Linear magnetic resonance imaging measurements of the hippocampal formation differ in young versus old dogs

Age-related hippocampal formation (HF) atrophy has been documented on MRI studies using volumetric analysis and visual rating scales.This retrospective cross-sectional study aimed to compare linear MRI measurements of the HF between young (1–3 years) and old (>10 years) non-brachycephalic dogs, with normal brain anatomy and cerebrospinal fluid (CSF) analysis. Right and left hippocampal formation height (HFH), height of the brain (HB) and mean HFH/HB ratio were measured by two observers on a transverse T2 fluid-attenuated inversion recovery sequence containing rostral colliculi and mesencephalic aqueduct.119 MRI studies were enrolled: 75 young and 44 old dogs. Left and right HFH were greater (p<0.0001) in young, while HB was greater in old dogs (p=0.024). Mean HFH/HB ratio was 15.66 per cent and 18.30 per cent in old and young dogs (p<0.0001). No differences were found comparing measurements between epileptic and non-epileptic dogs.Old dogs have a greater HB; this may represent the different study populations or a statistical phenomenon. Ageing affects HF linear measurements. A reduction of mean HFH/HB ratio between 18.30 per cent and 15.66 per cent should be considered a physiological age-related process of the canine lifespan. The use of mean HFH/HB ratio could be considered for quantifying brain atrophy in elderly dogs

A canine model of human aging and Alzheimer's disease

AbstractThe aged dog naturally develops cognitive decline in many different domains (including learning and memory) but also exhibits human-like individual variability in the aging process. The neurobiological basis for cognitive dysfunction may be related to structural changes that reflect neurodegeneration. Molecular cascades that contribute to degeneration in the aging dog brain include the progressive accumulation of beta-amyloid (Aβ) in diffuse plaques and in the cerebral vasculature. In addition, neuronal dysfunction occurs as a consequence of mitochondrial dysfunction and cumulative oxidative damage. In combination, the aged dog captures key features of human aging, making them particularly useful for the development of preventive or therapeutic interventions to improve aged brain function. These interventions can then be translated into human clinical trials. This article is part of a Special Issue entitled: Animal Models of Disease

Linfografía mediante imagen por resonancia magnética en modelo animal canino

Para este estudio se contó con dos grupos, uno de 12 animales sanos y otro con 10 animales que cursaban procesos patológicos en la glándula mamaria. Con los animales anestesiados se emplearon imágenes por resonancia magnética para visualizar los conductos linfáticos y linfonodos de la zona inguinal en series potenciadas en 3D TOF en plano dorsal. En los dos grupos se administró gadopentetato de dimeglumina. Para validar la técnica empleada se consideraron en las imágenes tres estructuras (aire, grasa y músculo) cuya IS mostró diferencia significativa entre tejido glandular mamario (IS 184,8 ± 28,2) y linfonodos regionales (IS de 51,3 ± 5,4), permitiendo determinar el patrón de referencia para el estudio. Se concluye que el empleo de un equipo de IRM de bajo campo proporciona suficiente información para diferenciar intensidades de señal de linfonodos que recogen linfa de procesos patológicos respecto a linfonodos sanos en caninos.For this study were included two groups, one of 12 healthy animals and another of 10 animals affected by disease conditions in the mammary gland. With the anesthetized animal were used magnetic resonance imaging to visualize the lymph ducts and lymph nodes in the inguinale area in potentiated series in 3D TOF in dorsal plane. In both groups it was administered gadopentetate dimeglumine. To validate the technique used, were considered in the images three structures (air, fat and muscle) which IS showed significant difference between glandular breast tissue (IS 184.8 ± 28.2) and regional lymph nodes (IS 51.3 ± 5, 4), allowing to determine the benchmark for the study. It is concluded that the use of a low field equipment of MRI provides enough information to differentiate signal intensities of lymph nodes that collect lymph from pathological processes regarding healthy lymph nodes in dog

Dogs with cognitive dysfunction syndrome: a natural model of Alzheimer's Disease

In the search for appropriate models for Alzheimer's disease (AD) involving animals other than rodents, several laboratories are working with animals that naturally develop cognitive dysfunction. Among the animals tested, dogs are quite unique in helping to elucidate the cascade of events that take place in brain amyloid-beta (Aβ)deposition aging, and cognitive deficit. Recent innovative research has validated human methods and tools for the analysis of canine neuropathology and has allowed the development of two different approaches to investigate dogs as natural models of AD. The first approach relates AD-like neuropathy with the decline in memory and learning ability in aged housed dogs in a highly controlled laboratory environment. The second approach involves research in family-owned animals with cognitive dysfunction syndrome. In this review, we compare the strengths and limitations of housed and family-owned canine models, and appraise their usefulness for deciphering the early mechanisms of AD and developing innovative therapies

Projet d'étude des conséquences physiologiques et pathologiques du vieillissement sur le cerveau des carnivores domestiques

Aujourd'hui, l'espérance de vie de la population humaine ainsi que celle de nos animaux de compagnie a considérablement augmenté, conduisant à une hausse significative de la population gériatrique. Or, le vieillissement est un processus qui s'accompagne d'un certain nombre de modifications de l'organisme et notamment du cerveau. Le vieillissement cérébral des carnivores domestiques partage de nombreuses similitudes avec celui de l’Homme, faisant d’eux un modèle d’étude particulièrement prometteur. Malheureusement malgré plusieurs travaux sur le sujet, certains points restent encore à élucider. Ce travail a pour objectif de mettre en place un projet d’étude ayant pour but de compléter et préciser les résultats qui ont pu être obtenus, mais aussi de créer une banque de cerveaux afin de faciliter les futures recherches sur le vieillissement du chien. Dans un premier temps, le volume de plusieurs structures cérébrales d’intérêt est déterminé à partir de l’imagerie cérébrale de 6 chats âgés de 3 à 4 ans et de 6 chats âgés de 10 à 11 ans et comparé entre les deux groupes. Ensuite, le tissu cérébral du groupe des chats les plus âgés sera examiné par des méthodes d’histologie conventionnelle et d’immunohistochimie. En parallèle de cette étude sur les chats, les cerveaux des chiens euthanasiés à l’Ecole Nationale Vétérinaire de Toulouse seront extraits et conservés dans une banque de cerveaux. Un examen morphologique sera également réalisé afin de mettre en évidence d’éventuelles différences macroscopiques liées à l’âge, mais aussi à l’atteinte des fonctions cognitives évaluée rétrospectivement par le biais d’un questionnaire à destination des propriétaires. Les premiers résultats de l’étude indiquent une diminution de la taille de l’adhésion interthalamique et une augmentation du volume des ventricules latéraux qui sont des marqueurs d’atrophie cérébrale chez les chats âgés tandis que le volume de l’hippocampe, des noyaux caudés ou du cervelet ne varie pas entre les deux groupe

Idiopaattinen epilepsia suomenpystykorvilla : Epidemiologinen, kliininen ja diagnostinen näkökulma

Epilepsy, a common neurologic disorder in dogs, has also been recognized in the Finnish Spitz dog (FSD) since the 1980s, but scientifically verified data has been lacking. In this thesis, epilepsy in FSDs was characterized. Diagnostic investigations, using tools such as magnetic resonance imaging (MRI) and electroencephalography (EEG), have not been used consistently in veterinary medicine to diagnose epilepsy in dogs. The usefulness of these modalities to diagnose different forms of canine epilepsy needs to be proven. Thus, FSDs with and without focal epilepsy were studied by MRI and EEG. In addition, the novel functional method to investigate epileptic dogs, 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET), was described and results were compared with EEG. Epidemiological information was based on 2141 FSDs, of which 143 were epileptic, and prevalence on 2069 living FSDs, of which 111 had epilepsy. The prevalence of idiopathic epilepsy (IE) in FSDs was found to be 5.3%; males were more predisposed to epilepsy. The median age at seizure onset was 3 years, seizure frequency was 3 per year, and duration of seizure episode was 12 min. Focal onset seizures, characterized by frequent behavioral and autonomic signs were the main phenotype of epilepsy in FSDs. Although epilepsy in FSDs follows a generally benign course, generalization of seizure indicate a progressive course of epilepsy. The heritability estimate of IE in FSDs (0.22) was best explained by polygenic traits. Although characterized with focal seizures, FSDs have non-lesional epilepsy based on 1.5T MRI examinations. Infrequent reversible brain changes can be found, as a consequence of seizures. Visual evaluation of EEG in epileptic FSDs showed interictal epileptiform paroxysmal activity (20%) less frequently than had been described previously. This activity was expressed by spikes, polyspikes, and spike slow-wave complexes in the posterior-occipital derivation. Epileptiform activity, consisting of midline spikes, was recognized in healthy FSDs. Sleep transients, which were frequently found in FSDs from both groups, could be easily misinterpreted as epileptiform activity. Quantitative EEG showed significant difference in various frequency bands related to diseased status or medication. Cerebral glucose utilization was examined by FDG-PET in 11 epileptic and 8 healthy FSDs. Glucose uptake abnormalities/asymmetries were detected in various brain regions of 82% of epileptic and in 50% of control FSDs; findings in the occipital cortex specifically associated with epilepsy. The epileptic dogs had significantly lower standardized uptake values in numerous cortical regions, cerebellum, and hippocampus compared to the control dogs. The low cortical glucose uptake values found in the occipital lobe in both groups of FSDs is an unique finding and may indirectly reflect the lowered seizure threshold in that region characteristic for this dog breed. Inability to reveal significant difference of white matter normalized uptake values and left-right asymmetry indexes between epileptic and control groups might be related to the method used to define regions of interest. Based on these results, epilepsy in FSDs is defined as idiopathic epilepsy, as FSDs lack changes on the brain MRI and epilepsy is genetically determined. EEG and FDG-PET suggest involvement of the occipital region, although also wider posterior cortical areas could be related to epileptogenesis in FSDs. Visual evaluation of both EEG and FDG-PET can support the diagnosis of IE in dogs. Although diagnostic yield of EEG to diagnose epilepsy seems to be lower than suggested for dogs, it is a method of choice for everyday clinical settings. FDG-PET is a useful research modality for examining epileptic dogs, where visual detection of hypometabolic areas provides the highest sensitivity. Quantitative assessment methods of EEG and FDG-PET can be beneficial, but should be used alongside visual evaluation in epileptic dogs.Epilepsia on yleinen neurologinen sairaus koirilla. Sitä on tavattu suomenpystykorvilla jo 1980-luvulta lähtien, mutta tieteellisesti varmennettua tietoa ei ole aiemmin ollut saatavilla kyseisen rodun epilepsiasta. Tässä väitöskirjassa kuvataan suomenpystykorvien epilepsian esiintyvyyttä, kliinisia oireita ja diagnostiikka. Koiria tutkitiin magneettikuvauksen (MRI) ja aivosähkökäyrätutkimuksen (EEG) avulla. Uutena toiminnallisen-kuvantamisen menetelmänä koirien epilepsian tutkimisissa käytetiin positroniemissiotomografia (PET). ----- Epidemiologinen tieto perustui 2141 suomenpystykorvan tietoihin ja esiintyvyys 2069 elossa olevan Suomenpystykorvan tietoihin. Epilepsian esiintyvyys suomenpystykorvilla todettiin olevan 5,3% urosten ollessa alttiimpia sairastumaan epilepsiaan. Kohtaukset alkavat pystykorvilla keskimäärin 3 vuoden iässä, niitä on keskimäärin kolmesti vuodessa, ja kohtauksen tyypillinen kesto on 12 minuuttia. Rodulle tyypillisiä olivat paikallisalkuiset kohtaukset, joihin liittyi tavallisesti käytösmuutoksia ja autonomisia oireita, kuten oksentelua ja kuolaamista. Kohtausten yleistyminen voi viitata epilepsian etenemiseen, vaikka pystykorvien epilepsian kulku on yleensä hyvänlaatuinen. Suomenpystykorvien idiopaattisen epilepsian perinnöllisyysasteen arvio (0.22) selittyy parhaiten usean geenin mallin avulla. Vaikkakin suomenpystykorvien epilepsialle tyypillisiä ovat paikalliset kohtaukset, korkeakenttämagneetilla tehtyjen tutkimuksien perusteella kyseessä on epilepsia, jossa ei havaita aivoissa rakenteellisia muutoksia. Harvakseltaan voidaan kuitenkin havaita palautuvia, kohtausten seurauksena syntyneitä muutoksia aivoissa. Epilepsiaa sairastavien suomenpystykorvien aivosähkökäyrässä havaittiin kohtausten välillä epileptistä aktiivisuutta harvemmin (20%) kuin on raportoitu aiemmin. Tietyntyyppistä epänormaalia aktiivisuutta havaittiin myös terveillä pystykorvilla, mutta löydöksen kliininen merkitys on tuntematon. Uneen liittyvää aktiivisuutta, joka voidaan helposti tulkita virheellisesti epileptiseksi aktiivisuudeksi, todettiin sekä terveillä että sairailla koirilla. Aivosähkökäyrän kvantitatiivisessa tulkinnassa havaittiin merkittäviä eroja riippuen terveysstatuksesta tai lääkityksestä. ------ Aivojen glukoosinkäyttöä tutkittiin 2-deoksi-2-[18F]fluoro-D-glukoosi (FDG)-PET avulla 11 epileptisellä ja 8 terveellä suomenpystykorvalla. Glukoosinkäytössä todettiin epänormaaliutta tai epäsymmetrisyyttä eri aivoalueilla 82%:lla epileptisistä ja 50%:lla terveistä koirista; muutokset erityisesti isoaivojen takaraivonlohkon kuorikerroksen alueella liittyivät epilepsiaan. Epileptisillä koirilla todettiin merkittävästi alhaisemmat glukoosinkäyttöarvot useilla aivoalueilla verrattuna kontrollikoiriin. Isoaivojen kuorikerroksen takaraivonlohkon alhaiset glukoosinkäyttöarvot molemmissa koiraryhmissä ovat aiemmin havaitsematon löydös ja tämä saattaa epäsuorasti viitata alentuneeseen kohtauskynnykseen kyseisellä alueella luonteenomaisena tutkitulle rodulle. Kyvyttömyys havaita merkittäviä eroja epileptisten ja kontrolliryhmien välillä valkeaan ainekseen suhteutetuissa glukoosinkäyttöarvoissa ja vasen-oikea epäsymmetria-indekseissä voi liittyä käytettyihin menetelmiin. Näihin tuloksiin perustuen suomenpystykorvien epilepsia luokitellaan idiopaattiseksi epilepsiaksi, koska aivojen magneettikuvauksessa ei havaita muutoksia ja epilepsia on perinnöllinen kyseessä olevalla rodulla. EEG ja FDG-PET viittaavat takaraivonlohkon osallisuuteen, vaikkakin myös laajempi taaimmaisten aivoalueiden mukanaolo on mahdollinen pystykorvien epilepsian synnyssä. EEG ja FDG-PET visuaalinen analyysi voivat tukea idiopaattisen epilepsian diagnoosin tekemistä koirilla. Vaikkakin EEG:n tuoma diagnostinen apu koirilla näyttää olevan alhaisempi kuin aiemmin on ehdotettu, se on ensisijainen menetelmä jokapäiväisessä kliinisessä työssä. FDG-PET on hyödyllinen menetelmä tutkimusmielessä arvioitaessa epileptisiä koiria, ja siinä hypometabolisten alueiden visuaalinen havaitseminen antaa parhaimman herkkyyden. EEG ja FDG-PET tulosten kvantitatiivinen arviointi voi olla hyödyllistä, mutta niitä tulisi käyttää rinnakkain visuaalisen analyysin kanssa

Bilingualism across the lifespan: Neuroanatomical correlates

187 p.Recently, an increasing number of studies addressing the neuroanatomical bases of bilingualism have appeared (Garcia-Penton et al., 2016). However, the results are variable and in sorne cases conflicting,and consequen y it is still a matter of debate how brain changes due to bilingual experience.The present study will try to shed sorne light on the field by adding fresh new evidence testing children and elderly high proficient early Spanish-Basque bilinguals, two very typologically different languages . The proposed work will use large-scale brain-mapping techniques to explore the relationship between structure and function, as a more holistic and realistic approach to understanding comprehensively the neural bases of bilingualism. This integrational perspectiva will also promote convergent evidence about the specialization and integration of the neural networks in bilingualism. As such, this work will study the organisation of brain networks,either due to slow changes in brain areas and their wiring (namely, the structural plasticity), or due to fast modulation of their interactions (namely, functional plasticity).This thesis will employ Functional Magnetic Resonance lmaging (fMRI) during resting-state in combination with Diffusion-Weighted Magnetic Resonance lmaging (DW-MRI) to determine functional and structural connectivity, respectively. Both techniques will make it possible to model the large-scale structural/functional connectivity maps by means of a high­ dimensional parcellation of the grey matter (GM) in the brain instead of limiting analysis to specific regions of interest, as done in previous studies. A 30 high resolution whole-head anatomical sean (T1-MRI) will be used in order to generate GM parcellations employed in the connectivity analysis, but also to identify regional differential structural patterns associated with bilingualism, using voxel-based and surface-based analyses of the GM. Network­ based statistics (Zalesky et al., 2010) and graph theoretical approaches (Latora & Marchiori, 2001; Rubinov and Spoms, 201O) will be employed to investigate differences between groups in connectiv ity pattems, by isolating sets of regions interconnected differently between groups, and in topological properties of the networks, by measuring global/local efficiency. The main findings of this research on bilingualism across different groups of age (childhood and elderly) suggested that structural brain plasticity related to bilingualism was so small, unstable, subtle and transient that it was very difficult to detect even in lifelong bilinguals. A fact that is consisten! with the curren! ambiguous picture in bilingualism studies (Garcia-Pentón et al.,2016; see also others, Baum & Titone,2014; Costa,& Sebastián-Gallés , 2014; Li, Legault, & Litcofsky, 2014; Paap et al., 2015; de Bruin et al., 2015a). However, this study suggested that even when the brain did not display focal brain differences (i.e. did not show any specialization) it could still show differences at the global level. Specifically,the evidence draws attention that lifelong bilingualism could pinpoint a gain toward a better neural reserve in aging due to the whole-network graph-efficiency observed in elderly lifelono bilinouals

Bilingualism across the lifespan: Neuroanatomical correlates

187 p.Recently, an increasing number of studies addressing the neuroanatomical bases of bilingualism have appeared (Garcia-Penton et al., 2016). However, the results are variable and in sorne cases conflicting,and consequen y it is still a matter of debate how brain changes due to bilingual experience.The present study will try to shed sorne light on the field by adding fresh new evidence testing children and elderly high proficient early Spanish-Basque bilinguals, two very typologically different languages . The proposed work will use large-scale brain-mapping techniques to explore the relationship between structure and function, as a more holistic and realistic approach to understanding comprehensively the neural bases of bilingualism. This integrational perspectiva will also promote convergent evidence about the specialization and integration of the neural networks in bilingualism. As such, this work will study the organisation of brain networks,either due to slow changes in brain areas and their wiring (namely, the structural plasticity), or due to fast modulation of their interactions (namely, functional plasticity).This thesis will employ Functional Magnetic Resonance lmaging (fMRI) during resting-state in combination with Diffusion-Weighted Magnetic Resonance lmaging (DW-MRI) to determine functional and structural connectivity, respectively. Both techniques will make it possible to model the large-scale structural/functional connectivity maps by means of a high­ dimensional parcellation of the grey matter (GM) in the brain instead of limiting analysis to specific regions of interest, as done in previous studies. A 30 high resolution whole-head anatomical sean (T1-MRI) will be used in order to generate GM parcellations employed in the connectivity analysis, but also to identify regional differential structural patterns associated with bilingualism, using voxel-based and surface-based analyses of the GM. Network­ based statistics (Zalesky et al., 2010) and graph theoretical approaches (Latora & Marchiori, 2001; Rubinov and Spoms, 201O) will be employed to investigate differences between groups in connectiv ity pattems, by isolating sets of regions interconnected differently between groups, and in topological properties of the networks, by measuring global/local efficiency. The main findings of this research on bilingualism across different groups of age (childhood and elderly) suggested that structural brain plasticity related to bilingualism was so small, unstable, subtle and transient that it was very difficult to detect even in lifelong bilinguals. A fact that is consisten! with the curren! ambiguous picture in bilingualism studies (Garcia-Pentón et al.,2016; see also others, Baum & Titone,2014; Costa,& Sebastián-Gallés , 2014; Li, Legault, & Litcofsky, 2014; Paap et al., 2015; de Bruin et al., 2015a). However, this study suggested that even when the brain did not display focal brain differences (i.e. did not show any specialization) it could still show differences at the global level. Specifically,the evidence draws attention that lifelong bilingualism could pinpoint a gain toward a better neural reserve in aging due to the whole-network graph-efficiency observed in elderly lifelono bilinouals

OXIDATIVE STRESS AND REDOX PROTEOMICS STUDIES IN MODELS OF NEURODEGENERATIVE DISORDERS: I. THE CANINE MODEL OF HUMAN AGING; II. INSIGHTS INTO SUCCESSFUL AGING; AND III. TRAUMATIC BRAIN INJURY

The studies presented in this dissertation were conducted with the objective ofgaining greater understanding into the mechanisms of successful aging, the role ofmitochondria dysfunction in traumatic brain injury, and also on the mechanisms ofimproved learning and cognitive function in the aging.Aging is usually characterized by impairments in physiological functionsincreasing its susceptibility to dementia and neurodegenerative disorders. In thisdissertation, the mechanisms of dementia-free aging were investigated. The use of anantioxidant fortified diet and a program of behavioral enrichment in the canine model ofhuman aging was shown to result in a significant decrease in the levels of oxidativestress. A proteomic analysis of these brains also demonstrated a significant decrease inthe oxidative modification of key brain proteins and an increase in the expression levelsof other key brain proteins associated with energy metabolism and antioxidant systemswhich correlated with improved learning and memory.We show that following TBI key mitochondrial-related proteins undergoextensive oxidative modification, possibly contributing to the severe loss ofmitochondrial energetics and neuronal cell death previously observed in experimentalTBI.Taken together, these findings support the role of oxidative stress in thepathophysiology of aging and age-related neurodegenerative disorders and in CNS injury.These studies also show that antioxidants and a program of behavioral enrichmentprovide protection against oxidative stress-mediated cognitive impairments