Rafael Meyer

Arterial spin labeling imaging reveals widespread and Aβ-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers

Changes in cerebral blood flow are an essential feature of Alzheimer’s disease and have been linked to apolipoprotein E-genotype and cerebral amyloid-deposition. These factors could be interdependent or influence cerebral blood flow via different mechanisms. We examined apolipoprotein E-genotype, amyloid beta-deposition, and cerebral blood flow in amnestic mild cognitive impairment using pseudo-continuous arterial spin labeling MRI in 27 cognitively normal elderly and 16 amnestic mild cognitive impairment participants. Subjects underwent Pittsburgh Compound B (PiB) positron emission tomography and apolipoprotein E-genotyping. Global cerebral blood flow was lower in apolipoprotein E ɛ4-allele carriers (apolipoprotein E4+) than in apolipoprotein E4− across all subjects (including cognitively normal participants) and within the group of cognitively normal elderly. Global cerebral blood flow was lower in subjects with mild cognitive impairment compared with cognitively normal. Subjects with elevated cerebral amyloid-deposition (PiB+) showed a trend for lower global cerebral blood flow. Apolipoprotein E-status exerted the strongest effect on global cerebral blood flow. Regional analysis indicated that local cerebral blood flow reductions were more widespread for the contrasts apolipoprotein E4+ versus apolipoprotein E4− compared with the contrasts PiB+ versus PiB− or mild cognitive impairment versus cognitively normal. These findings suggest that apolipoprotein E-genotype exerts its impact on cerebral blood flow at least partly independently from amyloid beta-deposition, suggesting that apolipoprotein E also contributes to cerebral blood flow changes outside the context of Alzheimer’s disease.

Simultaneous quantitative susceptibility mapping and Flutemetamol-PET suggests local correlation of iron and β-amyloid as an indicator of cognitive performance at high age

ABSTRACT The accumulation of &bgr;‐amyloid plaques is a hallmark of Alzheimers disease (AD), and recently published data suggest that increased brain iron burden may reflect pathologies that synergistically contribute to the development of cognitive dysfunction. While preclinical disease stages are considered most promising for therapeutic intervention, the link between emerging AD‐pathology and earliest clinical symptoms remains largely unclear. In the current study we therefore investigated local correlations between iron and &bgr;‐amyloid plaques, and their possible association with cognitive performance in healthy older adults. 116 older adults (mean age 75±7.4 years) received neuropsychological testing to calculate a composite cognitive score of performance in episodic memory, executive functioning, attention, language and communication. All participants were scanned on a combined PET‐MRI instrument and were administered T1‐sequences for anatomical mapping, quantitative susceptibility mapping (QSM) for assessing iron, and 18F‐Flutemetamol‐PET for estimating &bgr;‐amyloid plaque load. Biological parametric mapping (BPM) was used to generate masks indicating voxels with significant (p<0.05) correlation between susceptibility and 18F‐Flutemetamol‐SUVR. We found a bilateral pattern of clusters characterized by a statistical relationship between magnetic susceptibility and 18F‐Flutemetamol‐SUVR, indicating local correlations between iron and &bgr;‐amyloid plaque deposition. For two bilateral clusters, located in the frontal and temporal cortex, significant relationships (p<0.05) between local &bgr;‐amyloid and the composite cognitive performance score could be observed. No relationship between whole‐cortex &bgr;‐amyloid plaque load and cognitive performance was observable. Our data suggest that the local correlation of &bgr;‐amyloid plaque load and iron deposition may provide relevant information regarding cognitive performance of healthy older adults. Further studies are needed to clarify pathological correlates of the local interaction of &bgr;‐amyloid, iron and other causes of altered magnetic susceptibility. HIGHLIGHTSVoxel‐wise correlation of quantitative susceptibility with &bgr;‐amyloid by PET‐MRI.Quantitative susceptibility mapping (QSM) as a measure of local iron deposition.18F‐Flutemetamol SUVR for estimating regional distribution of &bgr;‐amyloid plaques.Brain regions of interest were defined by local correlation of iron and &bgr;‐amyloid.Correlating &bgr;‐amyloid and iron may inform on cognitive performance at high age.

Subsyndromal delirium in the intensive care setting: Phenomenological characteristics and discrimination of subsyndromal delirium versus no and full-syndromal delirium

OBJECTIVE Similar to delirium, its subsyndromal form has been recognized as the cause of diverse adverse outcomes. Nonetheless, the nature of this subsyndromal delirium remains vastly understudied. Therefore, in the following, we evaluate the phenomenological characteristics of this syndrome versus no and full-syndromal delirium. METHOD In this prospective cohort study, we evaluated the Delirium Rating Scale-Revised, 1998 (DRS-R-98) versus the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnostic criteria and examined the diagnosis of delirium with respect to phenomenological distinctions in the intensive care setting. RESULTS Out of 289 patients, 36 with subsyndromal delirium versus 86 with full-syndromal and 167 without delirium were identified. Agreement with respect to the DSM-IV-TR diagnosis of delirium was perfect. The most common subtype in those with subsyndromal delirium was hypoactive, in contrast to mixed subtype in those with full-syndromal delirium versus no motor alterations in those without delirium. By presence and severity of delirium symptoms, subsyndromal delirium was intermediate. The ability of the DRS-R-98 items to discriminate between either form of delirium was substantial. Between subsyndromal and no delirium, the cognitive domain and sleep-wake cycle were more impaired and allowed a distinction with no delirium. Further, between full- and subsyndromal delirium, the prevalence and severity of individual DRS-R-98 items were greater. Although the differences between these two forms of delirium was substantial, the items were not very specific, indicating that the phenomenology of subsyndromal delirium is closer to full-syndromal delirium. SIGNIFICANCE OF RESULTS Phenomenologically, subsyndromal delirium was found to be distinct from and intermediate between no delirium and full-syndromal delirium. Moreover, the greater proximity to full-syndromal delirium indicated that subsyndromal delirium represents an identifiable subform of full-syndromal delirium.

Delirium in the intensive care setting and the Richmond Agitation and Sedation Scale (RASS): Drowsiness increases the risk and is subthreshold for delirium

INTRODUCTION Sedation is a core concept in the intensive care setting, however, the impact of sedation on delirium has not yet been studied to date. METHODS In this prospective cohort study, 225 patients with Richmond Agitation and Sedation (RASS) scores of -1 - drowsiness and 0 - alert- and calmness were assessed with the Delirium Rating Scale-Revised 1998 (DRS-R-98) and DSM-IV-TR-determined diagnosis of delirium assessing drowsiness versus alertness. RESULTS By itself, drowsiness increased the odds for developing delirium eightfold (OR 7.88 p<0.001) and rates of delirium were 68.2 and 21.4%, respectively. Further, in the drowsy patient, delirium was more severe. In the presence of drowsiness, delirium was characterized by sleep-wake cycle disturbances and language abnormalities. These two features, in addition to psychomotor retardation, allowed the correct classification of delirium at RASS-1. The same features, in addition to thought abnormalities and the impairment in the cognitive domain, orientation, attention, short- and long-term memory representing the core domains of delirium, or the temporal onset were very sensitive towards delirium, however lacked specificity. Conversely, delusions, perceptual abnormalities and lability of affect representing the non-core domain were very specific for delirium in the drowsy, however, not very sensitive. In the absence of delirium, drowsiness caused attentional impairment and language abnormalities. CONCLUSION Drowsiness increased the odds for developing delirium eightfold and caused more severe delirium, which was characterized by sleep-wake cycle and language abnormalities. Further, drowsiness by itself caused attentional impairment and language abnormalities, thus, with its disturbance in consciousness was subthreshold for delirium.

Management of Gamma-Butyrolactone Dependence with Assisted Self-Administration of GBL

Gamma-hydroxybutyric acid (GHB) and its liquid precursor gamma-butyrolactone (GBL) have become increasingly popular beyond the clubbing culture resulting in daily consumption and dependence in the broader population. This case report illustrates the challenges of managing GHB-withdrawal and a possibly superior future approach of its management by titration and tapering of the addictive agent.

Brief assessment of delirium subtypes: Psychometric evaluation of the Delirium Motor Subtype Scale (DMSS)-4 in the intensive care setting.

OBJECTIVE The management of and prognosis for delirium are affected by its subtype: hypoactive, hyperactive, mixed, and none. The DMSS-4, an abbreviated version of the Delirium Motor Symptom Scale, is a brief instrument for the assessment of delirium subtypes. However, it has not yet been evaluated in an intensive care setting. METHOD We performed a prospective/descriptive cohort study in order to determine the internal consistency, reliability, and validity of the relevant items of the DMSS-4 versus the Delirium Rating Scale-Revised-98 (DRS-R-98) and the original DMSS in a surgical intensive care setting. RESULTS A total of 289 elderly, predominantly male patients were screened for delirium, and 122 were included in our sample. The internal consistency of the DMSS-4 items was excellent (Cronbachs α = 0.92), and between the DMSS-4 and DRS-R-98 the overall concurrent validity was substantial (Cramers V = 0.67). Within individual motor subtypes, concurrent validity remained at least substantial (Cohens κ = 0.65-0.81) and sensitivity high (69.8 to 82.2%), in contrast to those of the no-motor subtype, with less validity and sensitivity (κ = 0.28, 22%). Similarly, total concurrent validity between the DMSS-4 and the original DMSS reached perfection (Cramers V = 0.83), as did agreement between the subtypes (κ = 0.83-0.92), while sensitivity remained high (88.2-100%). Only in those with delirium with no-motor subtype was agreement moderate (κ = 0.56) and sensitivity lower (67%). Specificity was high across all subtypes (91.2-99.1%). The DMSS-4 yielded very sensitive ratings, particularly for hypoactive and hyperactive motor symptoms, and interrater agreement was excellent (Fleisss κ = 0.83). SIGNIFICANCE OF RESULTS We found the DMSS-4 to be a most reliable and valid brief assessment of delirium in characterizing the subtypes of delirium in an intensive care setting, with increased sensitivity to hypoactive and hyperactive motor alterations.

Low cortical iron and high entorhinal cortex volume promote cognitive functioning in the oldest-old

The aging brain is characterized by an increased presence of neurodegenerative and vascular pathologies. However, there is substantial variation regarding the relationship between an individuals pathological burden and resulting cognitive impairment. To identify correlates of preserved cognitive functioning at highest age, the relationship between β-amyloid plaque load, presence of small vessel cerebrovascular disease (SVCD), iron-burden, and brain atrophy was investigated. Eighty cognitively unimpaired participants (44 oldest-old, aged 85-96 years; 36 younger-old, aged 55-80 years) were scanned by integrated positron emission tomography-magnetic resonance imaging for assessing beta regional amyloid plaque load (18F-flutemetamol), white matter hyperintensities as an indicator of SVCD (fluid-attenuated inversion recovery-magnetic resonance imaging), and iron load (quantitative susceptibility mapping). For the oldest-old group, lower cortical volume, increased β-amyloid plaque load, prevalence of SVCD, and lower cognitive performance in the normal range were found. However, compared to normal-old, cortical iron burden was lower in the oldest-old. Moreover, only in the oldest-old, entorhinal cortex volume positively correlated with β-amyloid plaque load. Our data thus indicate that the co-occurrence of aging-associated neuropathologies with reduced quantitative susceptibility mapping measures of cortical iron load constitutes a lower vulnerability to cognitive loss.

Severe Gamma-Hydroxy-Butyric Acid (GHB) Dependence with Repeated Withdrawal Syndrome and Induced Delirium

Gamma-Hydroxy-Butyric acid (GHB) and its liquid precursor Gamma-Butyro-Lactone (GBL) have become increasingly popular beyond the clubbing culture and daily consumption as well as dependence has become a more common problem. This case report illustrates the presentation and management of severe GHB-dependence and its sequelae, which are increasingly encountered in the addiction and general hospital setting.

Screening for delirium with the Intensive Care Delirium Screening Checklist (ICDSC): a re-evaluation of the threshold for delirium

BACKGROUND With its high incidence and subsequent adverse consequences in the intensive care setting, several instruments have been developed to screen for and detect delirium. One of the more commonly used is the Intensive Care Delirium Screening Checklist (ICDSC); however, the optimal cut-off score indicating delirium has been debated. METHODS In this prospective cohort study, the ICDSC threshold for delirium set at ≥3, ≥4, or ≥5 was compared with the DSM-IV-TR-determined diagnosis of delirium (used as standard), and with the Confusion Assessment Method for the ICU (CAM-ICU), with respect to their concurrent validity. RESULTS In total, 289 patients were assessed, including 122 with delirium. The cut-off score of ≥4 had several shortcomings: although 90% of patients with delirium were correctly classified, 23% remained undetected. The agreement with the DSM-IV-TR diagnosis of delirium was only moderate (Cohens κ 0.59) and the sensitivity was only 62%. In contrast, when the cut-off was ≥3, 83% of patients with delirium were correctly classified and only 14.5% remained undetected. The agreement with DSM-IV-TR was substantial (Cohens κ 0.68) and the sensitivity increased to 83%. The benefit of setting the cut-off at ≥5 was not convincing: although 90% of patients with delirium were correctly classified, 30% remained undetected. The concurrent validity was only moderate (Cohens κ 0.44), and the sensitivity reached only 44%. Changing the ICDSC cut-off score did not strengthen the moderate agreement with the CAM-ICU (Cohens κ 0.45-0.56). CONCLUSION In clinical routine, decreasing the ICDSC threshold for delirium to ≥3 increased the accuracy in detecting delirium at the cost of over-identification and is therefore recommended as the optimal threshold. Increasing the cut-off score to ≥5 decreased the concurrent validity and sensitivity; in addition, the under-detection of delirium was substantial.

Validation and Psychometric Properties of the German Version of the Delirium Motor Subtype Scale (DMSS)

Objective: Delirium has been characterized into its subtypes—hypoactive, hyperactive, mixed, or no motor subtype—along with the use of the Delirium Motor Symptom Scale (DMSS). The German version of this scale (DMSS-G), however, has not yet been validated. Method: We determined internal consistency, reliability, and validity of the DMSS-G in the surgical intensive care unit, using DSM-IV-TR criteria and the Delirium Rating Scale–Revised–98. Results: In total, 289 patients were included, and out of these, 122 were delirious. The DMSS-G showed excellent internal consistency (Cronbach’s α = 0.92) and interrater reliability (Fleiss κ = 0.83). Additionally, the overall concurrent validity was substantial (Cramer’s V = 0.69); within subtypes, hyperactive, hypoactive, or mixed, the concurrent validity remained at least substantial (Cohen’s κ = 0.73-0.82) and the sensitivity ranged from 60% to 97%. In contrast, in those with no motor subtype, we found the concurrent validity (Cohen’s κ = 0.31) and sensitivity to be low (22%). Overall, specificity for all individual subtypes was high (82% to 100%). The DMSS was very sensitive in both rating hyperactive and hypoactive motor symptoms of delirium. Conclusion: The DMSS-G is a highly reliable and valid instrument for detecting motor symptoms in delirium, which provides an accurate instrument to classify the motor subtypes of delirium.