Alzheimer's disease and glaucoma: Is there a causal relationship?

Evidence of a link between Alzheimer's disease (AD) and glaucoma has emerged from studies showing that patients with AD may have a significantly increased rate of glaucoma occurrence. In addition, it has been reported that patients with AD exhibit optic nerve degeneration and loss of retinal ganglion cells. In spite of intensive research, the clinical and genetic relationships between AD and glaucoma remain obscure. It is unclear whether the clinical correlation between the two diseases might be due to shared risk factors or the influence of one disorder on the other. Interestingly, certain observations may provide a clue towards a better understanding of the high rate of comorbidity reported between AD and glaucoma. In this article, we hypothesise that there may be a causal relationship between AD and glaucoma that may be explained by decreased cerebrospinal fluid pressure (CSFP) in patients with AD. A very recent study reported the intriguing new observation that mean CSFP was 33% lower in subjects with primary open-angle glaucoma than that of non-glaucomatous controls. It was noted that this observation supports the concept that an abnormal high trans-lamina cribrosa pressure difference, whether the result of elevated intraocular pressure, reduced CSFP, or both, plays an important role in glaucomatous optic nerve damage. Interestingly, it was also reported that a substantial proportion of AD patients have very low CSFP. Therefore, we hypothesise that an abnormal high trans-lamina cribrosa pressure difference may explain why patients with AD have a greater risk for developing glaucoma

Developmental Coordination Disorder: Disruption of the Cerebello-Cerebral Network evidenced by SPECT

Little is known about the neurobiological substrate of developmental coordination disorder (DCD), a neuro-developmental syndrome with significant, negative impact on the motor, cognitive and affective level throughout lifespan. This paper reports the clinical, neurocognitive and neuroradiological findings of a 19-year-old patient with typical DCD. As demonstrated by mild ataxia and a close semiological correspondence with the recently acknowledged ‘cerebellar cognitive affective syndrome’, clinical and neurocognitive investigations unambiguously indicated functional disruption of the cerebellum. Structural MRI of the brain confirmed cerebellar involvement revealing a slight anterior/superior asymmetry of vermal fissures consistent with rostral vermisdysplasia. Although this abnormality of vermal fissuration is generally considered an incidental neuroradiological finding without any clinical relevance, a potentially subtle impact on the developmental level has never been formally excluded. In addition to a generally decreased perfusion of the cerebellum, a quantified Tc-99m-ECD SPECT disclosed functional suppression of the anatomoclinically suspected supratentorial regions involved in the execution of planned actions, visuo-spatial processing and affective regulation. Based on these findings, it is hypothesised that the cerebellum is crucially implicated in the pathophysiologcial mechanisms of DCD, reflecting disruption of the cerebello-cerebral network involved in the execution of planned actions, visuo-spatial cognition and affective regulation

Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture

Four guanidino compounds that have been found to be markedly increased in cerebrospinal fluid and brain tissue of uremic patients, namely, guanidine, methylguanidine, creatinine, and guanidinosuccinic acid, were applied to mouse spinal cord neurons in primary dissociated cell culture to evaluate their effects on postsynaptic responses to gammaaminobutyric acid (GABA) and glycine. Intracellular microelectrode recording techniques were used. Guanidine, methylguanidine, creatinine, and guanidinosuccinic acid reversibly and in a dose-dependent manner inhibited both GABA and glycine responses. Guanidinosuccinic acid was the most potent inhibitor of the amino acid responses, followed in decreasing potency by methylguanidine, guanidine, and creatinine. Guanidinosuccinic acid inhibited responses to GABA and glycine, at concentrations similar to those found in cerebrospinal fluid and brain tissue of patients with terminal renal insufficiency. The other guanidino compounds tested exerted their effects only at concentrations higher than those found in uremic biological fluids and tissues. The inhibitory effect of guanidine and methylguanidine on responses to GABA was additive. The effect of the guanidino compounds on GABA responses was not antagonized by coapplication of the benzodiazepine-receptor antagonist CGS 9896. The results suggest that guanidine, methylguanidine, creatinine, and guanidinosuccinic acid inhibited responses to the inhibitory neurotransmitters GABA and glycine by blocking the chloride channel. The observed action of the studied guanidino compounds might contribute to the pathogenesis of the complex neurological symptomatology encountered in uremia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50338/1/410280505_ftp.pd

Foreign accent syndrome as a developmental motor speech disorder

Introduction: Foreign Accent Syndrome (FAS) is a relatively rare motor speech disorder in which the pronunciation of a patient is perceived by listeners of the same language community as distinctly foreign. FAS has been well documented in adult patients with etiologically heterogeneous, though mostly vascular brain lesions affecting the motor speech network of the language dominant hemisphere. In addition, reports exist of adult patients in whom FAS was due to a psychiatric illness. Although FAS has been reported in children, such accounts are rare and have remained largely anecdotal in that there have been no formally documented cases of FAS as a developmental motor speech disorder. Methods and results: For the first time, we describe the clinical, cognitive and neurolinguistic findings in two patients who in the absence of a history of psychiatric illness or acquired brain damage already presented with FAS at an early stage of speech and language development. In the first patient “developmental FAS” was associated with a dysharmonic distribution of neurocognitive test results indicating slight underdevelopment of visuo-spatial skills and visual memory. The second patient presented with “developmental FAS” associated with specific language impairment (SLI). Independent support for a diagnosis of FAS in both patients was obtained in an accent attribution experiment in which groups of native speakers of (Belgian) Dutch assessed the type of foreign accent of a sample of the patients’ conversational speech. Both patients were judged as non-native speakers of Dutch by the majority of participants who predominantly identified the accent as French. Conclusion: This paper for the first time documents two patients who presented with FAS on a developmental basis. The finding that FAS does not only occur in the context of acquired brain damage or psychogenic illness but also exists as developmental motor speech impairment requires a re-definition of FAS as a clinical syndrome

A foreign speech accent in a case of conversion disorder

Objective: The aim of this paper is to report the psychiatric, neuroradiological and linguistic characteristics in a native speaker of Dutch who developed speech symptoms which strongly resemble Foreign Accent Syndrome. Background: Foreign Accent Syndrome is a rare speech production disorder in which the speech of a patient is perceived as foreign by speakers of the same speech community. This syndrome is generally related to focal brain damage. Only in few reported cases the Foreign Accent Syndrome is assumed to be of psychogenic and/or psychotic origin. Method: In addition to clinical and neuroradiological examinations, an extensive test battery of standardized neuropsychological and neurolinguistic investigations was carried out. Two samples of the patient's spontaneous speech were analysed and compared to a 500,000-words reference corpus of 160 normal native speakers of Dutch. Results: The patient had a prominent French accent in her pronunciation of Dutch. This accent had persisted over the past eight years and has become progressively stronger. The foreign qualities of her speech did not only relate to pronunciation, but also to the lexicon, syntax and pragmatics. Structural as well as functional neuroimaging did not reveal evidence that could account for the behavioural symptoms. By contrast psychological investigations indicated conversion disorder. Conclusions: To the best of our knowledge this is the first reported case of a foreign accent like syndrome in conversion disorder

Sinus Sigmoideus Thrombosis Secondary to Graves' Disease: A Case Description

Cerebral venous thrombosis (CVT) is a distinct cerebrovascular condition that represents 0.5-1% of all strokes in the general population. Because of its procoagulant and antifibrinolytic effects [Horne et al.: J Clin Endocrinol Metab 2004;89:4469-4473], hyperthyroidism has been proposed as a predisposing factor for CVT [Saposnik et al.: Stroke 2011;42:1158-1192]. For the first time, we describe a 22-year-old right-handed woman with a sinus sigmoideus thrombosis due to Graves' disease. Although subclinical hyperthyroidism had been detected 2 years before the onset of neurological symptoms, she did not receive any medical follow-up. Early recognition, diagnosis and treatment are of crucial importance, as Graves' disease is a risk factor for CVT and stroke

Biofluid Markers for Prodromal Parkinson's Disease:Evidence From a Catecholaminergic Perspective

Parkinson's disease (PD) is the most frequent of all Lewy body diseases, a family of progressive neurodegenerative disorders characterized by intra-neuronal cytoplasmic inclusions of α-synuclein. Its most defining features are bradykinesia, tremor, rigidity and postural instability. By the time PD manifests with motor signs, 70% of dopaminergic midbrain neurons are lost, and the disease is already in the middle or late stage. However, there are various non-motor symptoms occurring up to 20 years before the actual parkinsonism that are closely associated with profound deficiency of myocardial noradrenaline content and peripheral sympathetic denervation, as evidenced by neuroimaging experiments in recent years. Additionally, there is an inherent autotoxicity of catecholamines in the neuronal cells in which they are produced, forming toxic catecholaldehyde intermediates that make α-synuclein prone to aggregation, initiating a cascade of events that ultimately leads to neuronal death. The etiopathogenesis of PD and related synucleinopathies thus may well be a prototypical example of a catecholamine-regulated neurodegeneration, given that the synucleinopathy in PD spreads in synergy with central and peripheral catecholaminergic dysfunction from the earliest phases onward. That is why catecholamines and their metabolites, precursors, or derivatives in cerebrospinal fluid or plasma could be of particular interest as biomarkers for prodromal and de novo PD. Because there is great demand for such markers, this mini-review summarizes all catecholamine-related studies to date, in addition to providing profound neurochemical evidence on a systemic and cellular level to further emphasize this hypothesis and with emphasis on extracellular vesicles as a novel diagnostic and therapeutic incentive

Functional connectivity differences in Alzheimer's disease and amnestic mild cognitive impairment associated with AT(N) classification and anosognosia

Alzheimer's continuum biological profiles (A+T-N-, A+T+N-, A+T-N+, and A+T+N+) were established in the 2018 National Institute on Aging and Alzheimer's Association research framework for Alzheimer's disease (AD). We aim to assess the relation between AT(N) biomarker profiles and brain functional connectivity (FC) and assess the neural correlates of anosognosia. We assessed local functional coupling and between-network connectivity through between-group intrinsic local correlation and independent component analyses. The neural correlates of anosognosia were assessed via voxel-wise linear regression analysis in prodromal AD. Statistical significance for the FC analysis was set at p ≤ 0.05 false discovery rate (FDR)-corrected for cluster size. One hundred and twenty-one and 73 participants were included in the FC and the anosognosia analysis, respectively. The FC in the default mode network is greater in prodromal AD than AD with dementia (i.e., local correlation: T = 8.26, p-FDR &lt; 0.001, k = 1179; independent component analysis: cerebellar network, T = 4.01, p-FDR = 0.0012, k = 493). The default mode network is persistently affected in the early stages of Alzheimer's biological continuum. The anterior cingulate cortex (T = 2.52, p-FDR = 0.043, k = 704) is associated with anosognosia in prodromal AD.</p

Signal loss due to oligomerization in ELISA analysis of amyloid-beta can be recovered by a novel sample pre-treatment method

According to the predominant theories, soluble amyloid-beta (Aβ) aggregates are the principal neurotoxic agents in Alzheimer’s disease pathology, making them a popular target for the development of therapeutics and diagnostic markers. One of the most commonly used methods for determining the concentration of Aβ is ELISA. However, ELISA was developed for monomeric proteins and may be ill-suited for detecting aggregates. Therefore, we investigated the effect of aggregation on the ELISA measurement and developed a novel chemical pre-treatment method, designed to disaggregate Aβ peptides, to improve the ELISA measurement of the total Aβ concentration. Synthetic Aβ40 monomers, Aβ42 oligomers and biological samples from mice and humans were subjected to a chemical pre-treatment protocol with: trifluoroacetic acid (TFA), formic acid (FA) or hexafluoroisopropanol (HFIP) prior to ELISA analysis. In our study we have shown that: • Aβ oligomerization leads to epitope masking and steric hindrance and results in an underestimation of the total Aβ content with ELISA. • Chemically pre-treating samples to disaggregate oligomers can (partially) recover the signal loss. • This novel sample pre-treatment method could provide a more accurate ELISA measurement of the total Aβ concentration in samples with a high oligomer content

Mechanical energy in toddler gait - A trade-off between economy and stability?

Mechanical energy expenditure was investigated in children who are just learning to walk and compared with adult mechanical energy expenditure during walking. First, we determined whether the inverted pendulum (IP) mechanism of energy exchange was present in toddlers. It seems that new walkers partially make use of this energy saving mechanism, but it is less efficient than in adults. The reduced recovery values (R=40% at optimal speeds in toddlers compared to 70% in adults) can be explained by their low self-selected walking speed in combination with their tossing gait (large vertical oscillations of the body) and by the observation that during as much as 25–50% of the gait cycle kinetic and potential energy are oscillating in-phase. The second step was to calculate positive external mechanical work (Wext). Since the IP mechanism is less efficient in toddlers, more mass-specific positive work has to be performed to lift and accelerate the centre of mass than in adults walking at the same speed, even when differences in body size are taken into account. The amount of positive internal work (Wint,k) necessary to move the body segments relative to the centre of mass was the third parameter we calculated. In toddlers Wint,k is largely determined by the kinetic energy of the lower limb. Compared to adults, toddlers have to perform less mass-specific work per unit distance to accelerate the body segments since the upper body is kept relatively stiff during walking and there is no arm swing. Apart from work performed on the centre of mass and work performed to move the body segments relative to the centre of mass, when walking some work is also performed during double contact as both legs are pushing against each other. Two methods were used to calculate this amount of work, both leading to the same conclusions. Mass-specific work during double contact is small in toddlers compared to adults because of their low walking speed. Finally the total amount of mechanical work performed in toddlers was compared to the work production observed in adults. Wext seems to be the major determinant for total mechanical energy expenditure. At intermediate froude numbers work production is comparable between adults and toddlers, but at low and high froude numbers Wtot increases due to the steep increases in Wext. Despite the fact that mechanical work requirements in toddler gait are underestimated if work during double contact is not taken into account, it is not a major determinant of the energy cost of walking