Guy Leschziner

Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimers disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimers disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimers disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left‐sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimers disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimers disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role. Ann Neurol 2001;49:433–442

Clinical factors and ABCB1 polymorphisms in prediction of antiepileptic drug response: a prospective cohort study

BACKGROUND The ABCB1 3435C-->T single-nucleotide polymorphism (SNP) or a three-SNP haplotype containing 3435C-->T has been implicated in multidrug resistance in epilepsy in three retrospective case-control studies, but a further three have failed to replicate the association. We aimed to determine the effect of the ABCB1 gene on epilepsy drug response, using a unique large cohort of epilepsy patients with prospectively measured seizure and drug response outcomes. METHODS The ABCB1 3435C-->T polymorphism and three-SNP haplotype, plus a comprehensive set of tag SNPs across ABCB1 and adjacent ABCB4, were genotyped in a cohort of 503 epilepsy patients with prospectively measured seizure and drug response outcomes. Clinical, demographic, and genetic data were analysed. Treatment outcome was measured in terms of time to 12-month remission, time to first seizure, and time to drug withdrawal due to inadequate seizure control or side-effects. Randomly selected genome-wide HapMap SNPs (n=129) were genotyped in all patients for genomic control. FINDINGS Number of seizures before treatment was the dominant feature predicting seizure outcome after starting antiepileptic drug therapy, measured by both time to first seizure (hazard ratio 1.34, 95% CI 1.21-1.49, p<0.0001) and time to 12-month remission (0.83, 0.73-0.94, p=0.003). There was no association of the ABCB1 3435C-->T polymorphism, the three-SNP haplotype, or any gene-wide tag SNP with time to first seizure after starting drug therapy, time to 12-month remission, or time to drug withdrawal due to unacceptable side-effects or to lack of seizure control. INTERPRETATION We found no evidence that ABCB1 common variation influences either seizure or drug withdrawal outcomes after initiation of antiepileptic drug therapy.

Sleep apnoea and the brain: a complex relationship

Intermittent hypoxia, reoxygenation, and hypercapnia or hypocapnia occur in both adults and children during untreated apnoea and hypopnoea, along with changes in cerebral blood flow and sleep fragmentation. These effects can result in cognitive deficits with functional effects on work and school efficiency. The assessment of how obstructive sleep apnoea affects cognition depends on the specificity and sensitivity of the tests, which are rarely developed specifically for obstructive sleep apnoea. In this Review, we discuss both the neural adaptive and maladaptive processes in response to hypoxaemia. The net result on cognitive and emotional performance depends on the stage of this dynamic process, effects on other body systems, cognitive reserve, and idiosyncratic susceptibility. We also explore the contribution of fragmented sleep, and the disruption of sleep structure, with focus on the effect at different times in the development of disease. This Review will address the gap in the underlying pathophysiology of new clinical and translational findings, and argue their contribution to the inherent complexity of the association between obstructive sleep apnoea and the brain.

The Association Between Obstructive Sleep Apnea and Alzheimer’s Disease: A Meta-Analysis Perspective

Alzheimer’s disease (AD) and obstructive sleep apnea (OSA) are highly prevalent, chronic conditions with intriguing, yet poorly understood epidemiological overlap. To date, the amount of OSA syndrome present in patients with AD across literature remains unknown. To address this question, we collected all available published clinical data and analyzed them through a quantitative meta-analytical approach. The results of our quantitative meta-analysis suggest that the aggregate odds ratio for OSA in AD vs. healthy control was 5.05 and homogeneous. This reflects that patients with AD have a five times higher chance of presenting with OSA than cognitively non-impaired individuals of similar age. Moreover, these data suggest that around half of patients with AD have experienced OSA at some point after their initial diagnosis. The additive impact of progressive changes in sleep quality and structure, changes in cerebral blood flow and the cellular redox status in OSA patients may all be contributing factors to cognitive decline and may further aggravate AD progression. It is hoped that the high OSA rate in AD patients, as suggested by the findings of our meta-analysis, might provide a sufficient clinical incentive to alert clinicians the importance of screening patients for OSA in AD, and stimulate further research in this area.

First rapid eye movement sleep periods and sleep-onset rapid eye movement periods in sleep-stage sequencing of hypersomnias

OBJECTIVES Discrimination between narcolepsy, idiopathic hypersomnia, and behavior-induced inadequate sleep syndrome (BIISS) is based on clinical features and on specific nocturnal polysomnography (NPSG) and multiple sleep latency test (MSLT) results. However, previous studies have cast doubt on the specificity and sensitivity of these diagnostic tools. METHODS Eleven variables of the NPSG were analyzed in 101 patients who were retrospectively diagnosed with narcolepsy with cataplexy (N+C) (n=24), narcolepsy without cataplexy (N-C) (n=38), idiopathic hypersomnia with long sleep period (IHL) (n=21), and BIISS (n=18). RESULTS Fifteen out of 24 N+C and 8 out of 38 N-C entered the first rapid eye movement (REM) sleep period (FREMP) from sleep stage 1 (N1) or wake (W), though this sleep-stage sequence did not arise in the other patient groups. FREMP stage sequence was a function of REM sleep latency (REML) for both N+C and N-C groups. FREMP stage sequence was not associated with mean sleep latency (MSL) in N+C but was associated in N-C, which implies heterogeneity within the N-C group. REML also was a useful discriminator. Depending on the cutoff period, REML had a sensitivity and specificity of up to 85.5% and 97.4%, respectively. CONCLUSIONS The FREMP stage sequence may be a useful tool in the diagnosis of narcolepsy, particularly in conjunction with sleep-stage sequence analysis of sleep-onset REM periods (SOREMPs) in the MSLT; it also may provide a helpful intermediate phenotype in the clarification of heterogeneity in the N-C diagnostic group. However, larger prospective studies are necessary to confirm these findings.

Restless legs syndrome

Restless legs syndrome is common; it is characterised by an urge to move and usually, but not exclusively, affects the legs. This urge to move is typically accompanied by abnormal sensations, variably described as burning, tingling, aching, or “insects crawling under the skin.” These sensations are transiently or partially relieved by movement, and there is a strong circadian influence—symptoms are worse in the evening. It may be idiopathic or secondary to iron deficiency, pregnancy, uraemia, or neurological problems. Estimates of prevalence of the syndrome range from 1.9% to 15%, depending on case ascertainment, and it affects all age groups, although prevalence increases with age. Prevalence is about twice as high in women as in men. Restless legs syndrome is a common cause of insomnia related to problems with sleep initiation and sleep maintenance, unrefreshing sleep, and excessive daytime sleepiness, and it may signify an underlying medical condition. Recognition of the condition and appropriate treatment therefore has a large impact on morbidity and quality of life. What is it?

Changes in Neurocognitive Architecture in Patients with Obstructive Sleep Apnea Treated with Continuous Positive Airway Pressure

Background Obstructive sleep apnea (OSA) is a chronic, multisystem disorder that has a bidirectional relationship with several major neurological disorders, including Alzheimers dementia. Treatment with Continuous Positive Airway Pressure (CPAP) offers some protection from the effects of OSA, although it is still unclear which populations should be targeted, for how long, and what the effects of treatment are on different organ systems. We investigated whether cognitive improvements can be achieved as early as one month into CPAP treatment in patients with OSA. Methods 55 patients (mean (SD) age: 47.6 (11.1) years) with newly diagnosed moderate–severe OSA (Oxygen Desaturation Index: 36.6 (25.2) events/hour; Epworth sleepiness score (ESS): 12.8 (4.9)) and 35 matched healthy volunteers were studied. All participants underwent neurocognitive testing, neuroimaging and polysomnography. Patients were randomized into parallel groups: CPAP with best supportive care (BSC), or BSC alone for one month, after which they were re-tested. Findings One month of CPAP with BSC resulted in a hypertrophic trend in the right thalamus [mean difference (%): 4.04, 95% CI: 1.47 to 6.61], which was absent in the BSC group [− 2.29, 95% CI: − 4.34 to − 0.24]. Significant improvement was also recorded in ESS, in the CPAP plus BSC group, following treatment [mean difference (%): − 27.97, 95% CI: − 36.75 to − 19.19 vs 2.46, 95% CI: − 5.23 to 10.15; P = 0.012], correlated to neuroplastic changes in brainstem (r = − 0.37; P = 0.05), and improvements in delayed logical memory scores [57.20, 95% CI: 42.94 to 71.46 vs 23.41, 95% CI: 17.17 to 29.65; P = 0.037]. Interpretation One month of CPAP treatment can lead to adaptive alterations in the neurocognitive architecture that underlies the reduced sleepiness, and improved verbal episodic memory in patients with OSA. We propose that partial neural recovery occurs during short periods of treatment with CPAP.

Sleep stage sequence analysis of sleep onset REM periods in the hypersomnias

Background The Multiple Sleep Latency Test (MSLT) remains an important diagnostic tool in the diagnosis of hypersomnias. However, a positive MSLT may be found in other sleep disorders, such as behaviourally induced inadequate sleep syndrome (BIISS). It has been demonstrated that in sleep onset rapid eye movement (SOREM) periods in BIISS, REM sleep tends to arise from stage 2 sleep (non-REM (NREM) 2), rather than stage 1 sleep (NREM1), as in narcolepsy. Methods We performed sleep stage sequence analysis on 127 patients with nocturnal polysomnography and MSLT, including 25 with narcolepsy with cataplexy (N+C), 41 with narcolepsy without cataplexy (N−C), 21 with idiopathic hypersomnia with long sleep time (IHL), 20 with BIISS and 20 with periodic limb movement disorder (PLMD). 537 naps were recorded, containing 176 SOREM periods. Results All SOREM periods in the IHL, BIISS and PLMD groups arose from NREM2 sleep, 75% of those in N+C arose from NREM1 and in N−C only 52% arose from NREM1. Within the N−C group, those with SOREM periods all arising from stage 1 had a shorter MSL (p=0.02). Conclusions These results suggest that SOREM periods arising from NREM1 have high sensitivity for the diagnosis of narcolepsy and that SOREM periods from NREM1 are a marker of severity, either of sleepiness or REM instability. Sleep stage sequence analysis of SOREM periods may also aid more accurate phenotyping of the hypersomnias and in particular clarify heterogeneity among patients with narcolepsy without cataplexy.

Functional reorganization in obstructive sleep apnoea and insomnia: A systematic review of the resting-state fMRI.

HighlightsResting state functional MRI studies is a promising non‐invasive tool for better understanding of the pathophysiology of sleep disorders.The salience network is involved in hyperarousal and affective symptoms in insomnia.The posterior default mode network appears to underlie cognitive and depressive symptoms of obstructive sleep apnoea.Disruption of intrinsic networks have been demonstrated in major depression, which is a common co‐morbidity of sleep disorders. ABSTRACT Functional neuroimaging techniques have accelerated progress in the study of sleep disorders. Considering the striking prevalence of these disorders in the general population, however, as well as their strong bidirectional relationship with major neuropsychiatric disorders, including major depressive disorder, their numbers are still surprisingly low. This review examines the contribution of resting state functional MRI to current understanding of two major sleep disorders, insomnia disorder and obstructive sleep apnoea. An attempt is made to learn from parallels of previous resting state functional neuroimaging findings in major depressive disorder. Moreover, shared connectivity biomarkers are suggested for each of the sleep disorders. Taken together, despite some inconsistencies, the synthesis of findings to date highlights the importance of the salience network in hyperarousal and affective symptoms in insomnia. Conversely, dysfunctional connectivity of the posterior default mode network appears to underlie cognitive and depressive symptoms of obstructive sleep apnoea.

Narcolepsy: a clinical review

Despite the classic tetrad of clinical features that typify it, narcolepsy remains much under-diagnosed, in part, because of the wide spectrum of clinical phenotypes, but also because of its insidious onset, usually in a young person. The median time to diagnosis from first symptoms remains very long, around 10 years in the UK. Conversely, in the specialist setting, it is likely over-diagnosed, largely because of failure to exclude other causes of hypersomnia. There is an over-reliance on a biological marker of the condition, the multiple sleep latency test (MSLT), which, like many tests, has a significant false-positive and false-negative rate. This review aims to discuss some of the difficulties in achieving a diagnosis, interpretation of investigations, differential diagnosis, and appropriate management of patients with narcolepsy.