Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction.

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD-DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α-synuclein pathology. We found moderate-severe vascular changes and high-vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub-set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α-synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging-related neurodegenerative disorders and characterize their end-stage clinical syndromes.

White matter capillaries in vascular and neurodegenerative dementias.

Previous studies suggest white matter (WM) integrity is vulnerable to chronic hypoperfusion during brain ageing. We assessed ~ 0.7 million capillary profiles in the frontal lobe WM across several dementias comprising Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease with dementia, vascular dementia, mixed dementias, post-stroke dementia as well as post-stroke no dementia and similar age ageing and young controls without significant brain pathology. Standard histopathological methods were used to determine microvascular pathology and capillary width and densities in 153 subjects using markers of the basement membrane (collagen IV; COL4) and endothelium (glucose transporter-1; GLUT-1). Variable microvascular pathology including coiled, tortuous, collapsed and degenerated capillaries as well as occasional microaneurysms was present in all dementias. As expected, WM microvascular densities were 20-49% lower than in the overlying cortex. This differential in density between WM and cortex was clearly demonstrated by COL4, which was highly correlated with GLUT-1 densities (Spearman's rho = 0.79, P = 0.000). WM COL4 immunopositive microvascular densities were decreased by ~ 18% across the neurodegenerative dementias. However, we found WM COL4 densities were increased by ~ 57% in post-stroke dementia versus ageing and young controls and other dementias. Using three different methods to measure capillary diameters, we found WM capillaries to be significantly wider by 19-45% compared to those in overlying neocortex apparent with both COL4 and GLUT-1. Remarkably, WM capillary widths were increased by ~ 20% across all dementias compared to ageing and young controls (P < 0.01). We also noted mean WM pathology scores incorporating myelin loss, arteriolosclerosis and perivascular spacing were correlated with COL4 immunopositive capillary widths (Pearson's r = 0.71, P = 0.032). Our key finding indicates that WM capillaries are wider compared to those in the overlying neocortex in controls but they dilate further during dementia pathogenesis. We suggest capillaries undergo restructuring in the deep WM in different dementias. This reflects compensatory changes to retain WM perfusion and integrity during hypoperfusive states in ageing-related dementias.

A multi-parameter system for use in neonatal resuscitation research and training.

Training staff in the resuscitation of neonates is an essential skill; resuscitation efficacy is difficult to quantify but critical to infant survival. Objective assessments of the efficacy of training methods, resuscitation techniques and devices have used concurrent measurements of air flow and air pressure in commercially available manikins. This system also simultaneously measures the force transmitted through the manikin head during simulated resuscitation, as applying excessive force may be deleterious to newborn infants. The overall accuracy of the force plate over the range 0-5 kg was 0.5%; the output was linear; the frequency response sufficiently high and there was no evidence of hysteresis. This system enables comparison of staff groups, resuscitation techniques and devices in an accurate and reproducible manner. Its use could improve training by offering a means of objective performance feedback through a range of parameters. Evaluation of clinical practice may also result in direct patient benefit.

Sleep deprivation lowers inhibition and enhances impulsivity to negative stimuli.

Sleep deprivation has previously been shown to intensify neural and autonomic responses to increasingly negative stimuli. Here, we report how this potential bias to negative stimuli manifests itself in behavioural performance. One night of sleep loss led to increased impulsivity to negative stimuli, such that sleep deprived individuals had an increased failure to inhibit a response and faster incorrect responses. This enhanced reactivity to negative stimuli has important consequences outside the confines of the laboratory.

Self-reported 'sleep deficit' is unrelated to daytime sleepiness.

Seemingly, many healthy adults have accrued a sleep debt, as determined by findings based on the multiple sleep latency test (MSLT). However, our recent, extensive survey found self-reported sleep deficit was not linked to daytime sleepiness determined by the Epworth sleepiness scale (ESS). Here, we report on the link between self-reported sleep deficit and gold standard measures of sleepiness: MSLT, Psychomotor vigilance test (PVT) and Karolinska Sleepiness Scale (KSS). Habitual sleep time in forty-three participants, from using a week long sleep diary and actiwatch data, compared with self-ratings of how much sleep they needed, provided estimates of apparent sleep deficit or otherwise. They were split into categories: 'sleep deficit' (Av. -47 min), 'sleep plus' (Av. 47 min) or 'neutral' (Av. 0+/-15 min), depicting perceived shortfall (or excess) sleep. Although the deficit group desired to sleep longer than the other groups, they actually obtained similar habitual nightly sleep as the neutral group, but less than the sleep plus group. 'Survival curves' based on those falling asleep during the MSLT showed no difference between the groups. Neither was there any difference between the groups for the PVT, KSS, or ESS. Here, factors other than sleepiness seem to influence self-perceived sleep deficits.

Sleep extension versus nap or coffee, within the context of 'sleep debt'.

Though extended night-time sleep mostly reduces the 'afternoon dip', little is known about evening benefits to alertness, or about comparisons with an afternoon nap or caffeine. Twenty healthy carefully screened adults, normal waking alertness levels, underwent four counterbalanced conditions: usual night sleep; night sleep extended<90 min (usual bed-time); up to 20 min afternoon nap; and 150 mg afternoon caffeine (versus decaffeinated coffee). Sleepiness was measured by afternoon and evening multiple sleep latency test (MSLTs), longer psychomotor vigilance test (PVT) sessions and a subjective sleepiness scale. Sleep was extended by average of 74 min, and all participants could nap 15-20 min. Sleep extension had little effect on PVT determined modest levels of morning sleepiness. Afternoon and evening MSLTs showed all active treatments significantly reduced the 'dip', with nap most effective until mid-evening; next effective was caffeine, then extension. Late evening sleepiness and subsequent sleep did not differ between conditions. Arguably, participants may have experienced some 'sleep debt', given they extended sleep and reflected some sleepiness within settings sensitive to sleepiness. Nevertheless, extended sleep seemed largely superfluous and inefficient in reducing modest levels of sleepiness when compared with a timely nap, and even caffeine. Sleep, such as food and fluid intakes, can be taken to excess of real biological needs, and for many healthy adults, there is a level of modest daytime sleepiness, only unmasked by very sensitive laboratory measures. It may reflect a requirement for more sleep or simply be within the bounds of normal acceptability.