DNA Mutation of the progranulin (GRN) gene in familial frontotemporal lobar degeneration (FTLD):a study of the pathology of nine cases

Frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP) is a neurodegenerative disease characterized by variable neocortical and allocortical atrophy principally affecting the frontal and temporal lobes. Histologically, there is neuronal loss, microvacuolation in the superficial cortical laminae, and a reactive astrocytosis. A variety of TDP-43 immunoreactive changes are present in FTLD-TDP including neuronal cytoplasmic inclusions (NCI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN) and, oligodendroglial inclusions (GI). Many cases of familial FTLD-TDP are caused by DNA mutations of the progranulin (GRN) gene. Hence, the density, spatial patterns, and laminar distribution of the pathological changes were studied in nine cases of FLTD-TDP with GRN mutation. The densities of NCI and DN were greater in cases caused by GRN mutation compared with sporadic cases. In cortical regions, the commonest spatial pattern exhibited by the TDP-43 immunoreactive lesions was the presence of clusters of inclusions regularly distributed parallel to the pia mater. In approximately 50% of cortical gyri, the NCI exhibited a peak of density in the upper cortical laminae while the GI were commonly distributed across all laminae. The distribution of the NII and DN was variable, the most common pattern being a peak of NII density in the lower cortical laminae and DN in the upper cortical laminae. These results suggest in FTLD-TDP caused by GRN mutation: 1) there are greater densities of NCI and DN than in sporadic cases of the disease, 2) there is degeneration of the cortico-cortical and cortico-hippocampal pathways, and 3) cortical degeneration occurs across the cortical laminae, the various TDP-43 immunoreactive inclusions often being distributed in different cortical laminae.

Relationships between beta-amyloid (Abeta) deposits and blood vessels in familial and sporadic Alzheimer's disease

Introduction: The density of diffuse, primitive and classic beta-amyloid (Abeta) deposits and blood vessels was studied in nine cases of sporadic Alzheimer's disease (SAD) and 10 cases of familial Alzheimer's disease (FAD) including two cases with amyloid precursor protein (APP) mutations (APP717, Val - Ile). Materials and Methods: Sections of frontal cortex stained for Abeta12-28 counterstained with collagen type IV antiserum. Densities measured along the upper cortex in 64-128, 1000 x 200 micron continuous sample fields. Results: The density of diffuse and primitive deposits was not correlated with blood vessels in FAD or SAD. The density of the classic deposits was positively correlated with the larger diameter (> 10 micron) blood vessels in all SAD cases and weakly correlated with blood vessel in three non-APP FAD cases. Conclusions: Blood vessels are less important in the formation of classic Abeta deposits in FAD compared with SAD.

Migraine, A study of environmental and intrapersonal factors

A study was carried out of 45 migrainous patients with visually induced migraine (VIM), and 25 migrainous students, each having an age and sex matched control. The study utilised questionnaires, interviews, electroencephalography (EEG) and visual evoked potentials (VEP). The experimental work and analysis was carried out in the Neuropsychology Unit in collaboration with the Birmingham Migraine Clinic, over a period of five years. The study suggests: 1. The literature on a possible relationship between migraine and epilepsy hitherto published is unreliable (supporting evidence is given). 2. That a much greater precision is needed in defining migraine for research purposes. 3. A revised methodology for the selection of controls is needed and this is proposed. 4. That despite what are now seen to be superficial similarities, there are clear distinctions of a fundamental nature between photo-sensitive epilepsy (PSE) and VIM. 5. Caution be used when taking headache as a symptom, since many of the precipitants of migrainous headache can also precipitate non-migrainous headache (NMH). 6. The list of visual precipitants of migraine is expanded (particularly flicker and pattern). 7. That colour (principally red) is a previously unreported precipitant of migraine. 8. The extended range of responses to flicker (the 'H' response) has no significant difference in its frequency of occurrence in patients and normal controls, which contradicts previous literature. 9. The mechanisms thought to underlie migraine serve to explain previously unexplained EEG findings. 10. Further research is needed and proposed.

Familial and disease specific abnormalities in the neural correlates of the Stroop Task in Bipolar Disorder

Patients with Bipolar Disorder (BD) perform poorly on tasks of selective attention and inhibitory control. Although similar behavioural deficits have been noted in their relatives, it is yet unclear whether they reflect dysfunction in the same neural circuits. We used functional magnetic resonance imaging and the Stroop Colour Word Task to compare task related neural activity between 39 euthymic BD patients, 39 of their first-degree relatives (25 with no Axis I disorders and 14 with Major Depressive Disorder) and 48 healthy controls. Compared to controls, all individuals with familial predisposition to BD, irrespective of diagnosis, showed similar reductions in neural responsiveness in regions involved in selective attention within the posterior and inferior parietal lobules. In contrast, hypoactivation within fronto-striatal regions, implicated in inhibitory control, was observed only in BD patients and MDD relatives. Although striatal deficits were comparable between BD patients and their MDD relatives, right ventrolateral prefrontal dysfunction was uniquely associated with BD. Our findings suggest that while reduced parietal engagement relates to genetic risk, fronto-striatal dysfunction reflects processes underpinning disease expression for mood disorders. © 2011 Elsevier Inc.

The pupillary light reflex in migraine

The literature suggests that there may be pupil size and response abnormalities in migraine headache sufferers. We used an infra-red pupillometer to measure dynamic pupil responses to light in 20 migraine sufferers (during non-headache periods) and 16 non-migraine age and gender matched controls. There was a significant increase in the absolute inter-ocular difference of the latency of the pupil light response in the migraine group compared with the controls (0.062 s vs 0.025 s, p = 0.014). There was also a significant correlation between anisocoria and lateralisation of headache such that migraine sufferers with a habitual head pain side have more anisocoria (r= 0.59, p < 0.01), but this was not related to headache laterally. The pupil changes were not correlated with the interval since the last migraine headache, the severity of migraine headache or the number of migraine headaches per annum. We conclude that subtle sympathetic and parasympathetic pupil abnormalities persist in the inter-ictal phase of migraine. © 2005 The College of Optometrists.

Laminar distribution of β-amyloid (Aβ) peptide deposits in the frontal lobe in familial and sporadic Alzheimer's disease

To determine whether genetic factors influence frontal lobe degeneration in Alzheimer's disease (AD), the laminar distributions of diffuse, primitive, and classic β-amyloid (Aβ) peptide deposits were compared in early-onset familial AD (EO-FAD) linked to mutations of the amyloid precursor protein (APP) or presenilin 1 (PSEN1) gene, late-onset familial AD (LO-FAD), and sporadic AD (SAD). The influence of apolipoprotein E (Apo E) genotype on laminar distribution was also studied. In the majority of FAD and SAD cases, maximum density of the diffuse and primitive Aβ deposits occurred in the upper cortical layers, whereas the distribution of the classic Aβ deposits was more variable, either occurring in the lower layers, or a double-peaked (bimodal) distribution was present, density peaks occurring in upper and lower layers. The cortical layer at which maximum density of Aβ deposits occurred and maximum density were similar in EO-FAD, LO-FAD and SAD. In addition, there were no significant differences in distributions in cases expressing Apo E ε4 alleles compared with cases expressing the ε2 or ε3 alleles. These results suggest that gene expression had relatively little effect on the laminar distribution of Aβ deposits in the frontal lobe of the AD cases studied. Hence, the pattern of frontal lobe degeneration in AD is similar regardless of whether it is associated with APP and PSEN1, mutation, allelic variation in Apo E, or with SAD.

A comparison of spatial patterns of TDP-43 cellular inclusions in familial and sporadic frontotemporal lobar degeneration with TDP-43 proteinopathy

Abnormal protein aggregates of transactive response (TAR) DNA-binding protein (TDP-43) in the form of neuronal cytoplasmic inclusions (NCI), oligodendroglial inclusions (GI), neuronal internuclear inclusions (NII), and dystrophic neurites (DN) are the pathological hallmark of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). To investigate the role of phosphorylated TDP-43 (pTDP-43) in neurodegeneration in FTLD-TDP, the spatial patterns of the pTDP-43-immunoreactive NCI, GI, NII, and DN were studied in frontal and temporal cortex in three groups of cases: (1) familial FTLD-TDP caused by progranulin (GRN) mutation, (2) a miscellaneous group of familial cases containing cases caused by valosin-containing protein (VCP) mutation, ubiquitin associated protein 1 (UBAP1) mutation, and cases not associated with currently known genes, and (3) sporadic FTLD-TDP. In a significant number of brain regions, the pTDP-43-immunoreactive inclusions developed in clusters and the clusters were distributed regularly parallel to the tissue boundary. The spatial patterns of the inclusions were similar to those revealed by a phosphorylation-independent anti-TDP-43 antibody. The spatial patterns and cluster sizes of the pTDP-43-immunoreactive inclusions were similar in GRN mutation cases, remaining familial cases, and in sporadic FTLD-TDP. Hence, pathological changes initiated by different genetic factors in familial cases and by unknown causes in sporadic FTLD-TDP appear to follow a parallel course resulting in very similar patterns of degeneration of frontal and temporal lobes.

Sub-cortical sources of the somatosensory pathway are hypoactive in migraine interictally:a Functional Source Separation analysis

Background: Recent morpho-functional evidence pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brainstem remains to be determined. We used a Functional Source Separation algorithm of EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura (MO) patients. Methods: Twenty MO patients and 20 healthy volunteers (HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brainstem and FS16 at thalamic level) and two cortical (FS20 radial and FS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450-750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced sub-cortical brainstem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between the two groups. Conclusions: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergic system may underline the interictal cortical abnormal information processing in migraine. Further studies are needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO. Written informed consent to publication was obtained from the patient(s).

Familial adrenal hypoplasia syndromes

The adrenal cortex secretes steroid hormones, including glucocorticoids and mineralocorticoids. Glucocorticoids control body homeostasis, stress, and immune responses, while mineralocorticoids regulate the water and electrolyte balance. A spectrum of genetic defects can disrupt the normal adrenal development, causing adrenal hypoplasia and various forms of adrenal insufficiency, which usually present in infancy or childhood with or without mineralocorticoid deficiency and with or without gonadal dysfunction. The genetic causes of adrenal hypoplasia can be broadly categorized into adrenal hypoplasia due to adrenocorticotropic hormone resistance syndromes (i.e., familial glucocorticoid deficiency and triple A syndrome) and adrenal hypoplasia due to primary defects in the development of the adrenal glands (i.e., X-linked adrenal hypoplasia congenita and primary adrenal hypoplasia caused by steroidogenic factor 1 mutations).

Impaired brainstem and thalamic high-frequency oscillatory EEG activity in migraine between attacks

INTRODUCTION: We investigated whether interictal thalamic dysfunction in migraine without aura (MO) patients is a primary determinant or the expression of its functional disconnection from proximal or distal areas along the somatosensory pathway. METHODS: Twenty MO patients and twenty healthy volunteers (HVs) underwent an electroencephalographic (EEG) recording during electrical stimulation of the median nerve at the wrist. We used the functional source separation algorithm to extract four functionally constrained nodes (brainstem, thalamus, primary sensory radial, and primary sensory motor tangential parietal sources) along the somatosensory pathway. Two digital filters (1-400 Hz and 450-750 Hz) were applied in order to extract low- (LFO) and high- frequency (HFO) oscillatory activity from the broadband signal. RESULTS: Compared to HVs, patients presented significantly lower brainstem (BS) and thalamic (Th) HFO activation bilaterally. No difference between the two cortical HFO as well as in LFO peak activations between the two groups was seen. The age of onset of the headache was positively correlated with HFO power in the right brainstem and thalamus. CONCLUSIONS: This study provides evidence for complex dysfunction of brainstem and thalamocortical networks under the control of genetic factors that might act by modulating the severity of migraine phenotype.

Parental and cultural influences on Hispanic college women's verbal intimate partner violence victimization: An examination of within group differences

Prior research has shown that college women in the United States are experiencing significantly high rates of verbal intimate partner violence (IPV); estimates indicate that approximately 20-30% of college women experience verbal IPV victimization (e.g., Hines, 2007; Muñoz-Rivas, Graña, O'Leary, & González, 2009). Verbal IPV is associated with physical consequences, such as chronic pain and migraine headaches, and psychological implications, including anxiety, depression, suicidal ideation, and substance use (Coker et al., 2002). However, few studies have examined verbal IPV in college populations, and none have focused on Hispanic college women who are members of the largest minority population on college campuses today (Pew Research Center, 2013), and experience higher rates of IPV victimization (Ingram, 2007). The current dissertation sought to address these gaps by examining the influence of familial conflict strategies on Hispanic college women's verbal IPV victimization. Further, within group differences were explored, with specific attention paid to the role of acculturation and gender role beliefs. A total of 906 from two Hispanic Serving Institutions (HSI) in the southeastern (N=502) and southwestern (N=404) United States participated in the three part study. Study one examined the influence of parental conflict strategies on Hispanic women's verbal IPV victimization in current romantic relationships. Consistent with previous research, results indicated that parental use of verbal violence influenced verbal IPV victimization in the current romantic relationship. A unidirectional effect of paternal use of verbal aggression towards the participant on maternal verbal aggression towards the participant was also found. Study two examined the influence of parental conflict strategies, acculturation, and gender role beliefs on victimization. Acculturation and gender role beliefs were found to not have an influence on participants' verbal IPV victimization. Study three examined within-group differences using Study two's model. Differences were found between the southeastern and southwestern participants; gender role beliefs increased rates of verbal IPV victimization in the southeastern population. The current dissertation fills a gap in the literature on IPV experiences in Hispanic college populations, the importance of examining verbal IPV trends, and highlights importance differing cultural influences within populations traditionally viewed as homogenous. The implications for future research are discussed.^

L'environnement familial des adolescents agresseurs sexuels

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Effets d'un suivi postnatal intensif et précoce auprès de mères adolescentes sur le niveau de soutien perçu et la structure de leur réseau familial et communautaire

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

La famille de l'employé, un frein à la mobilité internationale? : l'influence modératrice de la perception de l'organisation et du climat familial relatif au travail

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Hand somatosensory sub-cortical sources arehypoactive in migraine interictally: a functionalsource separation analysis

Background: Recent morpho-functional evidences pointed out that abnormalities in the thalamus could play a major role in the expression of migraine neurophysiological and clinical correlates. Whether this phenomenon is primary or secondary to its functional disconnection from the brain stem remains to be determined.Aim: We used a Functional Source Separation algorithmof EEG signal to extract the activity of the different neuronal pools recruited at different latencies along the somatosensory pathway in interictal migraine without aura(MO) patients. Method: Twenty MO patients and 20 healthy volunteers(HV) underwent EEG recording. Four ad-hoc functional constraints, two sub-cortical (FS14 at brain stem andFS16 at thalamic level) and two cortical (FS20 radial andFS22 tangential parietal sources), were used to extract the activity of successive stages of somatosensory information processing in response to the separate left and right median nerve electric stimulation. A band-pass digital filter (450–750 Hz) was applied offline in order to extract high-frequency oscillatory (HFO) activity from the broadband EEG signal. Results: In both stimulated sides, significant reduced subcortical brain stem (FS14) and thalamic (FS16) HFO activations characterized MO patients when compared with HV. No difference emerged in the two cortical HFO activations between two groups. Conclusion: Present results are the first neurophysiological evidence supporting the hypothesis that a functional disconnection of the thalamus from the subcortical monoaminergicsystem may underline the interictal cortical abnormal information processing in migraine. Further studiesare needed to investigate the precise directional connectivity across the entire primary subcortical and cortical somatosensory pathway in interictal MO.