Lipopolysaccharide, Immune Biomarkers and Cerebral Amyloid-Beta Deposition in Older Adults With Mild Cognitive Impairment & Major Depressive Disorder.

OBJECTIVE: Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). DESIGN: Cross-sectional analysis. SETTING: Five academic health centers in Toronto. PARTICIPANTS: Older adults with MCI with/without rMDD. MEASUREMENTS: We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation - Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography. RESULTS: Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta - 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22). CONCLUSION: In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition.

Agitation, Oxidative Stress, and Cytokines in Alzheimer Disease: Biomarker Analyses From a Clinical Trial With Nabilone for Agitation.

The endocannabinoid system has been a target of interest for agitation in Alzheimer disease (AD) because of potential behavioral effects and its potential impact on mechanisms implicated in AD such as oxidative stress (OS) and neuroinflammation. We explored whether serum markers of OS and neuroinflammation were associated with response to the cannabinoid nabilone in agitated patients with AD (N = 38). All participants were enrolled in a 14-week, double-blind, cross-over trial comparing nabilone to placebo (6 weeks each) with a 1-week washout between phases. Samples were collected at the start and end of each phase. The cross-sectional relationship agitation (Cohen Mansfield Agitation Inventory) and OS and inflammatory markers were investigated to select markers of interest. Significant markers were then explored for their relationship with response. The OS marker, 4-hydroxynonenal (4-HNE; F1, 35 = 6.41, P = .016), and the proinflammatory cytokine, tumor necrosis factor-α (TNF-α; F1, 29 = 3.97, P = .06), were associated with agitation severity, and TNF-α remained significantly associated (F2, 25 = 3.69, P = .04) after adjustment for cognition. In the placebo phase, lower baseline 4-HNE was associated with decreases in agitation severity only (b = 0.01, P = .01), while lower baseline TNF-α was associated with decreases in agitation severity in the nabilone phase only (b = 1.14, P = .045). Changes in 4-HNE were not associated with changes in agitation severity in either phase. In the nabilone phase, lower baseline TNF-α was associated with decreases in agitation severity (b = 1.14, P = .045), and decreases in TNF-α were associated with decreases in agitation severity (b = 1.12, P = .006). These findings suggest that OS and neuroinflammation may be associated with agitation severity, while nabilone may have anti-inflammatory effects.

Spontaneous oscillatory markers of cognitive status in two forms of dementia.

Abnormal oscillatory brain activity in dementia may indicate incipient neuronal/synaptic dysfunction, rather than frank structural atrophy. Leveraging a potential link between the degree of abnormal oscillatory activity and cognitive symptom severity, one could localize brain regions in a diseased but pre-atrophic state, which may be more amenable to interventions. In the current study, we evaluated the relationships among cognitive deficits, regional volumetric changes, and resting-state magnetoencephalography abnormalities in patients with mild cognitive impairment (MCI; N = 10; age: 75.9 ± 7.3) or primary progressive aphasia (PPA; N = 12; 69.7 ± 8.0), and compared them to normal aging [young (N = 18; 24.6 ± 3.5), older controls (N = 24; 67.2 ± 9.7]. Whole-brain source-level resting-state estimates of relative oscillatory power in the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), and beta (15-30 Hz) bands were combined with gray matter volumes and cognitive scores to examine between-group differences and brain-behavior correlations. Language and executive function (EF) abilities were impaired in patients with PPA, while episodic memory was impaired in MCI. Widespread oscillatory speeding and volumetric shrinkage was associated with normal aging, whereas the trajectory in PPA indicated widespread oscillatory slowing with additional volumetric reductions. Increases in delta and decreases in alpha power uniquely predicted group membership to PPA. Beyond volumetric reductions, more delta predicted poorer memory. In patients with MCI, no consistent group difference among oscillatory measures was found. The contributions of delta/alpha power on memory abilities were larger than volumetric differences. Spontaneous oscillatory abnormalities in association with cognitive symptom severity can serve as a marker of neuronal dysfunction in dementia, providing targets for promising treatments.

Randomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer's Disease.

OBJECTIVE: To investigate the efficacy and safety of nabilone for agitation in patients with moderate-to-severe Alzheimer's disease (AD). DESIGN: This 14-week randomized double-blind crossover trial compared nabilone to placebo (6 weeks each) with a 1-week washout between phases. SETTING: Patients were recruited from a long-term care facility and geriatric psychiatry clinics. PARTICIPANTS: Patients had AD (standardized Mini-Mental State Examination [sMMSE ≤24]) and agitation (Neuropsychiatric Inventory-Nursing Home version [NPI-NH]-agitation/aggression subscore ≥3). INTERVENTION: Nabilone (target 1-2 mg) versus placebo. MEASUREMENTS: The primary outcome was agitation (Cohen Mansfield Agitation Inventory [CMAI]). Secondary outcomes included NPI-NH total, NPI-NH caregiver distress, cognition (sMMSE and Severe Impairment Battery [SIB] or Alzheimer's Disease Assessment Scale of Cognition), global impression (Clinician's Global Impression of Change [CGIC]), and adverse events. RESULTS: Thirty-nine patients (mean ± SD age = 87 ± 10, sMMSE = 6.5 ± 6.8, CMAI = 67.9 ± 17.6, NPI-NH total = 34.3 ± 15.8, 77% male, nabilone dose = 1.6 ± 0.5 mg) were randomized. There were no crossover or treatment-order effects. Using a linear mixed model, treatment differences (95% CI) in CMAI (b = -4.0 [-6.5 to -1.5], t(30.2) = -3.3, p = 0.003), NPI-NH total (b = -4.6 [-7.5 to -1.6], t(32.9) = -3.1, p = 0.004), NPI-NH caregiver distress (b = -1.7 [-3.4 to -0.07, t(33.7) = -2.1, p = 0.041), and sMMSE (b = 1.1 [0.1-2.0], t(22.6) = 2.4, p = 0.026) all favored nabilone. However, in those who completed the SIB (n = 25) treatment differences favored placebo (b = -4.6 [-7.3 to -1.8], t(20.7) = -4.8, p = 0.003). CGIC improvement during nabilone (47%) and placebo (23%) was not significantly different (McNemar's test, exact p = 0.09). There was more sedation during nabilone (45%) compared to placebo (16%) phases (McNemar's test, exact p = 0.02), but treatment-limiting sedation was not significantly different (McNemar's test, exact p = 0.22). CONCLUSIONS: Nabilone may be an effective treatment for agitation. However, sedation and cognition should be closely monitored.

Negative Emotional Verbal Memory Biases in Mild Cognitive Impairment and Late-Onset Depression.

OBJECTIVE: Early and preferential targeting of limbic structures by Alzheimer disease (AD)-related pathology suggests emotion dysregulation may serve as a marker of AD risk. We studied emotional verbal memory in two groups at risk for AD, amnestic mild cognitive impairment (aMCI) and late-onset depression (LOD), to test the hypothesis that aMCI and LOD would be characterized by a negative bias in emotional memory, whereas cognitively normal (CN) adults would show the "positivity effect" associated with healthy aging. METHODS: Participants completed a novel test of emotional verbal memory, the Emotional Verbal Learning Test (EVeLT), consisting of a 15-item list of words with positive, negative, or neutral valence. Recall as a function of group and valence was analyzed using mixed analysis of variance. Spearman's rho was used to examine associations between EVeLT, mood, and executive function. MCI and CN participants had no current or past history of mood or anxiety disorders. aMCI participants met neuropsychological criteria for single-domain aMCI (sd-aMCI). LOD developed their first episode of depression at ≥60 years of age. RESULTS: CN adults recalled more positive words, whereas sd-aMCI and LOD adults recalled more negative, relative to neutral, words on the EVeLT. Positive emotional memory and negative attitudes regarding self were inversely correlated in CN adults. CONCLUSION: sd-aMCI and LOD groups show negative emotional memory biases, consistent with our hypothesis that emotion dysregulation is a signature of AD risk.

Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography study with translocator protein 18 kDa radioligand, [18F]-FEPPA.

The ability to quantify translocator protein 18 kDa (TSPO) in white matter (WM) is important to understand the role of neuroinflammation in neurological disorders with WM involvement. This article aims to extend the utility of TSPO imaging in WM using a second-generation radioligand, [18F]-FEPPA, and high-resolution research tomograph (HRRT) positron emission tomography (PET) camera system. Four WM regions of interests (WM-ROI), relevant to the study of aging and neuroinflammatory diseases, were examined. The corpus callosum, cingulum bundle, superior longitudinal fasciculus, and posterior limb of internal capsule were delineated automatically onto subject's T1 -weighted magnetic resonance image using a diffusion tensor imaging-based WM template. The TSPO polymorphism (rs6971) stratified individuals to three genetic groups: high-affinity binders (HAB), mixed-affinity binders (MAB), and low-affinity binders. [18F]-FEPPA PET scans were acquired on 32 healthy subjects and analyzed using a full kinetic compartment analysis. The two-tissue compartment model showed moderate identifiability (coefficient of variation 15-19%) for [18F]-FEPPA total volume distribution (VT ) in WM-ROIs. Noise affects VT variability, although its effect on bias was small (6%). In a worst-case scenario, ≤6% of simulated data did not fit reliably. A simulation of increased TSPO density exposed minimal effect on variability and identifiability of [18F]-FEPPA VT in WM-ROIs. We found no association between age and [18F]-FEPPA VT in WM-ROIs. The VT values were 15% higher in HAB than in MAB, although the difference was not statistically significant. This study provides evidence for the utility and limitations of [18F]-FEPPA PET to measure TSPO expression in WM.

A Cost-Benefit Analysis of a Group Memory Intervention for Healthy Older Adults with Memory Concerns.

This study examines whether memory intervention programs can mitigate health care costs. Research suggests these programs translate to a decreased intention of older adults who are worried about age-normal memory changes to seek traditional outlets for medical/psychiatric help. We employed a cost-benefit analysis approach to analyze the effectiveness of a memory intervention program within Ontario. We leveraged estimates of decreased intentionality to seek physician care following a community-based memory intervention with physician billing profiles to calculate the potential cost savings to the province's health care system. The intervention studied was found to reduce provincial health care spending by $6,094 per program group. This amount exceeds $121.25 in direct costs per attendee associated with administering five program sessions. This analysis justifies further research on how community-based memory and aging programs can offer low-cost solutions to help individuals cope with subjective memory complaints and assist the health care system in prioritizing care for aging patients.

Functional Connectivity Between the Posterior Default Mode Network and Parahippocampal Gyrus Is Disrupted in Older Adults with Subjective Cognitive Decline and Correlates with Subjective Memory Ability.

BACKGROUND: Subjective cognitive decline (SCD) is associated with increased risk of developing Alzheimer's disease (AD). However, the underlying mechanisms for this association remain unclear. Neuroimaging studies suggest the earliest AD-related changes are large-scale network disruptions, beginning in the posterior default mode (pDMN) network. OBJECTIVE: To examine the association between SCD and pDMN network connectivity with medial temporal lobe (MTL) regions using resting-state functional magnetic resonance imaging. METHODS: Forty-nine participants with either SCD (n = 23, 12 females; mean age: 70.7 (5.5)) or who were cognitively unimpaired (CU; n = 26, 16 females, mean age: 71.42 (7.3)) completed the Memory Functioning Questionnaire, a measure of subjective memory, and underwent resting state functional MRI at 3 Tesla. Functional connectivity between the posterior cingulate cortex (PCC), as the key pDMN node, and MTL regions were compared between SCD and CU groups. Further, the association between pDMN-MTL connectivity and the Frequency of Forgetting subscale of the Memory Functioning Questionnaire was examined. RESULTS: Connectivity between the PCC-MTL was observed in the CU group but was absent in SCD (t(47) = 2.69, p = 0.01). Across all participants, self-perception of frequency of forgetting, but not objective memory, was strongly correlated with connectivity between the PCC-left parahippocampal gyrus (r = 0.43, p = 0.002). CONCLUSION: These findings support the hypothesis that increased AD risk in SCD may be mediated by disrupted pDMN-parahippocampal connectivity. In addition, these findings suggest that frequency of forgetting may serve as a potential biomarker of SCD due to incipient AD.

Prefrontal GABA Levels Correlate with Memory in Older Adults at High Risk for Alzheimer's Disease.

γ-Aminobutyric acid (GABA), a primary inhibitory neurotransmitter in the brain, plays a significant role in aging and in neurodegenerative disorders, including Alzheimer's disease (AD). We investigated the relationship between GABA levels in the dorsomedial/dorsoanterolateral prefrontal cortex (DM/DA-PFC) and memory in high-AD risk participants. Thirty-eight participants (14 Cognitively Normal [CN], 11 with Subjective Cognitive Decline (SCD), and 13 Mild Cognitive Impairment [MCI]) underwent magnetic resonance spectroscopy at 3 Tesla. SCD and MCI participants were grouped together to form a single high-AD risk group (N = 24) for the purposes of statistical analyses. Partial correlations of GABA+/Cr level with verbal memory, assessed on California Verbal Learning Test-II, and nonverbal memory, assessed on Brief Visuospatial Memory Test and Rey-Osterrieth test, were examined separately within the high-AD risk and CN groups. GABA+/Cr levels were positively correlated with long-delayed verbal memory (r = 0.69, P = 0.009) and immediate nonverbal memory (r = 0.97, P = 0.03) in high-AD risk, but not in CN participants. These results remained significant after controlling for depression. These preliminary findings, which require replication due to the limited sample sizes, are the first report of an association between GABA+/Cr levels within the DM/DA-PFC and memory performance in high-AD risk individuals.

Structural Brain Magnetic Resonance Imaging to Rule Out Comorbid Pathology in the Assessment of Alzheimer's Disease Dementia: Findings from the Ontario Neurodegenerative Disease Research Initiative (ONDRI) Study and Clinical Trials Over the Past 10 Years.

BACKGROUND/OBJECTIVE: Structural brain magnetic resonance imaging (MRI) is not mandatory in Alzheimer's disease (AD) research or clinical guidelines. We aimed to explore the use of structural brain MRI in AD/mild cognitive impairment (MCI) trials over the past 10 years and determine the frequency with which inclusion of standardized structural MRI acquisitions detects comorbid vascular and non-vascular pathologies. METHODS: We systematically searched ClinicalTrials.gov for AD clinical trials to determine their neuroimaging criteria and then used data from an AD/MCI cohort who underwent standardized MRI protocols, to determine type and incidence of clinically relevant comorbid pathologies. RESULTS: Of 210 AD clinical trials, 105 (50%) included structural brain imaging in their eligibility criteria. Only 58 (27.6%) required MRI. 16,479 of 53,755 (30.7%) AD participants were in trials requiring MRI. In the observational AD/MCI cohort, 141 patients met clinical criteria; 22 (15.6%) had relevant MRI findings, of which 15 (10.6%) were exclusionary for the study. DISCUSSION: In AD clinical trials over the last 10 years, over two-thirds of participants could have been enrolled without brain MRI and half without even a brain CT. In a study sample, relevant comorbid pathology was found in 15% of participants, despite careful screening. Standardized structural MRI should be incorporated into NIA-AA diagnostic guidelines (when available) and research frameworks routinely to reduce diagnostic heterogeneity.

Cerebrovascular Pulsatility During Rest and Exercise Reflects Hemodynamic Impairment in Stroke and Cerebral Small Vessel Disease.

Although aerobic exercise is recommended as a core component of stroke rehabilitation, knowledge of acute cerebrovascular responses in patients is limited. This study tested the hypothesis that older adults with chronic stroke or cerebral small vessel disease (SVD) exhibit a greater increase in pulsatile hemodynamics during exercise compared with young and age-matched healthy adults. Middle cerebral artery blood flow velocity was acquired during 20 min of moderate intensity cycling in 51 participants from four groups (young, old, SVD and stroke). During rest, only the stroke group had a higher pulsatility index (PI) compared with the young group (1.02 ± 0.17 vs 0.83 ± 0.13; p = 0.038). During exercise, however, the SVD group exhibited a larger increase in PI (68 ± 20% relative to rest) than the young (47 ± 19%), old (45 ± 17%) and stroke (40 ± 25%) groups (p < 0.05, for each). The stress of aerobic exercise may reveal arterial dysfunction associated with latent and overt cerebrovascular disease.

Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer's disease: Study protocol for a cross-over randomized controlled trial.

Agitation is a prevalent and difficult-to-treat symptom in patients with moderate-to-severe Alzheimer's disease (AD). Though there are nonpharmacological and pharmacological interventions recommended for the treatment of agitation, the efficacy of these are modest and not always consistent. Furthermore, the safety profiles of currently prescribed medications are questionable. Nabilone, a synthetic cannabinoid, has a distinct pharmacological profile that may provide a safer and more effective treatment for agitation, while potentially having benefits for weight and pain. Additionally, emerging evidence suggests nabilone may have neuroprotective effects. We describe a clinical trial investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe AD. This will be a double-blind, randomized cross-over study comparing 6 weeks of nabilone (0.5-2 mg) and placebo, with a 1-week washout preceding each phase. Study outcomes will be measured at baseline and end of treatment for each treatment phase. The primary outcome measure will be agitation as assessed by the Cohen-Mansfield Agitation Inventory. The secondary outcomes include safety, behaviour (Neuropsychiatric Inventory), cognition (standardized Mini Mental Status Exam and either Severe Impairment Battery or Alzheimer's disease Assessment Scale-Cognitive subscale) and global impression (Clinician's Global Impression of Change). Exploratory outcomes include pain (Pain Assessment in Advanced AD), nutritional status (Mini-Nutritional Assessment-Short Form), caregiver distress (NPI caregiver distress), and blood-based biomarkers. A safe and efficacious pharmacological intervention for agitation, with effects on pain and weight loss in patients with moderate-to-severe AD could increase quality-of-life, reduce caregiver stress and avoid unnecessary institutionalization and related increases in health care costs. CLINICAL TRIALS NUMBER: NCT02351882.

24S-Hydroxycholesterol Is Associated with Agitation Severity in Patients with Moderate-to-Severe Alzheimer's Disease: Analyses from a Clinical Trial with Nabilone.

BACKGROUND: Agitation is a prevalent and difficult-to-treat symptom of Alzheimer's disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1. OBJECTIVE: To assess whether 24S-OHC was associated with agitation severity and response to nabilone. METHODS: 24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression). RESULTS: 24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = -35.2, 95% CI -65.6 to -5.0, p = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = -20.94, 95% CI -57.9 to -4.01, p = 0.03). CONCLUSION: 24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone.

Association between Sleep Disturbances and Medial Temporal Lobe Volume in Older Adults with Mild Cognitive Impairment Free of Lifetime History of Depression.

BACKGROUND: Previous studies examining the link between neuropsychiatric symptoms (NPS) and biomarkers of Alzheimer's disease (AD) may be confounded by remitted or past history of psychiatric illness, which in itself is associated with AD biomarkers such as reduced medial temporal lobe (MTL) volume. OBJECTIVE: We examined associations between mood and anxiety-related NPS and MTL in older adults with mild cognitive impairment (MCI) free of lifetime history of depression. We hypothesized an inverse relationship between NPS severity and MTL. METHODS: Forty-two MCI participants without current or past history of depression or other major psychiatric illness were assessed using the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Correlation and regression analyses were performed between selected NPI-Q items and regional MTL volumes from structural magnetic resonance imaging. RESULTS: Sleep disturbances were inversely associated with several regional volumes within the MTL. Sleep disturbances remained significantly correlated with left hippocampal and amygdala volume following correction for multiple comparisons. In contrast, depression and anxiety were not correlated with MTL. CONCLUSIONS: The relationship between reduced MTL and sleep, but not with depressed or anxious states, in MCI free of lifetime history of depression, suggests a potential mechanism for sleep as a risk factor for AD. The current findings highlight the importance of accounting for remitted psychiatric conditions in studies of the link between NPS and AD biomarkers and support the need for further research on sleep as clinical biomarker of AD and target for AD prevention.

Imaging microglial activation and amyloid burden in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) is defined as a transitional state between normal aging and Alzheimer's disease (AD). Given the replicated finding of increased microglial activation in AD, we sought to investigate whether microglial activation is also elevated in aMCI and whether it is related to amyloid beta (Aß) burden in-vivo . Eleven aMCI participants and 14 healthy volunteers completed positron emission tomography (PET) scans with [18F]-FEPPA and [11C]-PIB. Given the known sensitivity in affinity of second-generation TSPO radioligands, participants were genotyped for the TSPO polymorphism and only high-affinity binders were included. Dynamic [18F]-FEPPA PET images were analyzed using the 2-tissue compartment model with arterial plasma input function. Additionally, a supplementary method, the standardized uptake value ratio (SUVR), was explored. [11C]-PIB PET images were analyzed using the Logan graphical method. aMCI participants had significantly higher [11C]-PIB binding in the cortical regions. No significant differences in [18F]-FEPPA binding were observed between aMCI participants and healthy volunteers. In the aMCI group, [18F]-FEPPA and [11C]-PIB bindings were correlated in the hippocampus. There were no correlations between our PET measures and cognition. Our findings demonstrate that while Aß burden is evident in the aMCI stage, microglial activation may not be present.

Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking.

CONTEXT: Adaptations in gamma-aminobutyric acid type A (GABA(A))-benzodiazepine receptors contribute to the neurobiology of human alcohol dependence and withdrawal. OBJECTIVE: To study GABA(A)-benzodiazepine receptor adaptations in subjects with alcohol dependence over the first month of sobriety. DESIGN: Inpatients who were not receiving medication, were either smokers or nonsmokers, and had alcohol dependence completed 2 iodine I 123-labeled iomazenil single-photon emission computed tomographic scans: 1 scan at a mean +/- SD of 4.9 +/- 2.5 days of sobriety (n = 23) and 1 scan at a mean +/- SD of 29.8 +/- 7.6 days of sobriety (n = 20). Participants in a matched group of healthy subjects (n = 15) completed 1 single-photon emission computed tomographic scan. PARTICIPANTS: Men with alcohol dependence (n = 27) and a matched healthy comparison group (n = 15). MAIN OUTCOME MEASURES: (123)I-iomazenil single-photon emission computed tomographic images were converted to units of distribution volume (regional activity/free (123)I-iomazenil) and were analyzed using voxel-based statistical parametric mapping and regions of interest analyses. The relationships between (123)I-iomazenil distribution volume, clinical features of alcohol dependence, and smoking status were evaluated. RESULTS: (123)I-iomazenil uptake was elevated in several cortical regions, with a more prominent increase in nonsmokers with alcohol dependence as compared with smokers with alcohol dependence at 1 week of abstinence from alcohol. No significant differences were observed at 4 weeks of abstinence. At 1 week of abstinence, frontal (123)I-iomazenil uptake correlated with the severity of alcohol withdrawal and the number of days since the last alcoholic drink was consumed. No significant associations were observed for smokers with alcohol dependence. CONCLUSIONS: These data demonstrate time-dependent regulation of cortical GABA(A)-benzodiazepine receptors associated with the recovery from alcohol dependence. Higher GABA(A)-benzodiazepine receptor levels during acute withdrawal may reflect a compensation for reduced receptor function, which is thought to contribute to alcohol tolerance and withdrawal. The subsequent decline may reflect "normalization" of GABA(A) receptor function with sobriety. Smoking may attenuate GABA(A) receptor adaptations associated with alcohol dependence and may contribute to the comorbidity between alcoholism and smoking.

Acetylcholinergic neurotransmission and the beta-amyloid cascade: implications for Alzheimer's disease.

Alzheimer's disease is characterized by both decreases in acetylcholinergic neurotransmission and increases in beta-amyloid accumulation. Currently, available clinical psychopharmacologic treatment is focused on increasing acetylcholinergic neurotransmission, whereas no clinical treatments to directly reduce beta-amyloid accumulation are available. Cholinesterase inhibitors improve cognition, certain neuropsychiatric symptoms and functional impairment in patients with mild-to-moderate Alzheimer's disease, and it is believed that this is mainly symptomatic treatment. However, this review discusses various levels of interaction between acetylcholinergic neurotransmission and the beta-amyloid cascade, which suggest that some specific acetylcholinergic treatments may reduce beta-amyloid accumulation, and therefore may slow disease progression over the long term. Various suggestions are made on how such potential disease-modifying effects could be studied in the future.

Effect of subthalamic stimulation on mood state in Parkinson's disease: evaluation of previous facts and problems.

In an attempt to clarify the effect of deep brain stimulation (DBS) to the subthalamic nucleus (STN) on mood state, previous evidence and problems were evaluated through a systematic literature search. Twenty three articles reported the effect of STN DBS on mood state in Parkinson's disease (PD), and antidepressant, depressant, and mania-induced effects were reported in 16.7-76%, 2-33.3%, and 4.2-8.1% of the patients treated with STN DBS, respectively. Most articles reported larger subgroups showing antidepressant effects than those showing depressant effects. The average depression scale score of all subjects was improved or unchanged after STN DBS. Although there was a limitation due to the varied results, it was suggested that, in general, STN DBS had an antidepressant effect in PD. However, the studies reporting severe depressant symptoms, such as suicidal attempts, after STN DBS indicated the importance of careful attention to mood state as well as to motor symptoms after STN DBS. It may be crucial to reduce the variation in the results by, for example, the use of standardized protocols and the precise verification of the stimulated region in further investigations to address this issue.