Are high lumbar punctures safe? A magnetic resonance imaging morphometric study of the conus medullaris.

A high lumbar puncture (LP) at L2-L3 or above is often necessary to consider on technical grounds, but complications of conus medullaris (CM) damage during high LP are potentially concerning. We hypothesized that a high LP might be safer than previously thought by accounting for movements of the CM upon patient positional changes. We retrospectively reviewed standard normal supine lumbar spine magnetic resonance imaging of 58 patients and used electronic calipers on axial images at the T12-L1, L1-L2, and L2-L3 disc levels to measure the transverse diameter of the CM relative to the size of the dorsal thecal sac space (DTSS) through which a spinal needle could be inserted. On 142 axial images, the means for CM diameters were 8.2, 6.0, and 2.9 mm at the three levels, respectively. We then used known literature mean CM displacement values in the legs flexed and unflexed lateral decubitus position (LDP) to factor in CM shifts to the dependent side. We found that at all three levels, the likely positional shift of the CM would be too small and insufficient to displace the entire CM out of the DTSS. However, if needle placement could be confined to the midsagittal plane, an LP in the unflexed LDP would theoretically be entirely safe at both L1-L2 and L2-L3, and almost so at L2-L3 in the legs flexed LDP. Thus, high LPs at L1-L2 and L2-L3 are in theory likely safer than considered previously, more so in the legs unflexed than in the flexed LDP. Clin. Anat. 32:618-629, 2019. © 2019 Wiley Periodicals, Inc.

Eponymous "valves" of the nasolacrimal drainage apparatus. II. Frequency of visualization on dacryocystography.

Developmental remnants may follow segmental canalization of ectodermal epithelial cords forming the nasolacrimal drainage apparatus (NDA). This can result in false luminal "valves" along the path of the NDA, many of which have been named, but most have not been anatomically identified with consistency. By 1908, eight such "valves" were documented, those of: Foltz, Bochdalek, Rosenmüller, Huschke, Aubaret, Béraud or Krause, Taillefer, and Hasner or Cruveilhier or Bianchi. Digital subtraction dacryocystography (DS-DCG) is the highest spatial resolution imaging technique available to outline in vivo NDA anatomy, luminal profile, and pathology. We believe this is the first report of the conspicuousness and frequency of these "valves" on DS-DCG. We retrospectively analyzed routine DS-DCGs with normal findings for the presence and frequency of the eight NDA "valves." We examined 92 normal DS-DCGs on patients aged 14-82 years (71% female, 29% male). We observed "valves" most reliably in the inferior nasolacrimal duct: the inferior valve of Hasner (plica lacrimalis) was present in 98.9% of cases, and more superiorly, the valve of Taillefer (93.5%) and the valve of Krause (79.3%). Contrastingly, we infrequently identified the very superior "valves": Foltz or Bochdalek in 17.1%, Rosenmüller or Huschke in 46.4%, and Auberat in 40% of cases. Therefore, unlike the inferior NDA valves, these more superior "valves" were less consistently identified and are presumed to be simple mural mucosal irregularities rather than true structural valves. These findings will be useful in diagnostic interpretation of DS-DCGs and therapeutic planning for patients undergoing luminal procedures on the NDA. Clin. Anat., 2018. © 2018 Wiley Periodicals, Inc.

Eponymous "valves" of the nasolacrimal drainage apparatus. I. A historical review.

The nasolacrimal drainage apparatus (NDA) is of interest to anatomists, radiologists, and ophthalmologists alike, owing to its intricate luminal contour, complex surrounding structural morphology, and its clinical relevance. Here, we review the history of anatomical descriptions of so-called luminal "valves" of the NDA, including the numerous historical figures whose eponyms adorn the NDA. By 1908, multiple false "valves" that are likely no more than mounds of mucosa along the NDA had been recorded. In the modern era, these have all been largely considered speculative in nature and function aside from the consistently described true valve of Hasner (plica lacrimalis). Back then, eight so-called "valves" were believed to be identifiable. These were the "valves" of Foltz, Bochdalek, Rosenmüller, Huschke, Aubaret, Béraud or Krause, Taillefer, and Hasner or Cruveilhier or Bianchi. With the advent of detailed characterization through modern high-resolution imaging techniques, such as digital subtraction dacryocystography (DS-DCG), many of these valvular folds have come into question owing to their inconsistent identification. This historical review should be useful for greater understanding and accurate contextual interpretation of "valves" encountered on DS-DCG studies, and in clinical management and therapeutic planning of patients prior to undergoing luminal procedures on the NDA. Clin. Anat., 2018. © 2018 Wiley Periodicals, Inc.

Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy.

Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer's disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and ß-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

Increased incidence of intermittent hypoxemia in the Ts65Dn mouse model of Down syndrome.

In addition to nervous system, cardiovascular and respiratory systems are primarily affected in Down syndrome (DS). The Ts65Dn mouse model is widely used to recapitulate cognitive dysfunction in DS. While these mice consistently show failure in learning and memory along with functional and structural abnormalities in the hippocampal region, the underlying mechanisms behind cognitive dysfunction remain to be fully elucidated. Convergent evidence implicates chronic episodes of hypoxemia in cognitive dysfunction in people with DS. Using an infra-red detection system to assess oxygen saturation in free-moving mice, we assessed arterial blood oxygenation in both adolescent and adult Ts65Dn mice and found a significant increase in the incidence of hypoxemia in both groups. Notably, the severity of hypoxemia increased during the dark cycle, suggesting a link between hypoxemia and increased motor activity. Postmortem analysis showed significant increase in the expression of mitochondrial Cox4i2, the terminal enzyme of the mitochondrial respiratory chain and oxygen response element. Altogether these data suggest early and chronic occurrence of hypoxemia in the Ts65Dn mouse model of DS, which can contribute to cognitive dysfunction in these mice.

Assessment of dendritic arborization in the dentate gyrus of the hippocampal region in mice.

Dendritic arborization has been shown to be a reliable marker for examination of structural and functional integrity of neurons. Indeed, the complexity and extent of dendritic arborization correlates well with the synaptic plasticity in these cells. A reliable method for assessment of dendritic arborization is needed to characterize the deleterious effects of neurological disorders on these structures and to determine the effects of therapeutic interventions. However, quantification of these structures has proven to be a formidable task given their complex and dynamic nature. Fortunately, sophisticated imaging techniques can be paired with conventional staining methods to assess the state of dendritic arborization, providing a more reliable and expeditious means of assessment. Below is an example of how these imaging techniques were paired with staining methods to characterize the dendritic arborization in wild type mice. These complementary imaging methods can be used to qualitatively and quantitatively assess dendritic arborization that span a rather wide area within the hippocampal region.

The Link Between Physical Activity and Cognitive Dysfunction in Alzheimer Disease.

Alzheimer disease (AD) is a primary cause of cognitive dysfunction in the elderly population worldwide. Despite the allocation of enormous amounts of funding and resources to studying this brain disorder, there are no effective pharmacological treatments for reducing the severity of pathology and restoring cognitive function in affected people. Recent reports on the failure of multiple clinical trials for AD have highlighted the need to diversify further the search for new therapeutic strategies for cognitive dysfunction. Thus, studies detailing the neuroprotective effects of physical activity (PA) on the brain in AD were reviewed, and mechanisms by which PA might mitigate AD-related cognitive decline were explored. A MEDLINE database search was used to generate a list of studies conducted between January 2007 and September 2014 (n=394). These studies, along with key references, were screened to identify those that assessed the effects of PA on AD-related biomarkers and cognitive function. The search was not limited on the basis of intensity, frequency, duration, or mode of activity. However, studies in which PA was combined with another intervention (eg, diet, pharmacotherapeutics, ovariectomy, cognitive training, behavioral therapy), and studies not written in English were excluded. Thirty-eight animal and human studies met entry criteria. Most of the studies suggested that PA attenuates neuropathology and positively affects cognitive function in AD. Although the literature lacked sufficient evidence to support precise PA guidelines, convergent evidence does suggest that the incorporation of regular PA into daily routines mitigates AD-related symptoms, especially when deployed earlier in the disease process. Here the protocols used to alter the progression of AD-related neuropathology and cognitive decline are highlighted, and the implications for physical therapist practice are discussed.

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors.

Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.

The role of NMDA receptors in the pathophysiology and treatment of mood disorders.

Mood disorders such as major depressive disorder and bipolar disorder are chronic and recurrent illnesses that cause significant disability and affect approximately 350 million people worldwide. Currently available biogenic amine treatments provide relief for many and yet fail to ameliorate symptoms for others, highlighting the need to diversify the search for new therapeutic strategies. Here we present recent evidence implicating the role of N-methyl-D-aspartate receptor (NMDAR) signaling in the pathophysiology of mood disorders. The possible role of NMDARs in mood disorders has been supported by evidence demonstrating that: (i) both BPD and MDD are characterized by altered levels of central excitatory neurotransmitters; (ii) NMDAR expression, distribution, and function are atypical in patients with mood disorders; (iii) NMDAR modulators show positive therapeutic effects in BPD and MDD patients; and (iv) conventional antidepressants/mood stabilizers can modulate NMDAR function. Taken together, this evidence suggests the NMDAR system holds considerable promise as a therapeutic target for developing next generation drugs that may provide more rapid onset relief of symptoms. Identifying the subcircuits involved in mood and elucidating the role of NMDARs subtypes in specific brain circuits would constitute an important step toward the development of more effective therapies with fewer side effects.

Neurotransmitter-based strategies for the treatment of cognitive dysfunction in Down syndrome.

Down syndrome (DS) is a multisystem disorder affecting the cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, and musculoskeletal systems and is characterized by significant cognitive disability and a possible common pathogenic mechanism with Alzheimer's disease. During the last decade, numerous studies have supported the notion that the triplication of specific genes on human chromosome 21 plays a significant role in cognitive dysfunction in DS. Here we reviewed studies in trisomic mouse models and humans, including children and adults with DS. In order to identify groups of genes that contribute to cognitive disability in DS, multiple mouse models of DS with segmental trisomy have been generated. Over-expression of these particular genes in DS can lead to dysfunction of several neurotransmitter systems. Therapeutic strategies for DS have either focused on normalizing the expression of triplicated genes with important roles in DS or restoring the function of these systems. Indeed, our extensive review of studies on the pathogenesis of DS suggests that one plausible strategy for the treatment of cognitive dysfunction is to target the cholinergic, serotonergic, GABA-ergic, glutamatergic, and norepinephrinergic system. However, a fundamental strategy for treatment of cognitive dysfunction in DS would include reducing to normal levels the expression of specific triplicated genes in affected systems before the onset of neurodegeneration.

Formoterol, a long-acting ß2 adrenergic agonist, improves cognitive function and promotes dendritic complexity in a mouse model of Down syndrome.

BACKGROUND: Down syndrome is associated with significant failure in cognitive function. Our previous investigation revealed age-dependent degeneration of locus coeruleus, a major player in contextual learning, in the Ts65Dn mouse model of Down syndrome. We studied whether drugs already available for use in humans can be used to improve cognitive function in these mice. METHODS: We studied the status of ß adrenergic signaling in the dentate gyrus of the Ts65Dn mouse model of Down syndrome. Furthermore, we used fear conditioning to study learning and memory in these mice. Postmortem analyses included the analysis of synaptic density, dendritic arborization, and neurogenesis. RESULTS: We found significant atrophy of dentate gyrus and failure of ß adrenergic signaling in the hippocampus of Ts65Dn mice. Our behavioral analyses revealed that formoterol, a long-acting ß2 adrenergic receptor agonist, caused significant improvement in the cognitive function in Ts65Dn mice. Postmortem analyses revealed that the use of formoterol was associated with a significant improvement in the synaptic density and increased complexity of newly born dentate granule neurons in the hippocampus of Ts65Dn mice. CONCLUSIONS: Our data suggest that targeting ß2 adrenergic receptors is an effective strategy for restoring synaptic plasticity and cognitive function in these mice. Considering its widespread use in humans and positive effects on cognition in Ts65Dn mice, formoterol or similar ß2 adrenergic receptor agonists with ability to cross the blood brain barrier might be attractive candidates for clinical trials to improve cognitive function in individuals with Down syndrome.

Ascending monoaminergic systems alterations in Alzheimer's disease. translating basic science into clinical care.

Extensive neuropathological studies have established a compelling link between abnormalities in structure and function of subcortical monoaminergic (MA-ergic) systems and the pathophysiology of Alzheimer's disease (AD). The main cell populations of these systems including the locus coeruleus, the raphe nuclei, and the tuberomamillary nucleus undergo significant degeneration in AD, thereby depriving the hippocampal and cortical neurons from their critical modulatory influence. These studies have been complemented by genome wide association studies linking polymorphisms in key genes involved in the MA-ergic systems and particular behavioral abnormalities in AD. Importantly, several recent studies have shown that improvement of the MA-ergic systems can both restore cognitive function and reduce AD-related pathology in animal models of neurodegeneration. This review aims to explore the link between abnormalities in the MA-ergic systems and AD symptomatology as well as the therapeutic strategies targeting these systems. Furthermore, we will examine possible mechanisms behind basic vulnerability of MA-ergic neurons in AD.

Neurobiological elements of cognitive dysfunction in down syndrome: exploring the role of APP.

Down syndrome (DS) is the most common cause of cognitive dysfunction in children. Additionally, most adults with DS will eventually show both clinical and neuropathologic hallmarks of Alzheimer's disease (AD). The hippocampal formation constitutes the primary target for degeneration in both AD and DS. Over the past few years, we have studied the molecular mechanisms behind degeneration of this region and its major inputs in mouse models of DS. Our investigation has suggested that the loss of hippocampal inputs, particularly cholinergic and noradrenergic terminals, leads to de-afferentation of this region in the Ts65Dn mouse model of DS. Interestingly, we were able to link the overexpression of amyloid precursor protein (App) gene to degeneration of cholinergic and noradrenergic neurons in DS mouse models. We examined the underlying mechanisms of degeneration of multiple systems with extensive projections to the hippocampus in DS and its mouse models and the role of App overexpression in neurodegeneration. Understanding mechanisms behind hippocampal dysfunction has helped us to test several therapeutic strategies successfully in mouse models of DS. Here we review these strategies and mechanisms and discuss ways to translate our findings into possible interventions in humans.