Prevalence of mild behavioral impairment in mild cognitive impairment and subjective cognitive decline, and its association with caregiver burden.

BACKGROUND: Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic. METHODS: MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment - Alzheimer's Association (ISTAART-AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden. RESULTS: While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001). CONCLUSIONS: MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome.

Prevalence of problem and pathological gambling in Parkinson's disease.

Pathological gambling (PG) has been identified in patients with Parkinson's disease (PD) treated with dopamine agonists suggesting that dysregulation of brain dopaminergic activity may contribute to the development of gambling problems. The current study was undertaken to further establish the prevalence of problem and PG in patients with PD, identify any clinical correlates, and determine if psychiatric or substance use co-morbidity contributes to the increased prevalence of problem and PG. A cross-sectional survey of 140 serially recruited moderate to severe PD patients was undertaken utilizing the Canadian Problem Gambling Index, Alcohol Use Disorders Identification Test, Drug Abuse Screening Test, Beck Depression Inventory, Beck Anxiety Inventory, and Mini-Mental State Exam augmented by chart review, completed over an 8 month period. The 12 month prevalence of problem and PG in PD was 9.3% compared to 1.6% in the general population within a comparably aged sample. The increased prevalence of problem and PG in the PD group was related to dopamine agonist use and younger age, but not co-morbidity. Most subjects with problem and PG reported their gambling increased after being diagnosed with PD and starting treatment. The results suggest that brain dopaminergic activity is involved in the underlying neurobiology of problem and PG.

Pathological gambling associated with dopamine agonist use in restless legs syndrome.

Dopamine agonists (DA) have been associated with pathological gambling (PG) and other compulsive behaviors in Parkinson's disease (PD). Although these medications are used in other conditions, we are not aware of other reports of PG exclusive to treatment for idiopathic PD. We present a case of PG arising in the context of DA use for restless legs syndrome.

Cue-induced brain activity in pathological gamblers.

BACKGROUND: Previous studies using functional magnetic resonance imaging (fMRI) have identified differential brain activity in healthy subjects performing gambling tasks and in pathological gambling (PG) subjects when exposed to motivational and emotional predecessors for gambling as well as during gambling or response inhibition tasks. The goal of the present study was to determine if PG subjects exhibit differential brain activity when exposed to visual gambling cues. METHODS: Ten male DSM-IV-TR PG subjects and 10 matched healthy control subjects underwent fMRI during visual presentations of gambling-related video alternating with video of nature scenes. RESULTS: Pathological gambling subjects and control subjects exhibited overlap in areas of brain activity in response to the visual gambling cues; however, compared with control subjects, PG subjects exhibited significantly greater activity in the right dorsolateral prefrontal cortex (DLPFC), including the inferior and medial frontal gyri, the right parahippocampal gyrus, and left occipital cortex, including the fusiform gyrus. Pathological gambling subjects also reported a significant increase in mean craving for gambling after the study. Post hoc analyses revealed a dissociation in visual processing stream (dorsal vs. ventral) activation by subject group and cue type. CONCLUSIONS: These findings may represent a component of cue-induced craving for gambling or conditioned behavior that could underlie pathological gambling.

Brain neuroimaging in cannabis use: a review.

In this study, the authors systematically reviewed structural and functional neuroimaging studies of cannabis use. Structural abnormalities generally have not been identified with chronic use. Regular users demonstrate reciprocal changes in brain activity globally and in cerebellar and frontal regions. Abstinence results in decreases, and administration results in increases correlating with subjective intoxication. Chronic use and cannabis administration result in attenuated brain activity in task-activated regions or activation of compensatory regions. Findings correlate partially with neuropsychological data, but generalization is limited by the lack of use of diagnostic criteria, appropriately paired neuropsychological testing or means to better quantify cannabis use and abstinence.

Genetics and alcoholism: how close are we to potential clinical applications?

Rapid advancement of genetic knowledge has provided a wealth of data demonstrating a significant contribution of genes to the development of alcoholism but has suggested little in the way of clinical applicability. Twin and adoption studies suggest that 50% to 60% of the development of alcoholism is due to heritable factors, and linkage and association studies have identified chromosomal regions and individual genes that likely contribute to the development of this condition. Most of these genes are related to neurotransmitter systems and to alcohol metabolizing enzymes. We briefly review the evidence for this before discussing intermediate phenotypes of alcoholism under genetic control, pharmacogenetic aspects of alcoholism treatment, and the possibility of future clinical applications based on these areas.

The smaller isoforms of ankyrin 3 bind to the p85 subunit of phosphatidylinositol 3'-kinase and enhance platelet-derived growth factor receptor down-regulation.

The Src homology 2 (SH2) domains of the p85 subunit of phosphatidylinositol 3'-kinase have been shown to bind to the tyrosine-phosphorylated platelet-derived growth factor receptor (PDGFR). Previously, we have demonstrated that p85 SH2 domains can also bind to the serine/threonine kinase A-Raf via a unique phosphorylation-independent interaction. In this report, we describe a new phosphotyrosine-independent p85 SH2-binding protein, ankyrin 3 (Ank3). In general, ankyrins serve a structural role by binding to both integral membrane proteins at the plasma membrane and spectrin/fodrin proteins of the cytoskeleton. However, smaller isoforms of Ank3 lack the membrane domain and are localized to late endosomes and lysosomes. We found that p85 binds directly to these smaller 120- and 105-kDa Ank3 isoforms. Both the spectrin domain and the regulatory domain of Ank3 are involved in binding to p85. At least two domains of p85 can bind to Ank3, and the interaction involving the p85 C-SH2 domain was found to be phosphotyrosine-independent. Overexpression of the 120- or 105-kDa Ank3 proteins resulted in significantly enhanced PDGFR degradation and a reduced ability to proliferate in response to PDGF. Ank3 overexpression also differentially regulated signaling pathways downstream from the PDGFR. Chloroquine, an inhibitor of lysosomal-mediated degradation pathways, blocked the ability of Ank3 to enhance PDGFR degradation. Immunofluorescence experiments demonstrated that both small Ank3 isoforms colocalized with the lysosomal-associated membrane protein and with p85 and the PDGFR. These results suggest that Ank3 plays an important role in lysosomal-mediated receptor down-regulation, likely through a p85-Ank3 interaction.