Hannah A.D. Keage

Delirium is a strong risk factor for dementia in the oldest-old: a population-based cohort study.

Recent studies suggest that delirium is associated with risk of dementia and also acceleration of decline in existing dementia. However, previous studies may have been confounded by incomplete ascertainment of cognitive status at baseline. Herein, we used a true population sample to determine if delirium is a risk factor for incident dementia and cognitive decline. We also examined the effect of delirium at the pathological level by determining associations between dementia and neuropathological markers of dementia in patients with and without a history of delirium. The Vantaa 85+ study examined 553 individuals (92% of those eligible) aged ≥85 years at baseline, 3, 5, 8 and 10 years. Brain autopsy was performed in 52%. Fixed and random-effects regression models were used to assess associations between (i) delirium and incident dementia and (ii) decline in Mini-Mental State Examination scores in the whole group. The relationship between dementia and common neuropathological markers (Alzheimer-type, infarcts and Lewy-body) was modelled, stratified by history of delirium. Delirium increased the risk of incident dementia (odds ratio 8.7, 95% confidence interval 2.1–35). Delirium was also associated with worsening dementia severity (odds ratio 3.1, 95% confidence interval 1.5–6.3) as well as deterioration in global function score (odds ratio 2.8, 95% confidence interval 1.4–5.5). In the whole study population, delirium was associated with loss of 1.0 more Mini-Mental State Examination points per year (95% confidence interval 0.11–1.89) than those with no history of delirium. In individuals with dementia and no history of delirium (n = 232), all pathologies were significantly associated with dementia. However, in individuals with delirium and dementia (n = 58), no relationship between dementia and these markers was found. For example, higher Braak stage was associated with dementia when no history of delirium (odds ratio 2.0, 95% confidence interval 1.1–3.5, P = 0.02), but in those with a history of delirium, there was no significant relationship (odds ratio 1.2, 95% confidence interval 0.2–6.7, P = 0.85). This trend for odds ratios to be closer to unity in the delirium and dementia group was observed for neuritic amyloid, apolipoprotein ε status, presence of infarcts, α-synucleinopathy and neuronal loss in substantia nigra. These findings are the first to demonstrate in a true population study that delirium is a strong risk factor for incident dementia and cognitive decline in the oldest-old. However, in this study, the relationship did not appear to be mediated by classical neuropathologies associated with dementia.

Misinterpreting Emotional Expressions in Attention-Deficit/Hyperactivity Disorder: Evidence for a Neural Marker and Stimulant Effects

BACKGROUND In addition to cognitive impairment, there are disruptions to mood and emotion processing in attention-deficit/hyperactivity disorder (ADHD) but little is known about their neural basis. We examined ADHD disturbances in mood and emotion recognition and underlying neural systems before and after treatment with stimulant medication. METHODS Participants were 51 unmedicated ADHD adolescents and 51 matched healthy control subjects rated for depressed and anxious mood and accuracy for identifying facial expressions of basic emotion. Brain function was recorded using event-related potentials (ERPs) while subjects viewed these expressions. ADHD subjects were retested after 4 weeks, following treatment with methylphenidate (MPH). RESULTS ADHD subjects showed a profile of emotion-related impairment: higher depression and anxiety, deficits in identifying threat-related emotional expressions in particular, and alterations in ERPs. There was a pronounced reduction in occipital activity during the early perceptual analysis of emotional expression (within 120 msec), followed by an exaggeration of activity associated with structural encoding (120-220 msec) and subsequent reduction and slowing of temporal brain activity subserving context processing (300-400 msec). Methylphenidate normalized neural activity and produced some improvement of emotion recognition but had no impact on negative mood. Improvements in neural activity with MPH were consistent predictors of improvement in clinical features of emotional lability and hyperactivity. CONCLUSIONS Objective behavioral and brain function measures of emotion processing may provide a valuable addition to the clinical armamentarium for assessing emotional disturbances in ADHD and the efficacy of stimulants for treating these disturbances.

What sleep characteristics predict cognitive decline in the elderly

BACKGROUND Sleep is critical for optimal cognitive function, but as we age both cognitive impairment and sleep problems increase. Longitudinal, population-based studies can be used to investigate temporal relationships between sleep and cognition. METHODS A total of 2012 cognitively unimpaired individuals 65 years and over were drawn from the MRC Cognitive Function and Ageing Study (CFAS). They answered self-reported measures including: insomnia symptoms and age of onset, night time wakings, snoring, sleep onset latency, napping, daytime sleepiness and duration of night time sleep. Cognition was measured via the Mini-Mental State Examination. RESULTS It was found that daytime napping at baseline was associated with a lower risk of cognitive decline at two and 10 years, and that obtaining ≤6.5h of night-time sleep and excessive daytime sleepiness at baseline were associated with an increased risk at 10 years. CONCLUSIONS Daytime napping, night-time sleep duration, and excessive daytime sleepiness may be modifiable behaviours open to intervention strategies, or, clinical indicators of future decline in older individuals.

The dose-dependent effect of methylphenidate on performance, cognition and psychophysiology

The effects of methylphenidate (MPH) on 32 healthy human male volunteers (aged 18 to 25 years, mean age=22.26) were examined using a within-subject design. Each participant attended six testing periods, held once per week. Within each testing period, three repeat testing sessions were undertaken: pre-medication, on-medication and two hours post-medication. In these sessions, dose was manipulated (placebo, 5 mg, 15 mg or 45 mg) according a double-blind placebo design. In this report, we focus on behavioral, autonomic arousal (heart rate, skin conductance) and psychophysiological (ERP) data acquired during the working memory task. We found increased autonomic arousal (heart rate, skin conductance and blood pressure) with MPH. A linear reduction in reaction time, omission errors and target P3 latency, and a corresponding increase in background P3 amplitude was observed with increased MPH dose. The relationship between these measures supported an increase in performance and underlying brain function with MPH. To our knowledge, this is the first paper to use behavioral, arousal and electrophysiological measures in an integrative approach to study the effects of MPH on healthy adults.

Association of Delirium With Cognitive Decline in Late Life: A Neuropathologic Study of 3 Population-Based Cohort Studies

Importance Delirium is associated with accelerated cognitive decline. The pathologic substrates of this association are not yet known, that is, whether they are the same as those associated with dementia, are independent, or are interrelated. Objective To examine whether the accelerated cognitive decline observed after delirium is independent of the pathologic processes of classic dementia. Design, Setting, and Participants Harmonized data from 987 individual brain donors from 3 observational cohort studies with population-based sampling (Vantaa 85+, Cambridge City Over-75s Cohort, Cognitive Function and Ageing Study) performed from January 1, 1985, through December 31, 2011, with a median follow-up of 5.2 years until death, were used in this study. Neuropathologic assessments were performed with investigators masked to clinical data. Data analysis was performed from January 1, 2012, through December 31, 2013. Clinical characteristics of brain donors were not different from the rest of the cohort. Outcome ascertainment was complete given that the participants were brain donors. Exposures Delirium (never vs ever) and pathologic burden of neurofibrillary tangles, amyloid plaques, vascular lesions, and Lewy bodies. Effects modeled using random-effects linear regression and interactions between delirium and pathologic burden were assessed. Outcomes Change in Mini-Mental State Examination (MMSE) scores during the 6 years before death. Results There were 987 participants (290 from Vantaa 85+, 241 from the Cambridge City Over-75s Cohort, and 456 from the Cognitive Function and Ageing Study) with neuropathologic data; mean (SD) age at death was 90 (6.4) years, including 682 women (69%). The mean MMSE score 6 years before death was 24.7 points. The 279 individuals with delirium (75% women) had worse initial scores (−2.8 points; 95% CI, −4.5 to −1.0; P < .001). Cognitive decline attributable to delirium was −0.37 MMSE points per year (95% CI, −0.60 to −0.13; P < .001). Decline attributable to the pathologic processes of dementia was −0.39 MMSE points per year (95% CI, −0.57 to −0.22; P < .001). However, the combination of delirium and the pathologic processes of dementia resulted in the greatest decline, in which the interaction contributed an additional −0.16 MMSE points per year (95% CI, −0.29 to −0.03; P = .01). The multiplicative nature of these variables resulted in individuals with delirium and the pathologic processes of dementia declining 0.72 MMSE points per year faster than age-, sex-, and educational level–matched controls. Conclusions and Relevance Delirium in the presence of the pathologic processes of dementia is associated with accelerated cognitive decline beyond that expected for delirium or the pathologic process itself. These findings suggest that additional unmeasured pathologic processes specifically relate to delirium. Age-related cognitive decline has many contributors, and these findings at the population level support a role for delirium acting independently and multiplicatively to the pathologic processes of classic dementia.

The N170 and face perception in psychiatric and neurological disorders: A systematic review

OBJECTIVE To systematically evaluate evidence for configural and affective face processing abnormalities as measured by the N170 and Vertex Positive Potential (VPP) event-related potential components, and analogous M170 magnetoencephalography (MEG) component, in neurological and psychiatric disorders. METHODS 1251 unique articles were identified using PsychINFO and PubMed databases. Sixty-seven studies were selected for review, which employed various tasks to measure the N170, M170 or VPP; the 13 neurological/psychiatric conditions were Attention-Deficit Hyperactivity Disorder (ADHD), Alcohol Dependence, Alzheimers Disease, Autism Spectrum Disorders (ASDs), Bipolar Disorder, Bulimia Nervosa, Fibromyalgia, Huntingtons Disease, Major Depressive Disorder, Parkinsons Disease, Prosopagnosia, Schizophrenia and Social Phobia. RESULTS Smaller N170 and VPP amplitudes to faces compared to healthy controls were consistently reported in Schizophrenia but not in ASDs. In Schizophrenia N170 and VPP measures were not correlated with clinical symptoms. Findings from other disorders were highly inconsistent; however, reported group differences were almost always smaller amplitudes or slower latencies to emotional faces in disordered groups regardless of diagnosis. CONCLUSIONS Results suggest that N170/VPP abnormalities index non-specific facial affect processing dysfunction in these neurological and psychiatric conditions, reflecting social impairments being broadly characteristic of these groups. SIGNIFICANCE The N170 and analogous components hold promise as diagnostic and treatment monitoring biomarkers for social dysfunction.

Emoticons in mind: An event-related potential study

It is now common practice, in digital communication, to use the character combination “:-)”, known as an emoticon, to indicate a smiling face. Although emoticons are readily interpreted as smiling faces, it is unclear whether emoticons trigger face-specific mechanisms or whether separate systems are utilized. A hallmark of face perception is the utilization of regions in the occipitotemporal cortex, which are sensitive to configural processing. We recorded the N170 event-related potential to investigate the way in which emoticons are perceived. Inverting faces produces a larger and later N170 while inverting objects which are perceived featurally rather than configurally reduces the amplitude of the N170. We presented 20 participants with images of upright and inverted faces, emoticons and meaningless strings of characters. Emoticons showed a large amplitude N170 when upright and a decrease in amplitude when inverted, the opposite pattern to that shown by faces. This indicates that when upright, emoticons are processed in occipitotemporal sites similarly to faces due to their familiar configuration. However, the characters which indicate the physiognomic features of emoticons are not recognized by the more laterally placed facial feature detection systems used in processing inverted faces.

Cerebrovascular Function in Aging and Dementia: A Systematic Review of Transcranial Doppler Studies

Background/Aim: The contribution of cerebrovascular dysfunction to the manifestation of dementia and cognitive decline in late life is gaining increased attention. We aimed to systematically review evidence for associations between dementia or aging and cerebrovascular function as measured using transcranial Doppler (TCD) examination. Methods: A total of 1,172 articles were retrieved from PsychInfo and PubMed searches, and 34 relevant articles were identified using a variety of TCD methods. Results: The pulsatility index (vessel resistance), spontaneous emboli and cerebrovascular reactivity to hyper-/hypocapnia appeared good discriminators of dementia. Aging was associated with a slowing in blood flow velocity. Conclusion: TCD ultrasonography is inexpensive, portable and well tolerated by aged and demented subjects. The technique stands to make a valuable contribution to the knowledge regarding the underlying functional biology of age-related cognitive change and dementia.

TDP-43 Pathology in the Population: Prevalence and Associations with Dementia and Age

BACKGROUND The significance of TDP-43 pathology in relation to aging and dementia in the population is unclear. OBJECTIVE We aimed to determine the prevalence of transactive response DNA-binding protein of 43 kDA (TDP-43) neuronal inclusions in a population-based sample, and associations with age group at death (≤90 and >90 years) and clinical dementia status prior to death. Further, we investigate associations between TDP-43 inclusions and other key dementia-related neuropathologies (plaques, tangles, and neuronal loss) within the hippocampus and entorhinal and temporal cortices. METHODS All brain donors within the Cambridge City over-75 s Cohort (CC75C), which is population-based and longitudinally tracked (n = 228), were included. Age at death ranged from 78 to 106 years. TDP-43 neuronal inclusions were assessed in the hippocampus, entorhinal cortex, and temporal cortex. These data were combined with existing clinical and neuropathological data. RESULTS TDP-43 neuronal inclusions were present in 27% of the sample, 36% of those with clinical dementia and 18% without dementia. Individuals who died later (>90 years) or with clinical dementia were more likely to show TDP-43 inclusions. Hippocampal and entorhinal TDP-43 inclusions were significantly associated with dementia severity and increasing age, taking into account other neuropathologies. TDP-43 neuronal inclusions appeared to be co-localize with severe neuronal loss. CONCLUSION Findings indicate that hippocampal and entorhinal TDP-43 inclusions are important substrates of late onset dementia which appear to co-localize with severe neuronal loss, but not with Alzheimers disease markers of amyloid and tau. This broadens the accepted view of TDP-43 pathology in dementias.

Transcranial Doppler ultrasound to assess cerebrovascular reactivity: reliability, reproducibility and effect of posture

Transcranial Doppler ultrasound (TCD) allows measurement of blood flow velocities in the intracranial vessels, and can be used to assess cerebral vasodilator responses to a hypercapnic stimulus. The reliability of this technique has not been established, nor is there agreement about whether the technique should be performed in sitting or lying postures. We tested the intra- and inter-rater reliability of measures of cerebrovascular reactivity (CVR) in 10 healthy adults, in sitting and lying postures. Participants underwent triplicate bilateral ultrasound assessment of flow velocities in the middle cerebral arteries whilst sitting and lying supine prior to and during inhalation of Carbogen (5% CO2, 95% O2) for 2 min. This procedure was performed twice by each of two raters for a total of four sessions. CVR was calculated as the difference between baseline and the peak blood flow velocity attained during CO2 inhalation. Intraclass correlation coefficients (ICCs) for intra-rater reliability were greater sitting than lying for both raters (e.g. Rater 1 ICC sitting = 0.822, lying = 0.734), and inter-rater reliability was also greater in sitting (e.g. sitting ICC = 0.504, lying = 0.081). These results suggest that assessment of CVR using TCD should be performed with participants sitting in order to maximise CVR measurement reliability.