Cerebral blood flow and gray matter volume covariance patterns of cognition in aging

Advancing age results in altered cognitive and neuroimaging‐derived markers of neural integrity. Whether cognitive changes are the result of variations in brain measures remains unclear and relating the two across the lifespan poses a unique set of problems. It must be determined whether statistical associations between cognitive and brain measures truly exist and are not epiphenomenal due solely to their shared relationships with age. The purpose of this study was to determine whether cerebral blood flow (CBF) and gray matter volume (GMV) measures make unique and better predictions of cognition than age alone. Multivariate analyses identified brain‐wide covariance patterns from 35 healthy young and 23 healthy older adults using MRI‐derived measures of CBF and GMV related to three cognitive composite scores (i.e., memory, fluid ability, and speed/attention). These brain‐cognitive relationships were consistent across the age range, and not the result of epiphenomenal associations with age and each imaging modality provided its own unique information. The CBF and GMV patterns each accounted for unique aspects of cognition and accounted for nearly all the age‐related variance in the cognitive composite scores. The findings suggest that measures derived from multiple imaging modalities explain larger amounts of variance in cognition providing a more complete understanding of the aging brain. Hum Brain Mapp 34:3267–3279, 2013. © 2012 Wiley Periodicals, Inc.     

The 5‐HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans

The cerebral serotonin (5‐HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5‐HT type 4 receptor (5‐HT₄R) facilitates memory and learning and further that the 5‐HT₄R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5‐HT₄R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [¹¹C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5‐HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP_ND, (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP_ND and delayed recall (p = 0.014). These findings provide evidence that the 5‐HT₄R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp 34:3066–3074, 2013. © 2012 Wiley Periodicals, Inc.     

Auditory temporal envelope processing in a patient with left-hemisphere damage

Abstract

Auditory temporal envelope processing was investigated in a patient showing a mild speech identification impairment following left-hemisphere damage. Three tasks evaluated the patient's ability to: (1) detect a sinusoidal amplitude modulation (SAM) applied to a white noise, as a function of modulation rate (i.e. her ‘temporal modulation transfer function’ or TMTF); (2) discriminate between two white noises amplitude modulated by time-reversed temporally asymmetric envelopes; and (3) identify white noises amplitude modulated by the temporal envelope of speech stimuli. Measurements of intensity discrimination thresholds were performed as a control task. Compared to normal data, the results obtained with the brain-damaged patient showed: (1) increased thresholds for the detection of SAM; (2) increased thresholds for the discrimination of temporal asymmetry; and (3) a deficit in the identification of speechenvelope noise stimuli. In contrast, intensity discrimination thresholds were within the normal range. Taken together, the results indicate a general impairment in auditory temporal acuity, which is now specified as a deficit in the coding of envelope rate and shape, and a deficit in the ability to use temporal envelope cues in speech processing. These results support the hypothesis that left-hemisphere damage is associated with an impairment in time analysis, which may cause, in turn, speech intelligibility disorders.     

Assessing and Treating Different Suicidal States in a Danish Outpatient Sample

The studies presented compare two methodologies for categorizing suicidal patients based on clinical data. Discussion follows regarding implications for risk assessment and treatment. In these studies, 52 outpatient subjects were placed into different groups based on coding their “suicidal motivation” (Study 1) and their “internal struggle” ratings (Study 2) using data collected at intake. Self-report ratings of 6 Suicide Status Form (SSF) Core Constructs (Psychological Pain, Stress, Agitation, Hopelessness, Self-Hate, and Overall Risk of Suicide) recorded both at intake and at completion of treatment were then compared to determine differences in Core Construct ratings among groups at different time points. In Study 1, overall differences among motivation groups (Life-motivated, Ambivalent, and Death-motivated) were significant for ratings at treatment completion of Overall Risk of Suicide, Self-Hate, and Psychological Pain. In Study 2, overall differences among groups (Wish to live, Ambivalent, and Wish to die) were significant for ratings at intake of Overall Risk of Suicide. At completion of treatment, overall differences among groups were significant for ratings of Overall Risk of Suicide, Hopelessness, and Self-Hate. In addition, significant interactions were found between test time and group for Overall Risk of Suicide and Self-Hate. Results suggest that categorizing suicidal patients by motivation and by the nature of their internal struggle could be beneficial to differential risk assessment with implications for clinical treatment.     

Derivation of a Composite Measure of Embedded Symptom Validity Indices

Assessment of effort on cognitive testing has become a suggested standard in both forensic and clinical neuropsychological assessment. Both stand-alone and empirically derived embedded measures have been developed, however guidelines for combining several measures are not always available. This study used logistic regression analysis to derive a multivariable composite to detect suboptimal effort using scores extracted from commonly administered neuropsychological tests. A model predicting suboptimal effort, as defined by performance on the Medical Symptom Validity Test, was created with 124 participants using variables from the California Verbal Learning test 2nd edition, Rey Complex Figure Test and the Wechsler Memory Scale 3rd edition. The model reliably predicted suboptimal effort (χ^2?=?44.37, p?<?.001) with excellent discrimination (AUC?=?.84).     

Anti-N-Methyl-D-Aspartate Receptor Encephalitis with Favorable Outcome Despite Prolonged Status Epilepticus

Background

To describe a case of auto-immune encephalitis in an adolescent with favorable outcome despite prolonged status epilepticus.

Methods

A 17 year old Asian man without previous medical history developed alteration of consciousness and partial seizures. The diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was confirmed by the detection of specific antibodies in both cerebrospinal fluid and serum.

Results

The clinical course was complicated by prolonged status epilepticus which was refractory to a large number of antiepileptic drugs, including barbiturate coma. Immunomodulatory therapy included steroids, plasma exchanges, and intravenous immunoglobulins. After 86 days of intensive therapy, the patient regained consciousness progressively. Brain magnetic resonance imaging never demonstrated any lesion. Extensive search for a tumor was negative. At 12 month follow-up, the patient had made an excellent recovery.

Conclusion

Auto-immune encephalitis is likely underdiagnosed in adolescents. In their most severe presentation, seizures may be resistant to a large number of anti-epileptic drugs, and the clinical improvement seems to be mainly because of the immunomodulatory therapy. Relapse is possible, as well as the delayed development of a teratoma or other tumor.     

Intrathecal Saline Infusion: An Emergency Procedure in a Patient with Spontaneous Intracranial Hypotension

Background

Spontaneous intracranial hypotension (SIH) is a neurologic condition with the prototypical symptom of orthostatic headache. We report a dramatic case of SIH with life-threatening bilateral hygroma and uncal herniation.

Methods

Case report.

Results

A 44-year-old male patient presenting with orthostatic headache and double vision was diagnosed with SIH. Diagnostic imaging showed meningeal enhancement and bilateral hygroma. A conservative treatment regime was initiated. The patient’s condition rapidly deteriorated with progressive loss of consciousness. Cranial MRI showed beginning uncal herniation. As an emergency treatment measure, an intracranial pressure (ICP) probe was inserted and intrathecal lumbal saline infusion was initiated. This led to a stabilization of ICP and allowed further diagnostics and treatment.

Conclusion

Intrathecal lumbal saline infusion in combination with ICP monitoring can be a life-saving treatment option in unstable SIH patients.     

Insights into the structural biology of G-protein coupled receptors impacts drug design for central nervous system neurodegenerative processes**

In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selectivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and orthosteric binding sites on dopamine receptors for the treatment of Parkinson’s disease, and on muscarinic receptors for Alzheimer’s disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopamine receptor holds promise as a relevant therapeutic strategy for Parkinson’s disease. Regarding the treatment of Alzheimer’s disease, the design of dualsteric ligands for mono-oligomeric muscarinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.