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"Brain Chemistry"
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Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease
Parkinson’s disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.
Journal Article
Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease
Verubecestat, an orally administered inhibitor of BACE-1, reduces amyloid concentration in the cerebrospinal fluid. In a randomized, 78-week trial involving patients with mild or moderate Alzheimer’s disease, the drug did not slow cognitive decline as compared with placebo.
Journal Article
Identifying Neurobiological Phenotypes Associated with Alcohol Use Disorder Severity
Although numerous studies provide general support for the importance of genetic factors in the risk for alcohol use disorders (AUDs), candidate gene and genome-wide studies have yet to identify a set of genetic variations that explain a significant portion of the variance in AUDs. One reason is that alcohol-related phenotypes used in genetic studies are typically based on highly heterogeneous diagnostic categories. Therefore, identifying neurobiological phenotypes related to neuroadaptations that drive the development of AUDs is critical for the future success of genetic and epigenetic studies. One such neurobiological phenotype is the degree to which exposure to alcohol taste cues recruits the basal ganglia, prefrontal cortex, and motor areas, all of which have been shown to have a critical role in addictive behaviors in animal studies. To that end, this study was designed to examine whether cue-elicited responses of these structures are associated with AUD severity in a large sample (
n
=326) using voxelwise and functional connectivity measures. Results suggested that alcohol cues significantly activated dorsal striatum, insula/orbitofrontal cortex, anterior cingulate cortex, and ventral tegmental area. AUD severity was moderately correlated with regions involved in incentive salience such as the nucleus accumbens and amygdala, and stronger relationships with precuneus, insula, and dorsal striatum. The findings indicate that AUDs are related to neuroadaptations in these regions and that these measures may represent important neurobiological phenotypes for subsequent genetic studies.
Journal Article
The dividing sky
In 2460, eighteen-year-old Liv Newman dreams of a future beyond her lower-class life in the Metro. As a Proxy, she uses the neurochip in her brain to sell memories to wealthy clients. Maybe a few illegally, but money equals freedom. So when a customer offers her a ludicrous sum to go on an assignment in no-man's-land, Liv accepts. Now she just has to survive. Rookie Forceman Adrian Rao believes in order over all. After discovering that a renegade Proxy s shady dealings are messing with citizens brain chemistry, he vows to extinguish the threat. But when he tracks Liv down, there s one problem: her memories are gone. Can Adrian bring himself to condemn her for crimes she doesn t remember?
BOOK
Association between ADORA2A and DRD2 Polymorphisms and Caffeine-Induced Anxiety
Caffeine produces mild psychostimulant and sometimes anxiogenic effects by antagonizing adenosine at A
1
and A
2A
receptors, and perhaps through interactions with other transmitter systems. Adenosine receptors are colocalized and functionally interact with dopamine receptors in the brain. Thus, functional polymorphisms in the genes for either adenosine or dopamine receptors may affect responses to caffeine. In this study, we examined associations between self-reported anxiogenic effects of caffeine and variation in the genes for A
2A
(
ADORA2A
) and DRD
2
(
DRD2
) receptors. Healthy male and female individuals (
n
=102), who consumed less than 300 mg caffeine per week, ingested capsules containing 0, 50, 150, and 450 mg caffeine under double-blind conditions in four separate experimental sessions. Subjective anxiety was measured before and at repeated times after capsules were consumed. At the 150 mg dose of caffeine, we found a significant association between caffeine-induced anxiety (Visual Analog Scales, VAS) and
ADORA2A
rs5751876 (1976C/T), rs2298383 (intron 1a) and rs4822492 (3′-flank), and
DRD2
rs1110976 (intron 6). Caffeine-induced anxiety (VAS) was also associated with two-loci interactions of selected
ADORA2A
and
DRD2
polymorphisms. The lowest dose of caffeine did not increase ratings of anxiety while the highest dose increased anxiety in the majority of subjects. These findings provide support for an association between an
ADORA2A
polymorphism and self-reported anxiety after a moderate dose of caffeine. It is likely that other
ADORA2A
and
DRD2
polymorphisms also contribute to responses to caffeine.
Journal Article
Man and woman : an inside story
\"The saga of sex differences in brain and behavior begins with a tiny sperm swimming toward a huge egg, to contribute its tiny Y chromosome plus its copies of the other chromosomes. Genetic, anatomic and physiologic alterations in the male ensue, making his brain and behavior different in specific respects from his sister. Brain-wise, specific cell groups develop differently in males compared to females, in some cases right after birth and in other cases at puberty. But genetics and neuroanatomy do not dominate the scene. Prenatal stress, postnatal stress and lousy treatment at puberty all can affect males and females in different ways. The upshot of all these genetic and environmental factors produces small sex differences in certain abilities and huge sex differences in feelings, in pain and in suffering. Put this all together and the reader will see that biological and cultural influences on gender roles operate at so many different levels to influence behavioral mechanisms that gender role choices are flexible, reversible and non-dichotomous, especially in modern societies.\"--Book jacket.
Book
Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia
The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (
n
=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33),
p
=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (
r
s
=0.81,
p
=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (
r
s
=0.74,
p
=0.046). In addition, baseline pregnenolone (
r
s
=−0.76,
p
=0.037), pregnenolone sulfate (
r
s
=−0.83,
p
=0.015), and allopregnanolone levels (
r
s
=−0.83,
p
=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (
r
s
=0.74,
p
<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
Journal Article