Genome-wide association study and polygenic risk scores of retinal thickness across the cognitive continuum: data from the NORFACE cohort.

BACKGROUND: Several studies have reported a relationship between retinal thickness and dementia. Therefore, optical coherence tomography (OCT) has been proposed as an early diagnosis method for Alzheimer's disease (AD). In this study, we performed a genome-wide association study (GWAS) aimed at identifying genes associated with retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness assessed by OCT and exploring the relationships between the spectrum of cognitive decline (including AD and non-AD cases) and retinal thickness. METHODS: RNFL and GCIPL thickness at the macula were determined using two different OCT devices (Triton and Maestro). These determinations were tested for association with common single nucleotide polymorphism (SNPs) using adjusted linear regression models and combined using meta-analysis methods. Polygenic risk scores (PRSs) for retinal thickness and AD were generated. RESULTS: Several genetic loci affecting retinal thickness were identified across the genome in accordance with previous reports. The genetic overlap between retinal thickness and dementia, however, was weak and limited to the GCIPL layer; only those observable with all-type dementia cases were considered. CONCLUSIONS: Our study does not support the existence of a genetic link between dementia and retinal thickness.

Harnessing acoustic speech parameters to decipher amyloid status in individuals with mild cognitive impairment.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by a gradual decline in cognitive functions. Currently, there are no effective treatments for AD, underscoring the importance of identifying individuals in the preclinical stages of mild cognitive impairment (MCI) to enable early interventions. Among the neuropathological events associated with the onset of the disease is the accumulation of amyloid protein in the brain, which correlates with decreased levels of Aß42 peptide in the cerebrospinal fluid (CSF). Consequently, the development of non-invasive, low-cost, and easy-to-administer proxies for detecting Aß42 positivity in CSF becomes particularly valuable. A promising approach to achieve this is spontaneous speech analysis, which combined with machine learning (ML) techniques, has proven highly useful in AD. In this study, we examined the relationship between amyloid status in CSF and acoustic features derived from the description of the Cookie Theft picture in MCI patients from a memory clinic. The cohort consisted of fifty-two patients with MCI (mean age 73 years, 65% female, and 57% positive amyloid status). Eighty-eight acoustic parameters were extracted from voice recordings using the extended Geneva Minimalistic Acoustic Parameter Set (eGeMAPS), and several ML models were used to classify the amyloid status. Furthermore, interpretability techniques were employed to examine the influence of input variables on the determination of amyloid-positive status. The best model, based on acoustic variables, achieved an accuracy of 75% with an area under the curve (AUC) of 0.79 in the prediction of amyloid status evaluated by bootstrapping and Leave-One-Out Cross Validation (LOOCV), outperforming conventional neuropsychological tests (AUC = 0.66). Our results showed that the automated analysis of voice recordings derived from spontaneous speech tests offers valuable insights into AD biomarkers during the preclinical stages. These findings introduce novel possibilities for the use of digital biomarkers to identify subjects at high risk of developing AD.

A randomized, open-label clinical trial in mild cognitive impairment with EGb 761 examining blood markers of inflammation and oxidative stress.

Although beta-amyloid (Aß) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer's disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS) = 3] and an extension with an additional 12-month follow-up. During the first 12 months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240 mg orally (study group, n = 50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n = 50). After the first 12 months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240 mg tablet per day orally. All participants will be monitored for an additional 12 months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers ( https://www.olink.com/products/inflammation/ ) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1 years, and the mean time between symptom onset and MCI diagnosis was 2.9 years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI.Trial registration: Registro Español de estudios clínicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355.

Macular vessel density in the superficial plexus is not associated to cerebrospinal fluid core biomarkers for Alzheimer's disease in individuals with mild cognitive impairment: The NORFACE cohort.

Background: Optical coherence tomography angiography (OCT-A) is a novel method in the dementia field that allows the detection of retinal vascular changes. The comparison of OCT-A measures with established Alzheimer's disease (AD)-related biomarkers is essential to validate the former as a marker of cerebrovascular impairment in the AD continuum. We aimed to investigate the association of macular vessel density (VD) in the superficial plexus quantified by OCT-A with the AT(N) classification based on cerebrospinal fluid (CSF) Aß1-42, p181-tau and t-tau measurements in individuals with mild cognitive impairment (MCI). Materials and methods: Clinical, demographic, ophthalmological, OCT-A and CSF core biomarkers for AD data from the Neuro-ophthalmology Research at Fundació ACE (NORFACE) project were analyzed. Differences in macular VD in four quadrants (superior, nasal, inferior, and temporal) among three AT(N) groups [Normal, Alzheimer and Suspected non-Alzheimer pathology (SNAP)] were assessed in a multivariate regression model, adjusted for age, APOE ε4 status, hypertension, diabetes mellitus, dyslipidemia, heart disease, chronic obstructive pulmonary disease and smoking habit, using the Normal AT(N) group as the reference category. Results: The study cohort comprised 144 MCI participants: 66 Normal AT(N), 45 Alzheimer AT(N) and 33 SNAP AT(N). Regression analysis showed no significant association of the AT(N) groups with any of the regional macular VD measures (all, p > 0.16). The interaction between sex and AT(N) groups had no effect on differentiating VD. Lastly, CSF Aß1-42, p181-tau and t-tau measures were not correlated to VD (all r < 0.13; p > 0.13). Discussion: Our study showed that macular VD measures were not associated with the AT(N) classification based on CSF biomarkers in patients with MCI, and did not differ between AD and other underlying causes of cognitive decline in our cohort.

The Synergic Effect of AT(N) Profiles and Depression on the Risk of Conversion to Dementia in Patients with Mild Cognitive Impairment.

Few studies have addressed the impact of the association between Alzheimer's disease (AD) biomarkers and NPSs in the conversion to dementia in patients with mild cognitive impairment (MCI), and no studies have been conducted on the interaction effect of these two risk factors. AT(N) profiles were created using AD-core biomarkers quantified in cerebrospinal fluid (CSF) (normal, brain amyloidosis, suspected non-Alzheimer pathology (SNAP) and prodromal AD). NPSs were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). A total of 500 individuals with MCI were followed-up yearly in a memory unit. Cox regression analysis was used to determine risk of conversion, considering additive and multiplicative interactions between AT(N) profile and NPSs on the conversion to dementia. A total of 224 participants (44.8%) converted to dementia during the 2-year follow-up study. Pathologic AT(N) groups (brain amyloidosis, prodromal AD and SNAP) and the presence of depression and apathy were associated with a higher risk of conversion to dementia. The additive combination of the AT(N) profile with depression exacerbates the risk of conversion to dementia. A synergic effect of prodromal AD profile with depressive symptoms is evidenced, identifying the most exposed individuals to conversion among MCI patients.

Global Rostral Midbrain Syndrome (GRMS) and Corpus callosum infarction in the context of shunt overdrainage.

We report 3 cases of Global rostral midbrain syndrome (GRMS) and Corpus Callosum (CC) infarction, in the context of hydrocephalus followed by shunt dysfunction and slit ventricles. Prior shunt implantation had been indicated for adult-onset hydrocephalus secondary to aqueductal stenosis of varying causes. All three patients had been stable for months before developing repeated shunt dysfunctions, ultimately progressing to parkinsonism, Parinaud syndrome, akinetic mutism, pyramidal signs, cognitive impairment, CC infarction and slit ventricles, in the context of CSF overdrainage. Parkinsonism-related symptoms responded to dopa in all cases, but Parinaud syndrome and cognitive impairment persisted. Although GRMS has been described in the context of a transtentorial pressure gradient after shunt blockage, in these three cases with similar clinical presentation, reverse transtentorial pressure gradient and slit ventricles due to shunt overdrainage was the likely cause. The authors discuss the role of CC infarction and provide a detailed analysis after gathering previously described data, to unify information under a recognizable clinical entity and better understand the underlying pathophysiology, treatment options and outcome.

Internal thoracic veins: Anatomy, plasticity and clinico-imaging relevance in small animal practice.

The internal thoracic veins (ITVs) are small paired vessels located on the ventral surface of the thoracic cavity that drain the ventro-cranial abdominal wall, the ventro-lateral thoracic wall, the diaphragm and part of the mediastinum, conveying blood from these regions into the cranial vena cava. These vessels demonstrate a high level of anatomic plasticity and haemodynamic adaptability in both humans and small animals with blood flow impairment of the main abdominal and thoracic venous trunks. The ITVs may act as a natural bypass between the cranial and caudal venous system and between the portal vein and the cranial vena cava, depending on the level of the obstruction, giving rise to a wide spectrum of collateral pathways: intrathoracic cavo-caval, thoraco-abdominal cavo-caval, abdomino-thoracic cavo-caval, porto-cranial caval and lateral thoracic-azygos ITV collaterals. This paper provides a brief overview of the normal and pathologic anatomy of the ITVs described in dogs with cranial and caudal vena cava obstruction and portal hypertension as shown by CT angiography. Collateral ITV pathways need to be distinguished from other vascular anomalies in dogs, and their identification during routine CT studies could help radiologists to reach a more accurate diagnosis of caval or portal flow disturbance.

Acute amnestic syndromes.

Acute amnestic syndromes are usually rare clinical events occurring in emergency situations. Etiological diagnosis can be challenging and underlying causes diverse. They can be transient and totally reversible, or accompanied by other neurological symptoms resulting in serious and irreversible brain damage. Pathophysiology of these syndromes mainly corresponds to structural or functional alteration of memory circuits, including those in the hippocampus. One of the most frequent forms is transient global amnesia (TGA), characterized by sudden onset of anterograde amnesia lasting less than 24  hours, in the absence of other neurological signs or symptoms. Another acute and transient memory disorder is transient epileptic amnesia (TEA), due to focal crisis activity. Stroke injuries occurring at strategic memory-related sites can also present as sudden episodes of amnesia. In addition to neurological etiologies, amnesia may be a symptom of a psychiatric disorder (dissociative amnesia). Traumatic brain injuries, autoimmune encephalitis and acute toxic metabolic disorders can also cause amnesia and should be included among the differential diagnoses. In this review, we summarize the most relevant clinical findings in acute amnestic syndromes, and discuss the different ancillary tests needed to establish a correct diagnosis and management as well the best treatment options. Relevant anatomical and pathophysiological aspects underlying these conditions will be also be presented.

Diagnosis of Rapidly Progressive Dementia in a Referral Center in Argentina.

INTRODUCTION: Rapidly progressive dementia (RPD) is a broadly defined clinical syndrome. Our aim was to describe clinical and ancillary study findings in patients with RPD and evaluate their diagnostic performance for the identification of nonchronic neurodegenerative rapidly progressive dementia (ncnRPD). METHODS: We reviewed clinical records and ancillary methods of patients evaluated for RPD at our institution in Buenos Aires, Argentina from 2011 to 2017. We compared findings between chronic neurodegenerative RPD and ncnRPD and evaluated the diagnostic metrics using receiver operating characteristic curves. RESULTS: We included 104 patients with RPD, 29 of whom were chronic neurodegenerative RPD and 75 of whom were ncnRPD. The 6-month time to dementia cutpoint had a sensitivity of 89% and specificity of 100% for ncnRPD, with an area under the receiver operating characteristic curve of 0.965 (95% confidence interval=0.935-0.99; P<0.001). A decision tree that included time to dementia, brain magnetic resonance imaging, and cerebrospinal fluid analysis identified ncnRPD patients with a sensitivity of 100%, specificity of 79%, positive predictive value of 93%, and negative predictive value of 100% overall. DISCUSSION: RPD is a clinical syndrome that comprises different diagnoses, many of them for treatable diseases. Using the time to dementia, brain magnetic resonance imaging, and cerebrospinal fluid analysis when triaging these patients could help identify those diseases that need to be studied more aggressively.

ASSESSMENT OF RESIDUAL VASCULARIZATION OF THE LIMB AS A PROGNOSTIC FACTOR TO AVOID SEA TURTLE FLIPPER AMPUTATION.

Entanglement occurs when a marine turtle becomes trapped within anthropogenic materials such as debris or fishery gear, inducing strangulation of anatomical parts such as flippers or the neck, causing deep lacerations, maiming, amputation, or choking. Often, severely entangled flippers in captured or stranded turtles are removed surgically. Turtles with flipper impairment have difficulty in swimming, diving, and feeding. Our aim was to use color Doppler ultrasound and multi-detector computer tomography to evaluate residual vascularization or neovascularization in severely entangled flippers of loggerhead sea turtles (Caretta caretta) to assess viability of flippers, even in the absence of limb sensation. We studied 12 turtles with either unilateral (n=8) or bilateral (n=4) involvement. A total of 14 flippers were severely entangled and two flippers were spontaneously amputated. Only two of the 14 entangled flippers had to be removed surgically. For 12 entangled flippers, after surgical curettage, the treatment protocol was based on the use of a plant-derived commercial dressing. The animals were monitored and treated for 1-3 mo, until the soft tissue defects were completely healed by secondary intention. Interestingly, in the treated animals the healing flippers steadily recovered motility and sensation, restoring the complete functionality of the flipper. Vascularization of the limb was found to be critical to prevent amputation of entangled flippers, preserving the flipper and its functionality with conservative therapy and avoiding amputation as much as possible. Our study showed that in cases of entanglement, amputation does not need to be performed immediately but can wait for nonviability to declare itself following conservative therapy and should be reserved as a last-resort treatment.

Multidetector Computed Tomographic Anatomy of the Lungs in the Loggerhead Sea Turtle (Caretta caretta).

Multidetector computed tomographic (CT) anatomy was used to evaluate the lungs of 10 loggerhead sea turtle (Caretta caretta) without pulmonary disease, in order to provide a baseline of turtle lung anatomy by CT imaging. In all patients, in this retrospective anatomic study, the CT datasets were carefully evaluated for assessment of the bronchial tree morphology and branching pattern, of the arborization pattern of pulmonary arteries and veins and of the bronchoarterial-bronchovenous diameter ratios. Imaging anatomy was compared with previous published data based on dissection and microscopic anatomy. With the increasing availability of advanced imaging tools for wildlife animal patients, a detailed CT anatomy background is required to decipher correctly the pathologic respiratory conditions of sea turtles. Anat Rec, 302:1658-1665, 2019. © 2018 American Association for Anatomy.

Common venous renal trunk in two dogs: Multidetector computed tomographic imaging findings.

In dogs, variation in the branching pattern of renal veins is rare with only few patterns reported. This report describes two unusual anomalies of the renal vein branching patterns in two dogs. In dog 1, a common renal trunk drained both kidneys, in a T-shape pattern, in the caudal vena cava after a long right perirenal course. In dog 2, a common venous trunk branched cranially from the pre-renal segment of an azygos-caudal vena cava venous trunk and divided into the renal veins in a Y-shape pattern. Proper knowledge of the possible anatomical variations in renal venous drainage may be helpful during imaging assessment and surgical planning of several canine diseases involving the abdominal vasculature and retroperitoneal space.

Canine and feline abdominal arterioportal communications can be classified based on branching patterns in computed tomographic angiography.

Arterioportal vascular anomalies are communications between the splanchnic arteries and the portal system that represent a rare cause of presinusoidal portal hypertension in small animals. There is little information concerning the imaging findings of arterioportal communications in small animals and no classification could be found for radiologists and surgeons. The aims of this retrospective descriptive multicentric study were to describe the computed tomographic characteristics of arterioportal communications in a group of cats and dogs, and to propose a classification based on computed tomography (CT) angiographic anatomy. Computed tomography databases from multiple veterinary hospitals were searched for cats and dogs with a diagnosis of arterioportal communication. A total of 36 animals (33 dogs, three cats) met the inclusion criteria. There were 32 intrahepatic arterioportal malformations and four extrahepatic fistulae. The intrahepatic arterioportal malformations were classified as right divisional (11/32) and left divisional (21/32), and the left divisional were subclassified as left medial (16/21) and left lateral (4/21). One patient showed multiple intrahepatic arterioportal communications with concomitant left medial and left lateral conformations. Two patients with intrahepatic arteriovenous malformation showed concomitant congenital intrahepatic shunts. The proposed anatomical classification based on CT angiography could allow veterinary radiologists to have a more systematic approach and help improve the radiologist-surgeon communication.

Lung mesenchymal stem cells-derived extracellular vesicles attenuate the inflammatory profile of Cystic Fibrosis epithelial cells.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) are multi-potent non-hematopoietic stem cells, residing in most tissues including the lung. MSCs have been used in therapy of chronic inflammatory lung diseases such as Cystic Fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) but the main beneficial effects reside in the anti-inflammatory potential of the released extracellular vesicles (EVs). Recent reports demonstrate that EVs are effective in animal model of asthma, E.coli pneumonia, lung ischemia-reperfusion, and virus airway infection among others. Despite this growing literature, the EVs effects on CF are largely unexplored. METHODS: We treated IB3-1 cells, an in vitro human model of CF, with EVs derived from human lung MSCs under basal and inflammatory conditions (TNFα stimulation). RESULTS: We demonstrated here that treatment of IB3-1 CF cell line with EVs, down-regulates transcription and protein expression of pro-inflammatory cytokines such as IL-1ß, IL-8, IL-6 under TNFα - stimulated conditions. EVs treatment upregulates the mRNA expression of PPARγ, a transcription factor controlling anti-inflammatory and antioxidant mechanisms via NF-kB and HO-1. Accordingly, NF-kB nuclear translocation is reduced resulting in impairment of the downstream inflammation cascade. In addition, the mRNA of HO-1 is enhanced together with the antioxidant defensive response of the cells. CONCLUSIONS: We conclude that the anti-inflammatory and anti-oxidant efficacy of EVs derived from lung MSCs could be mediated by up-regulation of the PPARγ axis, whose down-stream effectors (NF-kB and HO-1) are well-known modulators of these pathways. GENERAL SIGNIFICANCE: EVs could be a novel strategy to control the hyper-inflamed condition in Cystic Fibrosis.

Usefulness of spinal unenhanced computed tomography and CT-myelography in the age of multidetector CT technology and magnetic resonance imaging - Preliminary considerations.

Over the last decade, magnetic resonance imaging (MRI) and multidetector computed tomography (MDCT) have revolutionized diagnostic potential in small animal practice, providing adequate assessment of spinal diseases at levels comparable to that achieved in human radiology. T2-weighted MRI images are extremely sensitive to intramedullary parenchymal disorders, while balanced steady-state free precession sequences provide high-quality myelographic images of the spine without the need of intrathecal contrast medium administration. Multidetector computed tomography, with its near-isotropic spatial resolution and multiplanar reformatting of the acquired datasets, provides sufficient stratigraphic details of the spinal cord and the epidural space, facilitating the detection of compressive pathologies without the need of subarachnoid opacification. Nowadays, MDCT and low-field (LF) MRI have become fairly standard and available in academic institutions and private veterinary facilities, appearing to be valuable, complementary, and non-invasive diagnostic tools for imaging the spine. In this scenario, this clinical communication provides a series of preliminary observations that may help to reconsider the usefulness of CT-myelography in the light of its invasiveness and actual diagnostic advantages compared to MRI and unenhanced MDCT for the assessment of compressive and non-compressive spinal diseases in small animals.

Comparative diagnostic imaging of a partial patellar ligament tear in a dog.

Traumatic lesions of the patellar ligament (PL) are rare in dogs. The resulting injury can be a complete or partial laceration, depending on the quantity of torn collagen fibres. Information obtained from imaging evaluation is of great value to the clinical approach towards PL injuries, because subsequent treatment options are affected by the distinction between complete or partial tears. Imaging diagnosis of PL damage in veterinary practice commonly relies on radiographic examination through the recognition of indirect signs, such as "patella alta", bone fragments at the level of the patellar or tibial insertion, and soft tissue opacity at the cranial aspect of the joint. Although ultrasound (US) and magnetic resonance imaging (MRI) have been described as useful diagnostic tools for the assessment of PL tears in human patients, specific comparative data regarding the evaluation of PL rupture in dogs using different imaging modalities is lacking in the veterinary literature. This paper describes the radiographic, ultrasonographic, CT and MRI imaging findings of a partial PL tear in a dog and discusses the utility of these techniques in diagnosing this condition. CT provided more detailed information than X-ray examination in the assessment of the osteoligamentous junction, the exclusion of microfracture and distal PL avulsion, but did not add information regarding PL integrity. MRI and US provided the most useful information regarding intra-ligamentous damage and as such their combined use may be considered for the assessment of PL injuries after clinical examination and survey radiographs.

Principles and applications of the balanced steady-state free precession sequence in small animal low-field MRI.

Magnetic resonance imaging (MRI) in small animal practice is largely based on classic two-dimensional spin-echo, inversion recovery and gradient-echo sequences which are largely limited by low spatial resolution, especially in low-field (LF)-MRI scanners. Nowadays, however, the availability of volumetric sequences can open new perspectives and enhance the diagnostic potential of this imaging modality. Balanced steady-state free precession (bSSFP) is a three-dimensional gradient-echo sequence in which image contrast is given by the ratio of T2 and T1, resulting in low soft-tissue signal, poor cerebral grey/white matter distinction and a bright signal from free fluid and fat. Such properties, along with a high signal-to-noise ratio and a very high spatial resolution deriving from acquisition of contiguous blocks of data, make this sequence perfectly suited for morphologic imaging, particularly for fluid-containing structures. Although bSSFP is widely adopted in human medical imaging, the use of this sequence in veterinary radiology is limited to anatomic studies of the inner ear and quadrigeminal cistern. This review aims to discuss the technical background of the bSSFP sequence and its possible advantageous applications in small animal LF-MRI for different specific disorders of the spine (arachnoid diverticula, small disc herniation, facet joint synovial cysts), brain (supracollicular fluid accumulation, traumatic injuries) and ligaments (complete and partial tears).

Nonclinical data supporting orphan medicinal product designations: lessons from rare neurological conditions.

Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs. This could not only inform future drug development in rare neurological conditions, but also indicate areas where the use of nonclinical models can be made more efficient.

Spontaneous nervous system concussion in dogs: a description of two cases and a review of terminology in veterinary medicine.

In human medicine, central nervous system (CNS) concussion is defined as a transient neurological dysfunction following a traumatic event, without evidence of structural abnormalities of the affected region on advanced diagnostic imaging. Depending on the anatomical region involved, three forms of concussive syndromes are described: brain concussion, spinal concussion and cerebellar concussion. Although major textbooks of veterinary neurology admit the existence of canine brain concussion, spontaneous cases of this pathological condition have not been reported in small animals so far. This report describes two cases of concussion in dogs: a 9-month-old, intact male, shih-tzu with brain concussion; and a 10-month-old, intact male, poodle with cerebellar concussion. In addition, a brief review of the definition of the term "concussion" in the veterinary medical literature is provided, in comparison to its meaning in the human medical literature. Finally, this paper proposes an appropriate definition of "concussion" in dogs, that may facilitate clinicians in the recognition of such an elusive syndrome.