Independent and combined effects of methamphetamine use disorders and APOEε4 allele on cognitive performance and brain morphometry.

AIMS: Prior studies showed that methamphetamine (METH) users had greater than normal age-related brain atrophy; whether having the apolipoprotein E (APOE)-ε4 allele may be a contributory factor has not been evaluated. We aimed to determine the independent and combined effects of chronic heavy METH use and having at least one copy of the APOE-ε4 allele (APOE-ε4+) on brain morphometry and cognition, especially in relation to aging. METHODS: We compared brain morphometry and cognitive performance in 77 individuals with chronic heavy METH use (26 APOE-ε4+, 51 APOE-ε4-) and 226 Non-METH users (66 APOE-ε4+, 160 APOE-ε4-), using a 2 × 2 design (two-way analysis of co-variance). Vertex-wise cortical volumes, thickness and seven subcortical volumes, were automatically measured using FreeSurfer. Linear regression between regional brain measures, and cognitive scores that showed group differences were evaluated. Group differences in age-related decline in brain and cognitive measures were also explored. RESULTS: Regardless of APOE-ε4 genotype, METH users had lower Motor Z-scores (P = 0.005), thinner right lateral-orbitofrontal cortices (P < 0.001), smaller left pars-triangularis gyrus volumes (P = 0.004), but larger pallida, hippocampi and amygdalae (P = 0.004-0.006) than nonusers. Across groups, APOE-ε4+ METH users had the smallest volumes of superior frontal cortical gyri bilaterally, and of the smallest volume in left rostral-middle frontal gyri (all P-values <0.001). Smaller right superior-frontal gyrus predicted poorer motor function only in APOE-ε4+ participants (interaction-P < 0.001). Cortical volumes and thickness declined with age similarly across all participants; however, APOE-ε4-carriers showed thinner right inferior parietal cortices than noncarriers at younger age (interaction-P < 0.001). CONCLUSIONS: Chronic heavy use and having at least one copy of the APOE-ε4 allele may have synergistic effects on brain atrophy, particularly in frontal cortices, which may contribute to their poorer cognitive function. However, the enlarged subcortical volumes in METH users replicated prior studies, and are likely due to METH-mediated neuroinflammation.

Neuronal and Glial Metabolite Abnormalities in Participants With Persistent Neuropsychiatric Symptoms After COVID-19: A Brain Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: The aim of this study was to determine whether neurometabolite abnormalities indicating neuroinflammation and neuronal injury are detectable in individuals post-coronavirus disease 2019 (COVID-19) with persistent neuropsychiatric symptoms. METHODS: All participants were studied with proton magnetic resonance spectroscopy at 3 T to assess neurometabolite concentrations (point-resolved spectroscopy, relaxation time/echo time = 3000/30 ms) in frontal white matter (FWM) and anterior cingulate cortex-gray matter (ACC-GM). Participants also completed the National Institutes of Health Toolbox cognition and motor batteries and selected modules from the Patient-Reported Outcomes Measurement Information System. RESULTS: Fifty-four participants were evaluated: 29 post-COVID-19 (mean ± SD age, 42.4 ± 12.3 years; approximately 8 months from COVID-19 diagnosis; 19 women) and 25 controls (age, 44.1 ± 12.3 years; 14 women). When compared with controls, the post-COVID-19 group had lower total N-acetyl compounds (tNAA; ACC-GM: -5.0%, P = .015; FWM: -4.4%, P = .13), FWM glutamate + glutamine (-9.5%, P = .001), and ACC-GM myo-inositol (-6.2%, P = .024). Additionally, only hospitalized patients post-COVID-19 showed age-related increases in myo-inositol, choline compounds, and total creatine (interaction P = .029 to <.001). Across all participants, lower FWM tNAA and higher ACC-GM myo-inositol predicted poorer performance on several cognitive measures (P = .001-.009), while lower ACC-GM tNAA predicted lower endurance on the 2-minute walk (P = .005). CONCLUSIONS: In participants post-COVID-19 with persistent neuropsychiatric symptoms, the lower-than-normal tNAA and glutamate + glutamine indicate neuronal injury, while the lower-than-normal myo-inositol reflects glial dysfunction, possibly related to mitochondrial dysfunction and oxidative stress in Post-COVID participants with persistent neuropsychiatric symptoms.

Contributions of chronic tobacco smoking to HIV-associated brain atrophy and cognitive deficits.

OBJECTIVES: Tobacco smoking is linked to cognitive deficits and greater white matter (WM) abnormalities in people with HIV disease (PWH). Whether tobacco smoking additionally contributes to brain atrophy in PWH is unknown and was evaluated in this study. DESIGN: We used a 2 × 2 design that included 83 PWH (43 nonsmokers, 40 smokers) and 171 HIV-seronegative (SN, 106 nonsmokers, 65 smokers) participants and assessed their brain structure and cognitive function. METHODS: Selected subcortical volumes, voxel-wise cortical volumes and thickness, and total WM volume were analyzed using FreeSurfer. Independent and interactive effects of HIV and smoking were evaluated with two-way analysis of covariance on cognitive domain Z-scores and morphometric measures on T1-weighted MRI. RESULTS: Regardless of smoking status, relative to SN, PWH had smaller brain volumes [basal ganglia, thalami, hippocampi, subcortical gray matter (GM) and cerebral WM volumes (P = 0.002-0.042)], steeper age-related declines in the right superior-parietal (interaction: P < 0.001) volumes, and poorer attention/working memory and learning (P = 0.016-0.027). Regardless of HIV serostatus, smokers tended to have smaller hippocampi than nonsmokers (-0.6%, P = 0.055). PWH smokers had the smallest total and regional subcortical GM and cortical WM volume and poorest cognitive performance. CONCLUSIONS: Tobacco smoking additionally contributed to brain atrophy and cognitive deficits in PWH. The greater brain atrophy in PWH smokers may be due to greater neuronal damage or myelin loss in various brain regions, leading to their poor cognitive performance. Therefore, tobacco smoking may exacerbate or increase the risk for HIV-associated neurocognitive disorders.

Greater Sensorimotor Deficits and Abnormally Lower Globus Pallidus Fractional Anisotropy in HIV+ Women than in HIV+ Men.

AIMS: Cognitive impairment may be greater in HIV-positive (HIV+) women than in HIV+ men. Whether sex-specific differences exist in brain microstructure of HIV+ individuals is unknown and was evaluated. METHOD: 39 HIV+ (21 men, 18 women) and 45 seronegative (SN, 20 men, 25 women) participants were assessed with brain diffusion tensor imaging and cognitive assessments (7 neuropsychological domains). Fractional anisotropy (FA) and mean diffusivity (MD) were measured with an automated atlas in selected brain regions. Group comparisons were assessed with linear mixed effects models, with sub-regions and hemisphere (left/right) as repeated factors for each region. RESULTS: HIV+ women, but not HIV+ men, were slower than sex-matched SN controls on sensorimotor function (Dominant-hand: interaction-p = 0.007; Non-dominant hand: interaction-p = 0.039). Similarly, only HIV+ women had lower FA in the globus pallidus (GP, interaction-p = 0.011). Additionally, regardless of sex, the HIV+ group had poorer Fluency, Speed, and Attention than SN-controls (p = 0.006-0.008), as well as lower FA and higher MD in multiple brain regions (p = <0.001-0.044). Across all participants, performance on Attention was predicted by uncinate-FA (p < 0.001, r = 0.5) and corpus callosum (CC)-FA (p = 0.038, r = 0.23), while the Speed of Information Processing was predicted by CC-FA (p = 0.009, r = 0.3). Furthermore, faster sensorimotor function correlated with higher CC-FA and uncinate-FA in men but not in women (Sex*DTI-interaction-p = 0.03-0.06). CONCLUSIONS: The relatively poorer sensorimotor function and abnormally lower GP_FA, suggesting lesser neuronal integrity, in HIV+ women demonstrate sex-specific effects from HIV-infection on these measures. These findings may be related to the greater immune activation and neuroinflammation in HIV+ women compared to HIV+ men. Graphical Abstract.

Microstructural brain abnormalities in HIV+ individuals with or without chronic marijuana use.

OBJECTIVE: Cognitive deficits and microstructural brain abnormalities are well documented in HIV-positive individuals (HIV+). This study evaluated whether chronic marijuana (MJ) use contributes to additional cognitive deficits or brain microstructural abnormalities that may reflect neuroinflammation or neuronal injury in HIV+. METHOD: Using a 2 × 2 design, 44 HIV+ participants [23 minimal/no MJ users (HIV+), 21 chronic active MJ users (HIV + MJ)] were compared to 46 seronegative participants [24 minimal/no MJ users (SN) and 22 chronic MJ users (SN + MJ)] on neuropsychological performance (7 cognitive domains) and diffusion tensor imaging metrics, using an automated atlas to assess fractional anisotropy (FA), axial (AD), radial (RD), and mean (MD) diffusivities, in 18 cortical and 4 subcortical brain regions. RESULTS: Compared to SN and regardless of MJ use, the HIV+ group had lower FA and higher diffusivities in multiple white matter and subcortical structures (p < 0.001-0.050), as well as poorer cognition in Fluency (p = 0.039), Attention/Working Memory (p = 0.009), Learning (p = 0.014), and Memory (p = 0.028). Regardless of HIV serostatus, MJ users had lower AD in uncinate fasciculus (p = 0.024) but similar cognition as nonusers. HIV serostatus and MJ use showed an interactive effect on mean diffusivity in the right globus pallidus but not on cognitive function. Furthermore, lower FA in left anterior internal capsule predicted poorer Fluency across all participants and worse Attention/Working Memory in all except SN subjects, while higher diffusivities in several white matter tracts also predicted lower cognitive domain Z-scores. Lastly, MJ users with or without HIV infection showed greater than normal age-dependent FA declines in superior longitudinal fasciculus, external capsule, and globus pallidus. CONCLUSIONS: Our findings suggest that, except in the globus pallidus, chronic MJ use had no additional negative influence on brain microstructure or neurocognitive deficits in HIV+ individuals. However, lower AD in the uncinate fasciculus of MJ users suggests axonal loss in this white matter tract that connects to cannabinoid receptor rich brain regions that are involved in verbal memory and emotion. Furthermore, the greater than normal age-dependent FA declines in the white matter tracts and globus pallidus in MJ users suggest that older chronic MJ users may eventually have lesser neuronal integrity in these brain regions.

Other drug use does not impact cognitive impairments in chronic ketamine users.

BACKGROUND: Ketamine abuse causes cognitive impairments, which negatively impact on users' abstinence, prognosis, and quality of life. RESULTS: of cognitive impairments in chronic ketamine users have been inconsistent across studies, possibly due to the small sample sizes and the confounding effects of concomitant use of other illicit drugs. This study investigated the cognitive impairment and its related factors in chronic ketamine users with a large sample size and explored the impact of another drug use on cognitive functions. METHODS: Cognitive functions, including working, verbal and visual memory and executive functions were assessed in ketamine users: 286 non-heavy other drug users and 279 heavy other drug users, and 261 healthy controls. Correlations between cognitive impairment and patterns of ketamine use were analysed. RESULTS: Verbal and visual memory were impaired, but working memory and executive functions were intact for all ketamine users. No significant cognitive differences were found between the two ketamine groups. Greater number of days of ketamine use in the past month was associated with worse visual memory performance in non-heavy other drug users. Higher dose of ketamine use was associated with worse short-term verbal memory in heavy other drug users. CONCLUSION: Verbal and visual memory are impaired in chronic ketamine users. Other drug use appears to have no impact on ketamine users' cognitive performance.

Neuroticism and Fatigue 3 Months After Ischemic Stroke: A Cross-Sectional Study.

OBJECTIVE: To examine the relation between neuroticism and fatigue in Chinese patients with stroke. DESIGN: Cross-sectional study. SETTING: Acute stroke unit. PARTICIPANTS: Survivors of ischemic stroke (N=191) recruited from the acute stroke unit between May 1, 2010, and September 1, 2011. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The personality trait of neuroticism was measured with the neuroticism subscale of the Chinese version of the NEO Five-Factor Inventory. The level of fatigue was measured with the Fatigue Assessment Scale. The National Institutes of Health Stroke Scale, Geriatric Depression Scale, Barthel Index, and Mini-Mental State Examination were administered to obtain demographic and clinical information. RESULTS: Fatigue severity 3 months after stroke positively correlated with Geriatric Depression Scale and NEO Five-Factor Inventory neuroticism scores and negatively correlated with the Barthel Index score. CONCLUSIONS: Neuroticism, independent of depressive symptoms, is a predictor of fatigue severity 3 months after stroke. Interventions such as psychological screening programs are warranted for early detection of patients at high risk of poststroke depression.

Poststroke agitation and aggression and social quality of life: a case control study.

BACKGROUND AND OBJECTIVE: Aggression and agitation are common after a stroke. The association between agitation/aggression following stroke and Health-Related Quality of Life (HRQoL) in stroke survivors is unknown. This study aimed to examine the association between agitation/aggression and HRQoL in Chinese stroke survivors. METHODS: Three hundred and twenty-four stroke patients entered this cross-sectional study. Agitation/aggression was assessed using the Chinese version of Neuropsychiatric Inventory (CNPI). HRQoL was measured with the Stroke Specific Quality of Life (SSQoL). RESULTS: Three months after the index stroke, agitation/aggression was found in 60 (18.5%) patients. In the agitation/aggression group, 44 patients (73.3%) showed passive agitation/aggression, whereas 16 (26.7%) displayed passive and active agitation/aggression. No patients showed only active agitation/aggression. Patients with agitation/aggression were more likely to have history of diabetes and greater severity of depression, as well as lower SSQoL total score and Personality Changes and Social Role scores. Controlling for diabetes and depression severity did not alter the above results. The Energy and Thinking scores of the SSQoL were significantly lower in the passive/active agitation/aggression group relative to the passive agitation/aggression group (adjusted for CNPI aggression/agitation score). CONCLUSION: In this study sample, agitation/aggression was preponderantly of the passive type and was associated with poorer HRQoL independently from depression or medical conditions. Patients with both passive and active agitation/aggression had lower Quality of Life (QoL) than patients with only passive agitation/aggression. The causality of the association between low QoL and agitation/aggression needs to be explored in future studies.

Ketamine users have high rates of psychosis and/or depression.

Ketamine has been linked to psychosis and used in the treatment of depression. However, no study has examined the prevalence of psychotic and depressive disorders in dependent ketamine users. This study aimed to examine the frequency of various psychopathologies among a series of patients seeking treatment for ketamine use in Hong Kong, China. The case records of 129 patients with a history of ketamine use receiving treatment at three substance use clinics between January 2008 and August 2012 were retrieved for data collection. Patients' demographic data, patterns of substance misuse, and comorbid psychiatric diagnoses were recorded and entered into analyses. The mean age of onset and length of ketamine use were 17.7 ± 4.4 and 8.7 ± 5.7 years, respectively. All patients were dependent on ketamine at the time of data collection. Multiple substance misuse was common. Eighty-four of the 129 (65.1%) patients were found to have comorbid psychiatric disorders, most commonly substance-induced psychotic disorder (31.8%) followed by depressive disorder (27.9%). Psychosis and/or depression were common in ketamine-dependent patients referred to a psychiatric substance use clinic. The findings provide evidence of an association between chronic ketamine use and the presence of psychosis and/or depression. The results raise the issue of safety when using ketamine in the long-term treatment of depression.

Psychiatric morbidity in ketamine users attending counselling and youth outreach services.

BACKGROUND: No study has examined ketamine users' psychiatric morbidity using structured diagnostic instruments. The aim of this study was thus to determine the psychiatric comorbidity of community-based ketamine users using the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), Axis I Disorders (SCID). METHODS: A convenience sample of 200 frequent ketamine users was recruited from community organizations in Hong Kong. Participants were screened with the Severity of Dependence Scale (SDS), Beck Depression Inventory (BDI), Anxiety subscale of the Hospital Anxiety Depression Scale (HADSA), and SCID psychotic symptoms. Those who scored above the threshold (cutoff point of 8/9 on the BDI and 4/5 on HADSA) or displayed evidence of psychotic symptoms were referred for a structured clinical interview conducted by a psychiatrist. RESULTS: One hundred and seventy participants scored above the cutoff point on 1 or more of the scales, and 115 participants attended the SCID interview. Fifty-one of these 115 participants received a psychiatric diagnosis of 1 or more comorbidities for the month preceding the interview. Mood disorders accounted for 80.4% of the diagnoses, anxiety disorders for 33.3%, and psychotic disorders for 7.8%. CONCLUSIONS: Female gender and history of psychiatric/psychological clinic attendance were significantly associated with comorbid psychiatric disorders, whereas ketamine dependence had a borderline association.

Subcortical white matter infarcts predict 1-year outcome of fatigue in stroke.

BACKGROUND: Fatigue is common in stroke survivors. Lesion location may influence the risk of poststroke fatigue (PSF) but it is uncertain whether location has an impact on the prognosis of PSF. This study examined the association between PSF outcome and infarct location. METHODS: The study sample comprised 435 Chinese patients with acute ischemic stroke admitted to the acute stroke unit of a university affiliated regional hospital in Hong Kong. Three and fifteen months after the onset of the index stroke a research assistant administered the Fatigue Severity Scale (FSS). PSF was defined as a FSS score of 4.0 or above. Of the 139 patients with PSF three months poststroke, 97 (69.8%) attended the 15-month follow-up, when 50 (51.5%) patients still had PSF ('non-remitters') and 47 (48.5%) did not report fatigue ('remitters'). The presence and location of infarcts were evaluated with magnetic resonance imaging. RESULTS: In comparison with the remitters, the non-remitters were more likely to have subcortical white matter infarcts (40.0% vs 21.3%, p = 0.046). These infarcts remained an independent predictor of non-remission of PSF in the multivariate analysis, with an odds ratio of 4.208 (p = 0.011). CONCLUSIONS: The results suggest that subcortical white matter infarcts may influence the outcome of PSF. Further investigations are needed to explore whether infarcts have any impact on the response of PSF to pharmacological or psychological interventions.

Brainstem infarcts predict REM sleep behavior disorder in acute ischemic stroke.

BACKGROUND: Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance in which patients enact their dreams while in REM sleep. The behavior is typically violent in association with violent dream content, so serious harm can be done to the patient or the bed partner. The prevalence of RBD is well-known in Parkinson's disease, Lewy body dementia, and multiple systems atrophy. However, its prevalence and causes in stroke remained unclear. The aim of this study was to determine factors influencing the appearance of RBD in a prospective cohort of patients with acute ischemic stroke. METHODS: A total of 2,024 patients with first-ever or recurrent acute ischemic stroke were admitted to the Acute Stroke Unit at the Prince of Wales Hospital between January 2010 and November 2011; 775 of them received an MRI scan. Within 2 days of admission, a research nurse collected demographic and clinical data and assessed the severity of each stroke using the National Institute of Health Stroke Scale (NIHSS). One hundred and nineteen of the 775 patients meeting study entry criteria formed the study sample. All eligible participants were invited to attend a research clinic 3 months after the onset of the index stroke. In the attendance, a research assistant administered the MMSE and the 13-item RBD questionnaire (RBDQ). RESULTS: Among 119 stroke patients, 10.9% were exhibited RBD, defined as an REM sleep behavior disorder questionnaire score of 19 or above. The proportion of patients with acute brainstem infarct was significantly higher in RBD patients than those without RBD. Compared with patients without RBD, RBD patients were more likely to have brainstem infarcts and had smaller infarct volumes. In a multivariate analysis, in which stroke location and infarct volume were inserted, brainstem infarcts were an independent predictor of RBD (odds ratio = 3.686; P = 0.032). CONCLUSIONS: The results support the notion of a predominant role of brainstem injury in the development of RBD and suggest that patients with brainstem infarcts RBD should be evaluated by a clinical neurologist.

Are sexes affected differently by ketamine? An exploratory study in ketamine users.

One hundred primary ketamine users and 100 controls were recruited in Hong Kong between December 2009 and December 2011. Cognitive assessment included general intelligence, working, verbal, and visual memory, and executive functions. A Univariate General Linear Model was used to compare cognitive performance between the male and female ketamine users and controls. The female users appeared to have a higher risk of visual memory impairment than their male counterparts. Further studies are warranted to clarify the mechanism of the sex-specific effect of ketamine on cognitive functions.

Cerebral microbleeds and suicidality in stroke.

OBJECTIVE: Cerebral microbleeds (CMBs) are common in stroke survivors. The clinical significance of CMBs in the development of suicidality (SI) following stroke is unknown. This study examined the association between SI and CMBs. The aim of the study reported here was to determine the relationship between CMBs and SI in ischemic stroke survivors. METHODS: A cohort of 367 patients with acute ischemic stroke admitted to the stroke unit of a university-affiliated regional hospital in Hong Kong was recruited. SI was assessed with the geriatric mental state examination at three months following the subjects' index stroke. Depressive symptoms were assessed using the geriatric depression scale (GDS). A qualified psychiatrist administered the Chinese version of the Structured Clinical Interview for DSM-IV to diagnose depressive disorders. The presence and location of CMBs were evaluated with magnetic resonance imaging (MRI). RESULTS: Compared with the non-SI patients, SI patients were more likely to have CMBs in any brain region (36.6% vs. 20.2%, p = 0.017), specifically more lobar (29.3% vs. 13.5%, p = 0.008) and thalamic CMBs (19.5% vs. 7.5%, p = 0.018). Presence of CMBs (odds ratio was 2.5, p = 0.026) and lobar CMBs (odds ratio 2.6, p = 0.034) were independent predictors of SI in the multivariate analysis. CONCLUSIONS: The results suggest that lobar CMBs may play roles in the development of SI. The importance of CMBs in the pathogenesis of SI in stroke survivors warrants further investigation.