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Article ; Online: Cerebral and cerebellar white matter tract alterations in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN).

Rivera, Diones / Roa-Sanchez, Pedro / Bidó, Pamela / Speckter, Herwin / Oviedo, Jairo / Stoeter, Peter

2022 Volume 98, Page(s) 1–6

Abstract: Background: To examine structural connectivity of white matter tracts in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) dystonia and identify those ones which correlate negatively to severity of symptoms.: Methods: In a group ... ...

Abstract	Background: To examine structural connectivity of white matter tracts in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) dystonia and identify those ones which correlate negatively to severity of symptoms. Methods: In a group of 41 patients suffering from PKAN dystonia and an age- and gender-matched control group, white matter tractography was carried out, based on diffusion tensor imaging magnetic resonance data. Postprocessing included assessment of Quantitative Anisotropy (QA) using q-space diffeomorphic reconstruction in order to reduce influence of iron accumulation in globus pallidus of patients. Results: Whole brain tractography presented significantly reduced QA values in patients (0.282 ± 0.056, as compared to controls (0.325 ± 0.046, p < 0.001). 9 fiber clusters of tracts correlated negatively to the dystonia score of patients: the middle cerebellar peduncle and the tracts of both cerebellar hemispheres as well as corpus callosum, forceps minor, the superior cortico-striate tracts and the superior thalamic radiations of both cerebral hemispheres (False Discovery Rate FDR = 0.041). Conclusion: The finding of a reduced global structural connectivity within the white matter and of negative correlation of motor system-related tracts, mainly those between the basal ganglia, cortical areas and the cerebellum, fits well to the concept of a general functional disturbance of the motor system in PKAN.
MeSH term(s)	Brain/pathology ; Cerebellum/diagnostic imaging ; Cerebellum/pathology ; Diffusion Tensor Imaging/methods ; Dystonia/pathology ; Humans ; Leukoaraiosis/pathology ; Pantothenate Kinase-Associated Neurodegeneration/diagnostic imaging ; Pantothenate Kinase-Associated Neurodegeneration/genetics ; White Matter/diagnostic imaging ; White Matter/pathology
Language	English
Publishing date	2022-04-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1311489-x
ISSN	1873-5126 ; 1353-8020
ISSN (online)	1873-5126
ISSN	1353-8020
DOI	10.1016/j.parkreldis.2022.03.017
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Article: Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer's Disease.

Vardarajan, Badri / Kalia, Vrinda / Reyes-Dumeyer, Dolly / Dubey, Saurabh / Nandakumar, Renu / Lee, Annie / Lantigua, Rafael / Medrano, Martin / Rivera, Diones / Honig, Lawrence / Mayeux, Richard / Miller, Gary

Research square

2024

Abstract: Background: We profiled circulating plasma metabolites to identify systemic biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD).: Methods: We used an untargeted approach with liquid chromatography coupled to ... ...

Abstract	Background: We profiled circulating plasma metabolites to identify systemic biochemical changes in clinical and biomarker-assisted diagnosis of Alzheimer's disease (AD). Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure small molecule plasma metabolites from 150 clinically diagnosed AD patients and 567 age-matched healthy elderly of Caribbean Hispanic ancestry. Plasma biomarkers of AD were measured including P-tau181, Aβ40, Aβ42, total-tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-abundant modules of metabolites were tested with clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels. Results: Over 6000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR = 0.91 [0.89-0.96], p = 2e-04). Association was restricted to individuals without an Conclusions: Unbiased metabolic profiling can identify critical metabolites and pathways associated with β-amyloid and phosphotau pathology. We also observed an
Language	English
Publishing date	2024-01-08
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3346076/v1
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Article: Rare genetic variation in Fibronectin 1 (

Bhattarai, Prabesh / Gunasekaran, Tamil Iniyan / Reyes-Dumeyer, Dolly / Jülich, Dörthe / Tayran, Hüseyin / Yilmaz, Elanur / Flaherty, Delaney / Lantigua, Rafael / Medrano, Martin / Rivera, Diones / Recio, Patricia / Ertekin-Taner, Nilüfer / Teich, Andrew F / Dickson, Dennis W / Holley, Scott / Mayeux, Richard / Kizil, Caghan / Vardarajan, Badri N

bioRxiv : the preprint server for biology

2024

Abstract: The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying ... ...

Abstract	The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.02.573895
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Article: Lysophosphatidylcholines are associated with P-tau181 levels in early stages of Alzheimer's Disease.

Kalia, Vrinda / Reyes-Dumeyer, Dolly / Dubey, Saurabh / Nandakumar, Renu / Lee, Annie J / Lantigua, Rafael / Medrano, Martin / Rivera, Diones / Honig, Lawrence S / Mayeux, Richard / Miller, Gary W / Vardarajan, Badri N

medRxiv : the preprint server for health sciences

2023

Abstract: Background: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD.: Methods: We used an untargeted ... ...

Abstract	Background: We investigated systemic biochemical changes in Alzheimer's disease (AD) by investigating the relationship between circulating plasma metabolites and both clinical and biomarker-assisted diagnosis of AD. Methods: We used an untargeted approach with liquid chromatography coupled to high-resolution mass spectrometry to measure exogenous and endogenous small molecule metabolites in plasma from 150 individuals clinically diagnosed with AD and 567 age-matched elderly without dementia of Caribbean Hispanic ancestry. Plasma biomarkers of AD were also measured including P-tau181, Aβ40, Aβ42, total tau, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Association of individual and co-expressed modules of metabolites were tested with the clinical diagnosis of AD, as well as biologically-defined AD pathological process based on P-tau181 and other biomarker levels. Results: Over 4000 metabolomic features were measured with high accuracy. First principal component (PC) of lysophosphatidylcholines (lysoPC) that bind to or interact with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AHA) was associated with decreased risk of AD (OR=0.91 [0.89-0.96], p=2e-04). Restricted to individuals without an Conclusions: Our findings indicate that unbiased metabolic profiling can identify critical metabolites and pathways associated with β-amyloid and phosphotau pathology. We also observed an
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.24.23294581
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Article ; Online: Can Apparent Diffusion Coefficient (ADC) maps replace Diffusion Tensor Imaging (DTI) maps to predict the volumetric response of meningiomas to Gamma Knife Radiosurgery?

Speckter, Herwin / Palque-Santos, Sarai / Mota-Gonzalez, Ruben / Bido, Jose / Hernandez, Giancarlo / Rivera, Diones / Suazo, Luis / Valenzuela, Santiago / Gonzalez-Curi, Maria / Stoeter, Peter

Journal of neuro-oncology

2023 Volume 161, Issue 3, Page(s) 547–554

Abstract: Purpose: Noninvasive methods are desired to predict the treatment response to Stereotactic Radiosurgery (SRS) to improve individual tumor management. In a previous study, we demonstrated that Diffusion Tensor Imaging (DTI)-derived parameter maps ... ...

Abstract	Purpose: Noninvasive methods are desired to predict the treatment response to Stereotactic Radiosurgery (SRS) to improve individual tumor management. In a previous study, we demonstrated that Diffusion Tensor Imaging (DTI)-derived parameter maps significantly correlate to SRS response. This study aimed to analyze and compare the predictive value of intratumoral ADC and DTI parameters in patients with meningiomas undergoing radiosurgery. Methods: MR images of 70 patients treated with Gamma Knife SRS for WHO grade I meningiomas were retrospectively reviewed. MR acquisition included pre- and post-treatment DWI and DTI sequences, and subtractions were calculated to assess for radiation-induced changes in the parameter values. Results: After a mean follow-up period (FUP) of 52.7 months, 69 of 70 meningiomas were controlled, with a mean volume reduction of 34.9%. Whereas fractional anisotropy (FA) values of the initial exam showed the highest correlation to tumor volume change at the last FU (CC = - 0.607), followed by the differences between first and second FU values of FA (CC = - 0.404) and the first longitudinal diffusivity (LD) value (CC = - 0.375), the correlation coefficients of all ADC values were comparably low. Nevertheless, all these correlations, except for ADC measured at the first follow-up, reached significance. Conclusion: For the first time, the prognostic value of ADC maps measured in meningiomas before and at first follow-up after Gamma Knife SRS, was compared to simultaneously acquired DTI parameter maps. Quantities assessed from ADC maps present significant correlations to the volumetric meningioma response but are less effective than correlations with DTI parameters.
MeSH term(s)	Humans ; Meningioma/diagnostic imaging ; Meningioma/radiotherapy ; Meningioma/surgery ; Diffusion Tensor Imaging/methods ; Radiosurgery/methods ; Retrospective Studies ; Meningeal Neoplasms/diagnostic imaging ; Meningeal Neoplasms/radiotherapy ; Meningeal Neoplasms/pathology
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-023-04243-4
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Article ; Online: MRI radiomics in the prediction of the volumetric response in meningiomas after gamma knife radiosurgery.

Speckter, Herwin / Radulovic, Marko / Trivodaliev, Kire / Vranes, Velicko / Joaquin, Johanna / Hernandez, Wenceslao / Mota, Angel / Bido, Jose / Hernandez, Giancarlo / Rivera, Diones / Suazo, Luis / Valenzuela, Santiago / Stoeter, Peter

Journal of neuro-oncology

2022 Volume 159, Issue 2, Page(s) 281–291

Abstract: Purpose: This report presents the first investigation of the radiomics value in predicting the meningioma volumetric response to gamma knife radiosurgery (GKRS).: Methods: The retrospective study included 93 meningioma patients imaged by three Tesla ... ...

Abstract	Purpose: This report presents the first investigation of the radiomics value in predicting the meningioma volumetric response to gamma knife radiosurgery (GKRS). Methods: The retrospective study included 93 meningioma patients imaged by three Tesla MRI. Tumor morphology was quantified by calculating 337 shape, first- and second-order radiomic features from MRI obtained before GKRS. Analysis was performed on original 3D MR images and after their laplacian of gaussian (LoG), logarithm and exponential filtering. The prediction performance was evaluated by Pearson correlation, linear regression and ROC analysis, with meningioma volume change per month as the outcome. Results: Sixty calculated features significantly correlated with the outcome. The feature selection based on LASSO and multivariate regression started from all available 337 radiomic and 12 non-radiomic features. It selected LoG-sigma-1-0-mm-3D_firstorder_InterquartileRange and logarithm_ngtdm_Busyness as the predictively most robust and non-redundant features. The radiomic score based on these two features produced an AUC = 0.81. Adding the non-radiomic karnofsky performance status (KPS) to the score has increased the AUC to 0.88. Low values of the radiomic score defined a homogeneous subgroup of 50 patients with consistent absence (0%) of tumor progression. Conclusion: This is the first report of a strong association between MRI radiomic features and volumetric meningioma response to radiosurgery. The clinical importance of the early and reliable prediction of meningioma responsiveness to radiosurgery is based on its potential to aid individualized therapy decision making.
MeSH term(s)	Humans ; Magnetic Resonance Imaging ; Meningeal Neoplasms ; Meningioma ; Radiosurgery ; Retrospective Studies ; Treatment Outcome
Language	English
Publishing date	2022-06-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-022-04063-y
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Article: "Spontaneous" CSF Fistula due to Transtegmental Brain Herniation in Combination with Signs of Increased Intracranial Pressure and Petrous Bone Hyperpneumatization: An Illustrative Case Report.

Rivera, Diones / Fermin-Delgado, Rafael / Stoeter, Peter

Journal of neurological surgery reports

2014 Volume 75, Issue 2, Page(s) e251–4

Abstract: Background and Importance Transtegmental brain herniation into the petrous bone is a rare cause of rhinoliquorrhea. Our case presents a combination of several typical clinical and imaging findings illustrating the ongoing etiologic discussion of such ... ...

Abstract	Background and Importance Transtegmental brain herniation into the petrous bone is a rare cause of rhinoliquorrhea. Our case presents a combination of several typical clinical and imaging findings illustrating the ongoing etiologic discussion of such cerebrospinal fluid (CSF) fistulas. Clinical Presentation A 53-year-old man presented with nasal discharge after a strong effort to suppress coughing. Imaging revealed a transtegmental herniation of parts of the inferior temporal gyrus into the petrous bone and in addition a combination of signs of chronically increased intracranial pressure and a hyperpneumatization of the petrous bone. The fistula was closed by a middle cranial fossa approach. Conclusion The case illustrates the two main predisposing factors for development of petrous bone CSF fistulas: increased intracranial pressure and thinning of the tegmental roof due to extensive development of air cells. Because the CSF leakage repair does not change the underlying cause, patients have to be informed about the possibility of developing increased intracranial pressure and recurrences of brain herniations at other sites.
Language	English
Publishing date	2014-11-12
Publishing country	Germany
Document type	Case Reports
ZDB-ID	2653397-2
ISSN	2193-6366 ; 2193-6358
ISSN (online)	2193-6366
ISSN	2193-6358
DOI	10.1055/s-0034-1387183
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Article ; Online: Compression of the middle cerebellar tract by posterior fossa tumors before and after Gamma Knife radiosurgery studied with diffusion tensor imaging.

Speckter, Herwin / Bido, Jose / Hernandez, Giancarlo / Rivera, Diones / Suazo, Luis / Valenzuela, Santiago / Gonzalez, Cesar / Stoeter, Peter

Journal of radiosurgery and SBRT

2019 Volume 6, Issue 1, Page(s) 11–17

Abstract: Purpose: To investigate if clinically asymptomatic compression of the middle cerebellar tract by extracerebral posterior fossa tumors can produce changes in diffusion tensor imaging (DTI) parameters and if these changes return to normal after Gamma ... ...

Abstract	Purpose: To investigate if clinically asymptomatic compression of the middle cerebellar tract by extracerebral posterior fossa tumors can produce changes in diffusion tensor imaging (DTI) parameters and if these changes return to normal after Gamma Knife radiosurgery (GKRS). Material and methods: In 22 patients (12 female, mean age 53.8 years) with posterior fossa tumors (14 schwannomas and 8 meningiomas), the middle cerebellar tract was tracked using DTI data. DTI parameters, such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) within these tracts were determined separately on the tumor side and on the contra-lateral side. As a surrogate parameter of tract compression, we used the distance between a tangential line extending between the anterior, not affected part of the pons and the cerebellum, and the furthest extension of the tumor into the lateral rim of the pons. In a subgroup of 15 patients, DTI parameters were recorded after a follow-up of more than 2 years (mean follow-up time 37.5 months) after GKRS and compared to initial findings. Results: Before GKRS, all DTI parameters within the compressed tract had increased. The increase in MD correlated significantly with the degree of tract compression (c = 0.443, p < 0.05). Follow-up examinations after GKRS showed reduction in FA and AD, whereas MD and RD increased. After correction for time elapsed after treatment and tumor type, the changes of MD and AD following treatment correlated significantly with the reduction of tract compression, but not with radiation dose. Conclusion: Although without obvious clinical symptoms, disorders of the middle cerebellar tract, as in the case of posterior fossa tumors, persist after reduction of tumor size. Because of the significant correlation between the change of parameters and the reduction of tract compression, initial compression and consequent relief are regarded as the main factors responsible for persistent disorders of the middle cerebellar tract. Radiosurgery dose did not contribute significantly to changes in DTI parameters.
Language	English
Publishing date	2019-01-21
Publishing country	United States
Document type	Journal Article
ISSN	2156-4647
ISSN (online)	2156-4647
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Article ; Online: Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease.

Bhattarai, Prabesh / Gunasekaran, Tamil Iniyan / Belloy, Michael E / Reyes-Dumeyer, Dolly / Jülich, Dörthe / Tayran, Hüseyin / Yilmaz, Elanur / Flaherty, Delaney / Turgutalp, Bengisu / Sukumar, Gauthaman / Alba, Camille / McGrath, Elisa Martinez / Hupalo, Daniel N / Bacikova, Dagmar / Le Guen, Yann / Lantigua, Rafael / Medrano, Martin / Rivera, Diones / Recio, Patricia /

Nuriel, Tal / Ertekin-Taner, Nilüfer / Teich, Andrew F / Dickson, Dennis W / Holley, Scott / Greicius, Michael / Dalgard, Clifton L / Zody, Michael / Mayeux, Richard / Kizil, Caghan / Vardarajan, Badri N

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 70

Abstract: The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the ... ...

Abstract	The risk of developing Alzheimer's disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer's Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood-brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b-the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk.
MeSH term(s)	Aged ; Animals ; Humans ; Alzheimer Disease/genetics ; Fibronectins/genetics ; Genetic Variation/genetics ; Gliosis ; Zebrafish
Chemical Substances	Fibronectins ; ApoE protein, human ; FN1 protein, human
Language	English
Publishing date	2024-04-10
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-024-02721-1
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Article: Long-term follow-up in two cases of intracranial Rosai-Dorfman Disease complicated by incomplete resection and recurrence.

Rivera, Diones / Pérez-Castillo, Miguelina / Fernández, Belkis / Stoeter, Peter

Surgical neurology international

2014 Volume 5, Page(s) 30

Abstract: Background: Although intracranial Rosai-Dorfman disease is a principally benign lymphohistiocytosis, some patients run a relapsing or progressive course. However, reports about long-term follow-up are extremely rare.: Case description: In two ... ...

Abstract	Background: Although intracranial Rosai-Dorfman disease is a principally benign lymphohistiocytosis, some patients run a relapsing or progressive course. However, reports about long-term follow-up are extremely rare. Case description: In two patients, initial tumor resection was incomplete or followed by recurrences over 3 years, which finally subsided after application of chemotherapy, and patients remained tumor-free for more than 7 years thereafter. Conclusion: Up to now there is no agreement on how to treat complicated cases of intracranial Rosai-Dorfman disease; our good experience with adjuvant chemotherapy and long-term follow-up will contribute to treatment planning in complicated cases.
Language	English
Publishing date	2014-02-28
Publishing country	United States
Document type	Case Reports
ISSN	2229-5097
ISSN	2229-5097
DOI	10.4103/2152-7806.128003
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