Alzheimer Disease and Human Consciousness: A Neurogenetic Connection

Abstract Alzheimer disease (AD) is a neurodegenerative disorder that slowly erodes some of the facets of human consciousness. During the pathological course of AD, beta-amyloid plaques form which-causes damage to neurons and results in the gross loss of brain volume. As a consequence of AD, the afflicted individual develops decreases in cognitive/executive function, memory impairment/loss, and the inability to inhibit inappropriate behaviors. Another way of saying this is that the afflicted individual ceases to be the person whom they once were, i.e., their modalities of consciousness has deteriorated. Mutations in several genes, e.g., the gene variant APOE-epsilon4, APP, PSEN1, PSEN2, and TREM2 have all been correlated with the increased incidence and more rapid progression of AD. This has given support to the proposal that there are neurogenetic correlates of consciousness (NgCC). In previous works, these NgCC have been delineated into three neurogenetic phases of human consciousness. AD is a primary example of gene-based neurodegeneration that can take place in the third neurogenetic phase. There is hope that symptoms of AD may be reversed with the development of novel genetic therapies. Some gene therapies are underway, e.g., FGF2, leptin, and NEU1 with the aim of reversing AD symptomatology. If these gene therapies are one day successful in reversing some of the symptoms of AD, can they eventually be used to enhance human consciousness in individuals without AD

Electrophysiological and Molecular Insights into Thalamocortical Rhythmicity and Hippocampal Theta Oscillations

Zusammenfassung Neuronale Netzwerke sind mit verschiedenen spannungsgesteuerten Kalziumkanälen verknüpft, die eine Schlüsselrolle in der Entstehung von Oszillationen im Hippocampus, aber auch in der thalamokortikalen Rhythmizität einnehmen. Innerhalb einer Vielzahl von Oszillationen konnte gezeigte werden, dass der Cav2.3 R-typ Kalziumkanal für die hippocampale Thetaaktivität maßgeblich verantwortlich ist. Thetaoszillationen im Frequenzbereich von 4-7 Hz repräsentieren ein spezifisches Aktivitätsmuster, das für kognitive Fertigkeiten, wie dem Abrufen von Gedächtnisinhalten, unerlässlich ist. Auf pharmakologischer Ebene werden zwei Subtypen von Thetaaktivität, der Atropin resistente Typ I und das Atropin sensitive Typ II Theta, differenziert. Typ II Theta wird dabei über eine durch den Cav2.3 R-typ Kalziumkanal vermittelte, muskarinerge Signalkaskade in der hippocampalen CA1 Region generiert. Interessanterweise treten Theta Oszillationen auch während des paradoxen bzw. REM (rapid eye movement) Schlafs auf, was daraufhin deutet, dass Thetaaktivität vom zirkadianen Rhythmus abhängt. Da Cav2.3 R-typ Kalziumkanäle ebenfalls im retikulär thalamischen Kern (RTN), der in die Schlafgenerierung eingebunden ist, exprimiert werden, kann vermutet werden, dass dem Cav2.3 Kalziumkanal eine regulatorische Funktion beim Schlaf zukommt. Bislang konnte allerdings nicht geklärt werden, welche genaue Rolle Cav2.3 R-typ Kalziumkanäle im thalamokortikalen Netzwerk übernehmen. Daher analysierten wir den Cav2.3 R-typ Kalziumkanal in spontanen und pharmakologisch induzierten Schlaf von Cav 2.3-/- Mäusen und Cav 2.3+/+ Kontrolltieren. Unsere Ergebnisse zeigen eine erhöhte Anzahl an Schlafübergängen sowie eine verminderte Gesamtwachdauer bei Cav 2.3-/- Mäusen und verdeutlichen folglich die tragende Rolle des Cav2.3 R-typ Kalziumkanals in Bezug auf die Schlafmodulation. Studien belegen, dass Cav2.3-/- Mäuse auch Absence-Epilepsien ausbilden können, was die Rolle des Cav2.3 R-typ Kalziumkanals in der Epileptogenese widerspiegelt. Pathologische Veränderungen in der zentralen Rhythmizität und eine damit einhergehende erhöhte Anfallswahrscheinlichkeit können unter anderem durch Akkumulation von Aß Plaques, wie sie bei der Alzheimererkrankung auftreten, gefördert werden. Dabei zeigte sich, dass in Mausmodellen der familiären Alzheimer-Demenz (FAD) erhöhte Aß Plaquebildung mit Veränderungen in der Proteinsynthese vom BACE1 Enzym (ß-site APP cleaving enzyme 1) einhergeht. In diesem Zusammenhang ist eine gesteigerte Translation des BACE1 Enzyms unmittelbar an die 6 Phosphorylierung vom Serin an Position 51 des eukaryotischen Translationsinitiationsfaktors 2 Alpha (elF2α) gebunden. Diese Tatsache wirft die Frage auf, ob eine Runterregulierung von elF2α zu einer geringeren Anfallswahrscheinlichkeit durch verminderte Plaquebildung beiträgt und somit den kognitiven Verfall in 5XFAD Mäusen verzögern kann. Dazu untersuchten wir mögliche präventive Effekte von elF2α auf die Epileptogenese, indem wir 5XFAD Mäuse mit einer elF2αS51A Knock-in Line kreuzten, bei denen, durch eine Substitution von Serin durch Alanin an Position 51 bedingt, elF2α nicht mehr phosphoryliert werden kann. Unsere Ergebnisse zeigen einen limitierten präventiven Effekt von elF2α auf motorische und kognitive Defizite in 5XFAD Mäusen. Veränderungen im Hippocampus gehen mit elektrophysiologischen Befunden einher, welche nicht-konvulsive Statusformen epileptiformer Aktivität bei 5XFAD Tieren mit elF2αS51A Allel belegen. Weiterhin untersuchten wir, wie sich Anfallsaktivität auf die muskaringere Signalkaskade in 5XFAD Mäusen auswirkt. Wir stellten fest, dass eine verstärkte muskarinerge Signalkaskade sowohl zu neuronaler Dysrhythmie, aber auch zu einer Erhöhung von Atropin sensitiven Typ II Theta beiträgt, die als möglicher Kompensationsmechanismus zu einem dysbalancierten neuronalen System bei Morbus Alzheimer in Betracht gezogen werden kann

Neuroimaging biomarkers associated with clinical dysfunction in Parkinson disease

Parkinson disease (PD) is the second most common neurodegenerative disorder in the world, directly affecting 2-3% of the population over the age of 65. People diagnosed with the disorder can experience motor, autonomic, cognitive, sensory and neuropsychiatric symptoms that can significantly impact quality of life. Uncertainty still exists about the pathophysiological mechanisms that underlie a range of clinical features of the disorder, linked to structural as well as functional brain changes. This thesis thus aimed to uncover neuroimaging biomarkers associated with clinical dysfunction in PD. A 'hubs-and-spokes' neural circuit-based approach can contribute to this aim, by analysing the component elements and also the interconnections of important brain networks. This thesis focusses on structures within basal ganglia-thalamocortical neuronal circuits that are linked to a range functions impacted in the disorder, and that are vulnerable to the consequences of PD pathology. This thesis investigated neuronal 'hubs' by studying the morphology of the caudate nucleus, putamen, thalamus and neocortex. The caudate nucleus, putamen and thalamus are all vital subcortical 'hubs' that play important roles in a number of functional domains that are compromised in PD. The neocortex, on the other hand, has a range of 'hubs' spread across it, regions of the brain that are crucial for neuronal signalling and communication. The interconnections, or 'spokes', between these hubs and other brain regions were investigated using seed-based resting-state functional connectivity analyses. Finally, a morphological analysis was used to investigate possible structural changes to the corpus callosum, the major inter-hemispheric white matter tract of the brain, crucial to effective higher-order brain processes. This thesis demonstrates that the caudate nucleus, putamen, thalamus, corpus callosum and neocortex are all atrophied in PD participants with dementia. PD participants also demonstrated a significant correlation between volumes of the caudate nuclei and general cognitive functioning and speed, while putamina volumes were correlated with general motor function. Cognitively unimpaired PD participants demonstrated minimal morphological alterations compared to control participants, however they demonstrated significant increases in functional connectivity of the caudate nucleus, putamen and thalamus with areas across the frontal lobe, and decreases in functional connectivity with parietal and cerebellar regions. PD participants with mild cognitive impairment and dementia show decreased functional connectivity of the thalamus with paracingulate and posterior cingulate cortices, respectively. This thesis contributes a deeper understanding of the relationship between structures of basal ganglia-thalamocortical neuronal circuits, corpus callosal and neocortical morphology, and the clinical dysfunction associated with PD. This thesis suggests that functional connectivity changes are more common in early stages of the disorder, while morphological alterations are more pronounced in advanced disease stages

Olfaction, among the First Senses to Develop and Decline

Olfaction is one of the most conserved senses across species. It plays a crucial role in animals’ and humans’ life by influencing food intake, reproduction and social behavior. The olfactory system is composed of a peripheral neuroepithelium and a central olfactory nerve and is one of the few central nervous system (CNS) structures with direct access to the external environment without passage through the Blood Brain Barrier (BBB). This makes this nerve system of importance for understanding how exogenous stimuli may contribute to neuronal damage as well as for diagnostic and therapeutic purposes. Interestingly, olfactory activity physiologically declines with aging, but its alteration can be further impaired by various neurological conditions. For example, in progressive neurodegenerative disorders, such as Alzheimer’s disease (AD), olfaction is the first sense to be impaired before the onset of cognitive symptoms, suggesting that olfactory transmission may characterize early neural network imbalances. In this work, we will explore the main olfactory anatomical structures, the cytoarchitecture, the neurogenesis, several pathological conditions characterized by olfactory deficit and the potential use of this sense to diagnose and treat CNS pathologies

Synaptic loss in the primary tauopathies of Progressive Supranuclear Palsy and Corticobasal Degeneration

In this thesis I address the debilitating symptom of cognitive dysfunction in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Both PSP and CBD are associated with an accumulation of 4-repeat tau in cortical and subcortical areas. As well as movement disorders, they impair cognitive function, even where there is minimal atrophy. Neurophysiological studies have also identified electrophysiological changes associated with cognitive dysfunction, in areas without atrophy. I propose that synaptic loss prior to cell loss contributes to these effects of disease. Chapter two summarises my cohort and principal methods. I quantify synaptic density in vivo with dynamic [11C]UCB-J PET, and molecular pathology with [18F]AV1451 PET. Brain structural changes are quantified by MRI. Disease severity and cognition are assessed with the PSP rating scale, and neuropsychological tests. Patients with CBD are negative on amyloid-imaging ([11C]PiB PET) to exclude those with Alzheimer’s pathology. In chapter three, [11C]UCB-J PET reveals widespread loss of synapses in PSP and CBD including areas with minimal atrophy. The loss of synapses correlated with cognition and disease severity. In chapter four, I test whether presynaptic changes (from [11C]UCB-J PET) are correlated with postsynaptic abnormalities (i.e. changes to postsynaptic dendritic microstructural integrity quantified by MRI using the Neurite Orientation and Dispersion Index, NODDI). In accordance with in vitro and animal models, I confirm that loss of dendritic complexity is tightly coupled with presynaptic density, over and above the effects of atrophy. In chapter five, I test the relationship between the molecular pathology in primary tauopathies (tau burden) and synaptic loss, using [18F]AV-1451 and [11C]UCB-J PET. The use of the “tau” ligand [18F]AV-1451 has become controversial in PSP. With due consideration to the caveats, I report that brain regions with a higher synaptic density have higher [18F]AV-1451 binding, consistent with the hypothesis of connectivity-based progression of tauopathy. I further show that accrual of pathology in any given area is associated with loss of synapses, consistent with synaptic injury from tauopathy. I conclude my thesis in chapter 6, by discussing and highlighting the importance of synaptic density in primary tauopathies. The findings are relevant to other neurodegenerative disorders, and support early interventional studies targeting synaptic maintenance and restoration.Association of British Neurologists - Patrick Berthoud Charitable Trus

Mechanisms underlying postnatal development of primary somatosensory cortex

Layer IV of the mouse somatosensory cortex contains discrete cytoarchitectonic units called 'barrels', formed in response to thalamocortical axon invasion by two processes: translocation of cortical cells to form a cell-dense barrel wall and cell-sparse barrel hollow, and selective dendritic elaboration toward thalamocortical afferents to form oriented dendritic branch patterns. Interestingly gene knockout of several members of the N-Methyl-D-Aspartate (NMDA) receptor -complex (NRC) disrupts barrel formation, indicating that synaptic activity is critical for barrel formation. Little is known of the cellular processes initiated by glutamate receptor activation; however, recent evidence suggests an interaction between neuronal activity and Wnt signalling. Wnts are secreted glycoproteins, are powerful regulators of cell proliferation and differentiation, and their signalling pathway involves proteins that directly participate in both gene transcription and cell adhesion. Wnt7a and Dv11 knockout mice exhibit delays in glomerular rosette formation; a cerebellar structure similar to barrels whose development involves granule cell migration and dendritic rearrangement. Furthermore activity dependent Wnt release can regulate the enhancement of dendrite arborisation, raising the possibility that NRC components and Wnts may interact to regulate barrel development.Recent findings suggest that membrane association guanylyl kinases (MAGUKs) may be the key scaffolding molecules that mediate the interaction between glutamate receptor and Wnt signalling pathways. The MAGUK family includes Postsynaptic Density (PSD)-95 and Synapse Associated Protein (SAP)-102, two key molecules of the NRC during barrel formation. These MAGUKs also bind the Wnt receptor family Frizzled and SAP-102 binds to APC, a key Frizzled-signalling protein. As a first step in examining a role for Wnts in barrel formation, the gene expression patterns of members of the Wnt, Frizzleds and secreted Frizzled related protein (sFRPs) families during barrel cortex development were measured using degenerate primer RT-PCR, quantitative real-time PCR and in-situ hybridization. Wnts 2b, 3, 4, 5a, la, 7b, 9a, 11, 16 were found in the barrel cortex, suggesting that these members of the Wnt family may play a role in barrel development, and Wnt7b, Frizzled 4, Frizzled 9, and Frizzled 3 were conspicuously downregulated in mutant mice that lack barrels, namely Plc-ß1⁻/⁻, Pkar2ß⁻/⁻ and Mglur5⁻/⁻ mice.In order to determine whether Wnts, members of the Wnt signaling machinery and MAGUKs associated with Wnt signaling are essential for barrel formation, the barrel phenotype of all available postnatally viable Wnt gene knockouts, Wnt2b⁻/⁻, Wnt7a⁻/⁻, Wnt8b⁻/⁻, Wnt signaling component knockouts Dvl⁻/⁻, MAGUK knockouts Sap-102'1', Psd-95'1' and double knockouts of Wnt7a"Dvr'~ and of Sap-102⁻/⁻Psd-95⁻/⁻ were examined. Barrels appeared normal in all mutants, apart from compound Sap-102⁻/⁻Psd-95⁻/⁻ and Sap-102⁻/⁻Psd-95⁻/⁻ mice, which exhibited poorer barrel segregation compared to wild type.In order to achieve a detailed understanding of the mechanisms by which neuronal activity regulates barrel development, we need a detailed understanding of the intracellular pathways activated by NMDA receptors during development. In searching the literature, data concerning the developmental expression patterns of NRC components can be difficult to locate, as the prevailing database tools used either search only title, author and keyword abstract text (NCBI PubMed) potentially missing desired information, or as in the unique case of Google Scholar, search the full text of electronically published papers, but yield overwhelming numbers of results in the process.The Jackson Laboratories MGI suite offers an impressive way of mining the literature for such data, but the content is sparse, relying on author submission and attempting to map expression throughout the whole mouse. For example, the only gene present in MGI for postnatal layer IV cerebral cortex is Apc2.In order to bring together the data in the literature and from the mouse genome projects into a usable and accessible way, we decided to create a web-based centralised resource for the developmental neuroscience community, containing expression profiles of NRC components within mouse somatosensory cortex. By performing exhaustive literature searches utilising Google Scholar and PubMed, and linking to sequence and mutant mouse availability information elsewhere, BGI offers a portal for such information and also offers a forum for the notification of unpublished observations of transgenic animals displaying normal barrel formation, preventing duplication of experiments. Barrelgene.info should provide a key resource for any researcher interested in the molecular basis of cortical development

Immunophilins: new biomarkers and therapeutic targets for neurodegenerative diseases

Immunophilins (IP) are receptors for immunosuppressive drugs like cyclosporin A, FK506, rapamycin and their analogs, which are collectively referred to as "immunophilin ligands" (IPL). The receptors for FK506 belong to the family of FK506- binding proteins (FKBP). Previous studies showed that FK506 augments neuronal growth in vitro. In animal models, the drug promotes morphologic and functional recovery following neuronal lesioning. Here we show for the first time that FK506 has neurotrophic effects in human brain primary cultures. Our data support a possible use of FK506 and its analogues in the treatment of neurodegenerative disorders and as adjuvants in neural tissue transplants. The effect of the drug in vivo, in patients, will ultimately depend on the presence and distribution of IP receptors in the normal and degenerating human brain.FKBP12, the archetypal member of the FKBP family, plays a role in protein folding, protein complexes assembly and intracellular calcium release. Crush injury of facial or sciatic nerves in rat leads to markedly increased FKBP12 levels in the respective nerve nuclei in parallel with nerve regeneration. The presence of FKBP IP has never been demonstrated in the human brain. Using light and immunofluorescent microscopy, laser confocal microscopy and western blotting, we studied FKBP12 expression in a set of archival brain material from Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, encephalitic and non- encephalitic HIV- positive patients and age matched controls. We show that FKBP12 is present in the human brain, predominantly in neurons. Its levels and distribution are altered in the mid- frontal cortex, deep gray matter and midbrain of patients with neurodegenerative diseases. Moreover, it colocalizes with markers of pathology (Lewy bodies, neurofibrillary tangles and neuritic plaques) in areas of neurodegeneration. Disease- specific and region- specific changes are evident. Alterations in basal ganglia FKBP12 levels are also observed in MPTP- treated primates in association with dopaminergic loss (evidenced using PET functional imaging). We propose that the altered expression and distribution of FKBP12 is linked to abnormal protein folding and axonal transport. It may also reflect a compensatory regenerative response that renders immunophilins promising diagnostic and therapeutic targets

Diagnosis and Treatment of Parkinson's Disease

Parkinson's disease is diagnosed by history and physical examination and there are no laboratory investigations available to aid the diagnosis of Parkinson's disease. Confirmation of diagnosis of Parkinson's disease thus remains a difficulty. This book brings forth an update of most recent developments made in terms of biomarkers and various imaging techniques with potential use for diagnosing Parkinson's disease. A detailed discussion about the differential diagnosis of Parkinson's disease also follows as Parkinson's disease may be difficult to differentiate from other mimicking conditions at times. As Parkinson's disease affects many systems of human body, a multimodality treatment of this condition is necessary to improve the quality of life of patients. This book provides detailed information on the currently available variety of treatments for Parkinson's disease including pharmacotherapy, physical therapy and surgical treatments of Parkinson's disease. Postoperative care of patients of Parkinson's disease has also been discussed in an organized manner in this text. Clinicians dealing with day to day problems caused by Parkinson's disease as well as other healthcare workers can use beneficial treatment outlines provided in this book

GABAergic interneurons and prenatal ethanol exposure: from development to aging

Fetal Alcohol Spectrum Disorders are the most common non-genetic cause of neurodevelopmental disability worldwide. Individuals with Fetal Alcohol Spectrum Disorder experience clinical symptoms including differences in physical, cognitive and behavioral development beginning in early childhood, but continue to face challenges into adulthood. There is a critical need to examine the effects of prenatal ethanol exposure across early development, and to establish how the developmental effects of prenatal ethanol exposure may or may not progress in aging individuals. To contribute to these two areas, I asked how a binge-type prenatal ethanol exposure might affect: (1) early postnatal development of striatal neurons and, relate to the development of early motor behaviors over time, and (2) synaptic function in the medial prefrontal cortex, and affect the onset and severity of cognitive deficits in a transgenic mouse model of familial Alzheimer’s disease. I used whole-cell patch clamp electrophysiology to assess the functional and synaptic maturation of two populations of striatal neurons: striatal GABAergic interneurons and spiny striatal projection neurons, and the excitatory-inhibitory balance in deep layer medial prefrontal cortex pyramidal neurons. I found that prenatal ethanol exposure altered the postnatal developmental trajectory of striatal neurons in a sex-dependent manner, that coincided with sex-differences in the development of early motor behaviors, and morphological differences in striatal projection neurons. I also determined that prenatal ethanol exposure resulted in an earlier onset of deficits in GABAergic synaptic activity in cortical pyramidal neurons, that was an associated with a decreased number of parvalbumin expressing GABAergic interneurons, and an increase in intraneuronal APP/β-amyloid. These findings highlight the dynamic effects of prenatal ethanol exposure on synaptic function and behavioral outcomes during early development, and the lasting effects of prenatal ethanol exposure on neural circuits, modifying the aging process