzyme- and energy-requiring process dependent on a specific nucleic acid code for the transfer of biological information with high fidelity. Early neuronal toxicity in Alzheimer's disease may therefore be mediated to a greater extent by a reduction in the pool of soluble, normal-functioning protein than its accumulation in the polymerized state. This alternative loss-of-function hypothesis of pathogenicity can be examined by assessing the clinical and neuroimaging effects of administering non-aggregating peptide analogs to replace soluble amyloid-β levels above the threshold below which neuronal toxicity may occur. Correcting the depletion of soluble amyloid-β, however, would only exemplify 'rescue medicine.' Precision medicine will necessitate identifying the pathogenic factors catalyzing the protein aggregation in each affected individual. Only then can we stratify patients for etiology-specific treatments and launch precision medicine for Alzheimer's disease and other neurodegenerative disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210415DOI Listing
June 2021

Plasma NfL, clinical subtypes and motor progression in Parkinson's disease.

Parkinsonism Relat Disord 2021 Apr 27;87:41-47. Epub 2021 Apr 27.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Introduction: neurofilament light chain (NfL) levels have been proposed as reliable biomarkers of neurodegeneration in Parkinson's disease (PD) but the relationship between plasma NfL, clinical subtypes of PD and motor progression is still debated.

Methods: plasma NfL concentration was measured in 45 healthy controls and consecutive 92 PD patients who underwent an extensive motor and non-motor assessment at baseline and after 2 years of follow-up. PD malignant phenotype was defined as the combination of at least two out of cognitive impairment, orthostatic hypotension and REM sleep behavior disorder. PD patients were divided according to the age-adjusted cut-offs of plasma NfL levels into high and normal NfL (H-NfL and N-NfL, respectively). A multivariable linear regression model was used to assess the value of plasma NfL as predictor of 2-years progression in PD.

Results: NfL was higher in PD patients than in controls (p = 0.037). H-NfL (n = 16) group exhibited more severe motor and non-motor symptoms, higher prevalence of malignant phenotype and worse motor progression (MDS-UPDRS-III 11.3 vs 0.7 points, p = 0.003) compared to N-NfL group (n = 76). In linear regression analyses plasma NfL emerged as the best predictor of 2-year motor progression compared to age, sex, disease duration, baseline motor/non-motor variables.

Conclusion: increased plasma NfL concentration is associated with malignant PD phenotype and faster motor progression. These findings support the role of NfL assessment as a useful measure for stratifying patients with different baseline slopes of decline in future clinical trials of putative disease-modifying treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2021.04.016DOI Listing
April 2021

Levodopa-responsive progressive encephalomyelitis with rigidity and myoclonus associated with glycine receptor antibodies.

Parkinsonism Relat Disord 2021 01 14;82:7-9. Epub 2020 Nov 14.

Neurology and Stroke Unit, ASST Settelaghi, Ospedale di Circolo, Varese, Italy; Università Degli Studi Dell'Insubria, Varese, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2020.11.008DOI Listing
January 2021

Genetic parkinsonisms and cancer: a systematic review and meta-analysis.

Rev Neurosci 2021 02 5;32(2):159-167. Epub 2020 Nov 5.

Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, 260 Stetson St., Cincinnati, OH45219, USA.

Genes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967-2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, was predominantly associated with gastrointestinal cancers with breast cancer, and with head-and-neck cancers. In asymptomatic carriers, was predominantly associated with gastrointestinal and prostate cancers, with prostate and genitourinary tract cancers, with sarcoma, and deletion with leukemia. In symptomatic genetic parkinsonism, was associated with nonmelanoma skin cancers and breast cancers, and with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/revneuro-2020-0083DOI Listing
February 2021

Phenotype-Agnostic Molecular Subtyping of Neurodegenerative Disorders: The Cincinnati Cohort Biomarker Program (CCBP).

Front Aging Neurosci 2020 8;12:553635. Epub 2020 Oct 8.

James J. and Joan A. Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, United States.

Ongoing biomarker development programs have been designed to identify serologic or imaging signatures of clinico-pathologic entities, assuming distinct biological boundaries between them. Identified putative biomarkers have exhibited large variability and inconsistency between cohorts, and remain inadequate for selecting suitable recipients for potential disease-modifying interventions. We launched the Cincinnati Cohort Biomarker Program (CCBP) as a population-based, phenotype-agnostic longitudinal study. While patients affected by a wide range of neurodegenerative disorders will be deeply phenotyped using clinical, imaging, and mobile health technologies, analyses will not be anchored on phenotypic clusters but on bioassays of to-be-repurposed medications as well as on genomics, transcriptomics, proteomics, metabolomics, epigenomics, microbiomics, and pharmacogenomics analyses blinded to phenotypic data. Unique features of this cohort study include (1) a reverse biology-to-phenotype direction of biomarker development in which clinical, imaging, and mobile health technologies are subordinate to biological signals of interest; (2) hypothesis free, causally- and data driven-based analyses; (3) inclusive recruitment of patients with neurodegenerative disorders beyond clinical criteria-meeting patients with Parkinson's and Alzheimer's diseases, and (4) a large number of longitudinally followed participants. The parallel development of serum bioassays will be aimed at linking biologically suitable subjects to already available drugs with repurposing potential in future proof-of-concept adaptive clinical trials. Although many challenges are anticipated, including the unclear pathogenic relevance of identifiable biological signals and the possibility that some signals of importance may not yet be measurable with current technologies, this cohort study abandons the anchoring role of clinico-pathologic criteria in favor of biomarker-driven disease subtyping to facilitate future biosubtype-specific disease-modifying therapeutic efforts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2020.553635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578373PMC
October 2020

The odyssey of complex neurogenetic disorders: From undetermined to positive.

Am J Med Genet C Semin Med Genet 2020 12 20;184(4):876-884. Epub 2020 Oct 20.

Neurogenetics Unit, Hospital JM Ramos Mejía, Buenos Aires, Argentina.

The genetic and phenotypic heterogeneity of neurogenetic diseases forces patients and their families into a "diagnostic odyssey." An increase in the variability of genetic disorders and the corresponding gene-disease associations suggest the need to periodically re-evaluate the significance of variants of undetermined pathogenicity. Here, we report the diagnostic and clinical utility of Targeted Gene Panel Sequencing (TGPS) and Whole Exome Sequencing (WES) in 341 patients with suspected neurogenetic disorders from centers in Buenos Aires and Cincinnati over the last 4 years, focusing on the usefulness of reinterpreting variants previously classified as of uncertain significance. After a mean of ±2years (IC 95:0.73-3.27), approximately 30% of the variants of uncertain significance were reclassified as pathogenic. The use of next generation sequencing methods has facilitated the identification of both germline and mosaic pathogenic variants, expanding the diagnostic yield. These results demonstrate the high clinical impact of periodic reanalysis of undetermined variants in clinical neurology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31848DOI Listing
December 2020

Rivastigmine in Parkinson's Disease Dementia with Orthostatic Hypotension.

Ann Neurol 2021 01 20;89(1):91-98. Epub 2020 Oct 20.

Neuroscience Translational Medicine, Novartis Institutes for Biomedical Research, Neurology, and Neurosurgery, McGill University, Montreal, Quebec, Canada.

Objective: The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD).

Methods: We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH-). The primary end point was the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention-to-treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses.

Results: Overall safety was comparable between OH+ (n = 288, 27.5%) and OH- (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo-adjusted effect of rivastigmine on ADAS-Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH- (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs -1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476).

Interpretation: The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect. ANN NEUROL 2021;89:91-98.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25923DOI Listing
January 2021

Kinematic but not clinical measures predict falls in Parkinson-related orthostatic hypotension.

J Neurol 2021 Mar 26;268(3):1006-1015. Epub 2020 Sep 26.

Department of Neurology, Wexner Medical Center, Ohio State University, Columbus, OH, USA.

Objective: We sought to test the hypothesis that technology could predict the risk of falls in Parkinson's disease (PD) patients with orthostatic hypotension (OH) with greater accuracy than in-clinic assessment.

Methods: Twenty-six consecutive PD patients with OH underwent clinical (including home-like assessments of activities of daily living) and kinematic evaluations of balance and gait as well as beat-to-beat blood pressure (BP) monitoring to estimate their association with the risk of falls. Fall frequency was captured by a diary collected prospectively over 6 months. When applicable, the sensitivity, specificity, and diagnostic accuracy were measured using the area under the receiver operating characteristics curve (AUC). Additional in-clinic assessments included the OH Symptom Assessment (OHSA), the OH Daily Activity Score (OHDAS), and the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS).

Results: The prevalence of falls was 53.8% over six months. There was no association between the risk of falls and test of gait and postural stability (p ≥ 0.22) or home-like activities of daily living (p > 0.08). Conversely, kinematic data (waist sway during time-up-and-go, jerkiness, and centroidal frequency during postural sway with eyes-opened) predicted the risk of falls with high sensitivity and specificity (> 80%; AUC ≥ 0.81). There was a trend for higher risk of falls in patients with orthostatic mean arterial pressure ≤ 75 mmHg.

Conclusions: Kinematic but not clinical measures predicted falls in PD patients with OH. Orthostatic mean arterial pressure ≤ 75 mmHg may represent a hemodynamic threshold below which falls become more prevalent, supporting the aggressive deployment of corrective measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10240-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914136PMC
March 2021

Progressive Ataxia with Hemiplegic Migraines: a Phenotype of CACNA1A Missense Mutations, Not CAG Repeat Expansions.

Cerebellum 2021 Feb 5;20(1):134-139. Epub 2020 Sep 5.

Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología José María Ramos Mejía, Buenos Aires, Argentina.

We report a 52-year-old woman presenting with autosomal dominant progressive cerebellar ataxia and familial hemiplegic migraine type 1 whose genetic evaluation, negative for spinocerebellar ataxia (SCA) types 1, 2, 3, and 6, revealed instead a heterozygous pathogenic missense mutation in CACNA1A (NM_001127221:c.1748G > A:p.Arg583Gln). A systematic literature review showed that Arg583Gln is associated predominantly with progressive ataxia combined with episodic disorders (overwhelmingly hemiplegic migraine) whereas Thr666Met, the other most common CACNA1A missense mutation, with a combination of progressive ataxia and episodic disorders in half the cases and episodic disorders only in the other half. While uncertainties remain in the genotype-phenotype correlation of all CACNA1A mutations, the accumulated evidence suggests that that the co-occurrence of hemiplegic migraine and autosomal dominant progressive cerebellar ataxia should guide the clinician to test for CACNA1A missense mutation rather than CAG expansions or truncating mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-020-01185-9DOI Listing
February 2021

Implementation of Mobile Health Technologies in Clinical Trials of Movement Disorders: Underutilized Potential.

Neurotherapeutics 2020 10;17(4):1736-1746

Gardner Family Center for Parkinson's disease and Movement Disorders, Department of Neurology, University of Cincinnati Academic Health Center, 260 Stetson St., Suite 2300, Cincinnati, OH, 45267-0525, USA.

Mobile health technologies (mHealth) are patient-worn or portable devices aimed at increasing the granularity and relevance of clinical measurements. The implementation of mHealth has the potential to decrease sample size, duration, and cost of clinical trials. We performed a review of the ClinicalTrials.gov database using a standardized approach to identify adoption in and usefulness of mHealth in movement disorders interventional clinical trials. Trial phase, geographical area, availability of data captured, constructs of interest, and outcome priority were collected. Eligible trials underwent quality appraisal using an ad hoc 5-point checklist to assess mHealth feasibility, acceptability, correlation with patient-centered outcome measures, and clinical meaningfulness. A total of 29% (n = 54/184) registered trials were using mHealth, mainly in Parkinson's disease and essential tremor (59.3% and 27.8%). In most cases, mHealth were used in phase 2 trials (83.3%) as secondary outcome measures (59.3%). Only five phase 3 trials, representing 9.3% of the total, used mHealth (1 as primary outcome measure, 3 as secondary, and 1 as tertiary). Only 3.7% (n = 2/54) of all trials used mHealth for measuring both motor and non-motor symptoms, and 23.1% (n = 12/52) used mHealth for unsupervised, ecologic outcomes. Our findings suggest that mHealth remain underutilized and largely relegated to phase 2 trials for secondary or tertiary outcome measures. Efforts toward greater alignment of mHealth with patient-centered outcomes and development of a universal, common-language platform to synchronize data from one or more devices will assist future efforts toward the integration of mHealth into clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-020-00901-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851293PMC
October 2020

Skin Cancer May Delay Onset but Not Progression of Parkinson's Disease: A Nested Case-Control Study.

Front Neurol 2020 28;11:406. Epub 2020 May 28.

Department of Neurology, James J. and Joan A. Gardner Center for Parkinson's Disease and Movement Disorders, University of Cincinnati, Cincinnati, OH, United States.

To evaluate the extent to which cancer, a biological opposite to neurodegenerative disorders, may affect the onset and progression of Parkinson's disease (PD). A nested case-control design in consecutive PD patients with (cases) vs. without (controls) cancer was used to compare time to clinical diagnosis and time to Hoehn & Yahr (H&Y) staging score ≥ 3 as a measure of progression. Further, we compared PD onset and progression between cases with cancer diagnosis before (cancer before PD group) and after (cancer after PD group) PD onset. Independent variables were age at PD onset, motor subscale of the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, sex, cognitive impairment, falls, depression, anxiety, dementia, and autonomic symptoms. Time to H&Y ≥ 3 was determined using Cox proportional hazards, with adjusted results summarized as hazards ratio (HR). Group differences were evaluated using unpaired -test or Fisher's exact test. The clinical PD onset was later in cases vs. controls (median 67.2 vs. 59.8 years; < 0.001), but the adjusted time to H&Y ≥ 3 was similar between groups (HR = 0.67; = 0.13). Skin cancers constituted 75% of all cancers in cases. Amongst skin cancers, compared to controls, cases had an older age at PD onset (67.8 vs. 59.8 years; < 0.001). There was no difference in risk of progression in PD patients with skin cancer compared to controls (HR = 0.54, = 0.09). Cancer, in particular of the skin, may delay the onset but not the progression of PD. Future prospective observational studies are warranted to elucidate the complex interactions between these biologically divergent disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270344PMC
May 2020

When does postural instability appear in monogenic parkinsonisms? An individual-patient meta-analysis.

J Neurol 2020 May 20. Epub 2020 May 20.

Department of Neurology, Gardner Family Center for Parkinson's Disease and Movement Disorders, University 6 of Cincinnati, Cincinnati, OH, USA.

Background: Postural instability is a disease milestone signaling advanced disease.

Objectives: To estimate the onset of postural instability in monogenic parkinsonisms.

Methods: We systematically reviewed studies (PubMed 1996-2017) in SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, FBXO7, VPS35, DNAJC6, or SYNJ1-related monogenic parkinsonisms, with documented postural instability. Genes with ≥ 15 patients were included in an individual-patient meta-analysis and compared with a retrospectively collected sporadic Parkinson's disease cohort from our center. The primary outcome measure was the progression-free survival from postural instability using Kaplan-Meier survival curves. Cox proportional hazards analyses were summarized using hazards ratio (HR).

Results: Of 2085 eligible studies, 124 met full criteria (636 patients) for the systematic review, whereas a total of 871 subjects (270 from sporadic cohort, 601 monogenic parkinsonisms) were included in the individual-patient meta-analysis. Postural instability was reported in 80% of DJ-1, 40% of PRKN, 39% of PINK1, 34% of ATP13A2, 31% of LRRK2, and 29% of SNCA patients. Progression-free survival from postural instability at 10 years after disease onset was longest in ATP13A2 (97%) and shortest in SNCA (50%). Halfway between these two extremes were PRKN (88%), PINK1 (87%), and LRRK2 (81%), similar to sporadic Parkinson's disease (72%). Higher risk of postural instability was observed in SNCA (HR = 3.2, p = 0.007) and DJ-1 (HR = 3.96, p = 0.001) compared to sporadic Parkinson's disease. Young age at onset in PINK1 and female sex in LRRK2 were associated with a decreased risk of postural instability.

Conclusions: Monogenic parkinsonisms exhibit differential timelines to postural instability, informing prognostic counseling and interpretation of future genotype-specific treatment trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-09892-3DOI Listing
May 2020

Disentangling the Amyloid Pathways: A Mechanistic Approach to Etiology.

Front Neurosci 2020 21;14:256. Epub 2020 Apr 21.

Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Stockholm, Sweden.

Amyloids are fibrillar protein aggregates associated with diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes and Creutzfeldt-Jakob disease. The process of amyloid polymerization involves three pathological protein transformations; from natively folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow seed-induced (prions) or surface-induced (including microbially induced) HEN pathways. Critically, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions, including replacement therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2020.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186396PMC
April 2020

Thalamic Deep Brain Stimulation for tremor: The critical role of intraoperative testing.

Parkinsonism Relat Disord 2020 04 25;73:45-49. Epub 2020 Mar 25.

The Ohio State Wexner Medical Center, Department of Neurology, Columbus, OH, USA. Electronic address:

Introduction: Optimal placement of Deep Brain Stimulation (DBS) lead is critical to ensure an adequate therapeutic benefit and minimize stimulation-induced side effects.

Methods: We reviewed data from 2004 to 2018 of all cases of essential tremor treated with thalamic DBS at the University of Cincinnati. All procedures were performed with the patient awake. Change in parallel trajectory was classified as major repositioning, whereas a change in depth of electrode classified as minor repositioning. The following data were compared between groups (no vs. minor vs. major repositioning): age at surgery, sex, AC-PC length, third ventricle width, cerebral atrophy, small vessel disease burden, and intraoperative tremor control. Univariate and multivariate analyses were conducted to identify factors associated with intraoperative repositioning.

Results: Of the 127 encounters with essential tremor, 71 required repositioning (33 major and 38 minor). Comparing procedures with major, minor, and no repositioning, mean number of changes per procedure (4 vs. 1.2 vs 0; p < 0.001) and AC-PC length (26 vs. 27 vs. 27.2 mm; p = 0.021) differed between the three groups. Older age at surgery (OR 1.04, p = 0.042), left side (OR 2.56, p = 0.04) and decrease in AC-PC length (OR 1.33, p = 0.026) were associated with greater odds of any (minor or major) repositioning. A decrease in AC-PC length was associated with greater odds of major repositioning (OR 1.37, p = 0.009).

Conclusion: Intraoperative functional testing may be critical to ensure the accuracy of thalamic DBS targeting based on neuroimaging data, particularly in patients with reduced AC-PC length.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2020.03.022DOI Listing
April 2020

Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta-analysis.

J Neurol Neurosurg Psychiatry 2020 04 20;91(4):426-433. Epub 2020 Feb 20.

Department of Neurology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Objective: Genetic subtypes of dystonia may respond differentially to deep brain stimulation of the globus pallidus pars interna (GPi DBS). We sought to compare GPi DBS outcomes among the most common monogenic dystonias.

Methods: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines. We searched PubMed for studies on genetically confirmed monogenic dystonia treated with GPi DBS documenting pre-surgical and post-surgical assessments using the Burke-Fahn-Marsden Dystonia Rating Scale Motor Score (BFMMS) and Burke-Fahn-Marsden Disability Score (BFMDS). We performed (i) meta-analysis for each gene mutation; (ii) weighted ordinary linear regression analyses to compare BFMMS and BFMDS outcomes between DYT- and other monogenic dystonias, adjusting for age and disease duration and (iii) weighted linear regression analysis to estimate the effect of age, sex and disease duration on GPi DBS outcomes. Results were summarised with mean change and 95% CI.

Results: DYT- (68%, 38.4 points; p<0.001), DYT- (37% 14.5 points; p<0.001) and NBIA/DYT- (27%, 21.4 points; p<0.001) improved in BFMMS; only DYT- improved in BFMDS (69%, 9.7 points; p<0.001). Improvement in DYT- was significantly greater than in DYT- (BFMMS -31%), NBIA/DYT- (BFMMS -35%; BFMDS -53%) and CHOR/DYT- (BFMMS -36%; BFMDS -42%). Worse motor outcomes were associated with longer dystonia duration and older age at dystonia onset in DYT-, longer dystonia duration in DYT/PARK- and younger age at dystonia onset in DYT-.

Conclusions: GPi DBS outcomes vary across monogenic dystonias. These data serve to inform patient selection and prognostic counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2019-322169DOI Listing
April 2020

Impaired Saccade Adaptation in Tremor-Dominant Cervical Dystonia-Evidence for Maladaptive Cerebellum.

Cerebellum 2020 Jan 22. Epub 2020 Jan 22.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.

We examined the role of the cerebellum in patients with tremor-dominant cervical dystonia by measuring the adaptive capacity of rapid reflexive eye movements (saccades). We chose the saccade adaptation paradigm because, unlike other motor learning paradigms, the real-time modification of saccades cannot "wait" for the sensory (visual) feedback. Instead, saccades rely primarily on the internal reafference modulated by the cerebellum. The saccade adaptation happens over fast and slow timescales. The fast timescale has poor retention of learned response, while the slow timescale has strong retention. Cerebellar defects resulting in loss of function affect the fast timescale but the slow timescale of saccade adaptation is retained. In contrast, maladaptive cerebellar disorders feature the absence of both fast and slow timescales. We were able to measure both timescales using noninvasive oculography in 6 normal individuals. In contrast, both timescales were absent in 12 patients with tremor-dominant cervical dystonia. These findings are consistent with maladaptive cerebellar outflow as a putative pathophysiological basis for tremor-dominant cervical dystonia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-020-01104-yDOI Listing
January 2020

SNAP25 Gene Polymorphisms Protect Against Parkinson's Disease and Modulate Disease Severity in Patients.

Mol Neurobiol 2019 Jun 17;56(6):4455-4463. Epub 2018 Oct 17.

IRCCS Fondazione Don Carlo Gnocchi, Milano, Italy.

Parkinson's disease (PD) is a α-synucleinopathy in which intracellular aggregates of α-synuclein (α-syn) result in neurodegeneration and in the impairment of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex-mediated release of neurotransmitters. SNAP25 is a SNARE complex component: its concentration is increased in the cerebrospinal fluid of PD patients and this is related to the severity of cognitive and motor symptoms. Five SNAP25 single-nucleotide polymorphisms (SNPs) that modulate gene expression and were described to play a role in neurologic conditions (rs363050, rs363039, rs363043, rs3746544, and rs1051312) were analyzed in a cohort of 412 sporadic Italian PD patients and 1103 healthy controls (HC) in order to identify possible correlation with the disease. The SNAP25 rs1051312 C allele and CC genotype confer protection against PD onset, in particular in males (p = 0.003, OR(95%CI) = 0.67(0.51-0.88)) (p = 0.008, OR(95%CI) = 0.28(0.10-0.70)). Co-segregation analyses revealed that the rs1051312 effect was reinforced when present within the rs363043 C-rs3746544 T-rs1051312 C haplotype (p = 3.3 × 10, OR = 0.47, 95%CI = 0.31-0.72), once again in males. Finally, rs363039 influenced age at onset (p = 0.02) and MMSE (Mini-Mental State Examination) scores (p = 0.01). The SNAP25 SNPs analyzed herein modulate gene expression at different levels as they are involved in binding miRNA and transcription factors; this suggests a possible synergistic effect of SNAP25 SNPs in the pathogenesis of PD. A replication in a larger and independent sample will help to further explore this hypothesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-018-1386-0DOI Listing
June 2019

Technology-based assessment of motor and nonmotor phenomena in Parkinson disease.

Expert Rev Neurother 2018 Nov 8;18(11):825-845. Epub 2018 Oct 8.

a James J and Joan A Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology , University of Cincinnati , Cincinnati , OH , USA.

Introduction: The increasing development and availability of portable and wearable technologies is rapidly expanding the field of technology-based objective measures (TOMs) in neurological disorders, including Parkinson disease (PD). Substantial challenges remain in the recognition of disease phenomena relevant to patients and clinicians, as well as in the identification of the most appropriate devices to carry out these measurements. Areas covered: The authors systematically reviewed PubMed for studies employing technology as outcome measures in the assessment of PD-associated motor and nonmotor abnormalities. Expert commentary: TOMs minimize intra- and inter-rater variability in clinical assessments of motor and nonmotor phenomena in PD, improving the accuracy of clinical endpoints. Critical unmet needs for the integration of TOMs into clinical and research practice are the identification and validation of relevant endpoints for individual patients, the capture of motor and nonmotor activities from an ecologically valid environment, the integration of various sensor data into an open-access, common-language platforms, and the definition of a regulatory pathway for approval of TOMs. The current lack of multidomain, multisensor, smart technologies to measure in real time a wide scope of relevant changes remain a significant limitation for the integration of technology into the assessment of PD motor and nonmotor functional disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737175.2018.1530593DOI Listing
November 2018

Parkinson's disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients.

J Neuroinflammation 2018 Jul 12;15(1):205. Epub 2018 Jul 12.

Center of Research in Medical Pharmacology, University of Insubria, Via Ottorino Rossi n. 9, 21100, Varese, VA, Italy.

Background: Parkinson's disease (PD) affects an estimated 7 to 10 million people worldwide, and only symptomatic treatments are presently available to relieve the consequences of brain dopaminergic neurons loss. Neuronal degeneration in PD is the consequence of neuroinflammation in turn influenced by peripheral adaptive immunity, with CD4+ T lymphocytes playing a key role. CD4+ T cells may however acquire proinflammatory phenotypes, such as T helper (Th) 1 and Th17, as well as anti-inflammatory phenotypes, such as Th2 and the T regulatory (Treg) one, and to what extent the different CD4+ T cell subsets are imbalanced and their functions dysregulated in PD remains largely an unresolved issue.

Methods: We performed two cross-sectional studies in antiparkinson drug-treated and drug-naïve PD patients, and in age- and sex-matched healthy subjects. In the first one, we examined circulating Th1, Th2, Th17, and in the second one circulating Treg. Number and frequency of CD4+ T cell subsets in peripheral blood were assessed by flow cytometry and their functions were studied in ex vivo assays. In both studies, complete clinical assessment, blood count and lineage-specific transcription factors mRNA levels in CD4+ T cells were independently assessed and thereafter compared for their consistency.

Results: PD patients have reduced circulating CD4+ T lymphocytes, due to reduced Th2, Th17, and Treg. Naïve CD4+ T cells from peripheral blood of PD patients preferentially differentiate towards the Th1 lineage. Production of interferon-γ and tumor necrosis factor-α by CD4+ T cells from PD patients is increased and maintained in the presence of homologous Treg. This Th1-biased immune signature occurs in both drug-naïve patients and in patients on dopaminergic drugs, suggesting that current antiparkinson drugs do not affect peripheral adaptive immunity.

Conclusions: The complex phenotypic and functional profile of CD4+ T cell subsets in PD patients strengthen the evidence that peripheral adaptive immunity is involved in PD, and represents a target for the preclinical and clinical assessment of novel immunomodulating therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-018-1248-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044047PMC
July 2018

The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): normative values with gender, age and education corrections in the Italian population.

BMC Neurol 2014 Sep 10;14:171. Epub 2014 Sep 10.

Background: BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) has been recently developed as brief, practical and universal assessment tool for cognitive impairment in MS subjects. It includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test-Revised (BVMT-R) . In this study we aimed at gathering regression based normative data for the BICAMS battery in the Italian population.

Methods: Healthy subjects were consecutively recruited among patient friends and relatives. Corrections for demographics were calculated using multivariable linear regression models. Test-retest reliability was assessed using the Pearson correlation coefficient.

Results: The BICAMS battery was administered to 273 healthy subjects (180 women, mean age 38.9 ± 13.0 years, mean education 14.9 ± 3.0 years). Test-retest reliability was good for all the tests.

Conclusions: The study provided normative data of the BICAMS for the Italian population confirming good test-retest reliability which can facilitate the use of the battery in clinical practice, also for longitudinal patient assessments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-014-0171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172942PMC
September 2014

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.

BMC Neurol 2014 May 26;14:114. Epub 2014 May 26.

Department of NEUROFARBA, Section Neurosciences, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.

Background: Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.

Methods: Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.

Results: Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.

Conclusions: Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2377-14-114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4059028PMC
May 2014

Postpartum relapses increase the risk of disability progression in multiple sclerosis: the role of disease modifying drugs.

J Neurol Neurosurg Psychiatry 2014 Aug 8;85(8):845-50. Epub 2014 Jan 8.

Department of NEUROFARBA, University of Florence, Florence, Italy.

Objective: To assess relapses, disability progression and the role of disease modifying drugs (DMDs) in the year after delivery in women with multiple sclerosis (MS).

Methods: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centres. The risk of relapses and disability progression in the year after delivery was assessed using time-dependent Cox regression analysis.

Results: 350 out of 423 pregnancies were assessed (pregnancies not resulting in live birth and with a postpartum follow-up period shorter than 1 year were excluded from the analysis). 148 patients (42.3%) had at least one relapse in the year after delivery. An Expanded Disability Status Scale (EDSS) score at conception ≥2.0 (HR=1.4; 95% CI 1.1 to 2.0; p=0.046) and a higher number of relapses before (HR=1.5; 95% CI 1.2 to 1.8; p<0.001) and during pregnancy (HR=2.3; 95% CI 1.6 to 3.4; p<0.001) were related to a higher risk of postpartum relapses. On the contrary, early DMD resumption after delivery marginally reduced the risk of postpartum relapses (HR=0.7, 95% CI 0.4 to 1.0; p=0.079). Moreover, 44/338 women progressed by at least one point on the EDSS. Disability progression was associated with a higher number of relapses before (HR=1.4, 95% CI 1.1 to 1.9; p=0.047) and after delivery (HR=2.7, 95% CI 1.4 to 5.2; p=0.002).

Conclusions: Our findings show an increased risk of postpartum relapses and disability accrual in women with higher disease activity before and during pregnancy. Since it may reduce the risk of postpartum relapses, early DMD resumption should be encouraged, particularly in patients with more active disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2013-306054DOI Listing
August 2014