Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n?=?272, mean duration 17.9 months) or LPV/r (n?=?173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p?<?0.001), were less likely to have AIDS (p?<?0.001) or hepatitis C virus (HCV) coinfection (p?<?0.05), had higher CD4+ T cell nadirs (p?<?0.001), had lower peak (p?<?0.001) and current (p?<?0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p?<?0.001). Overall, EFV users had worse speed of information processing (p?=?0.04), verbal fluency (p?=?0.03), and working memory (p?=?0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n?=?329), EFV users performed poorly, whereas among HCV seropositives (n?=?116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n?=?269), EFV users had worse speed of information processing (p?=?0.02) and executive functioning (p?=?0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.     

Primary lateral sclerosis and the amyotrophic lateral sclerosis–frontotemporal dementia spectrum

Aim

To investigate whether primary lateral sclerosis (PLS) represents part of the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum of diseases.

Methods

Comprehensive assessment was taken on 21 patients with PLS and results were compared to patients diagnosed with pure motor ALS (n?=?27) and ALS–FTD (n?=?12). Clinical features, Addenbrooke’s Cognitive Examination (ACE) scores, Motor Neuron Disease Behaviour (Mind-B) scores, motor disability on the ALS functional rating scale (ALSFRS) and survival times were documented. Motor cortex excitability was evaluated using transcranial magnetic stimulation (TMS).

Results

Global cognition was impaired in PLS (mean total ACE score 82.5?±?13.6), similar to ALS–FTD (mean total ACE score 76.3?±?7.7, p?>?0.05) while behavioural impairments were not prominent. TMS revealed that resting motor threshold (RMT) was significantly higher in PLS (75.5?±?6.2) compared ALS–FTD (50.1?±?7.2, p?<?0.001) and ALS (62.3?±?12.6, p?=?0.046). Average short-interval intracortical inhibition (SICI) was similar in all three patient groups. The mean survival time was longest in PLS (217.4?±?22.4 months) and shortest in ALS–FTD (38.5?±?4.5 months, p?=?0.002). Bulbar onset disease (β?=???0.45, p?=?0.007) and RMT (β?=?0.54, p?=?0.001) were independent predictors of global cognition while motor scores (β?=?0.47, p?=?0.036) and SICI (β?=?0.58, p?=?0.006) were significantly associated with ALSFRS.

Conclusion

The cognitive profile in PLS resembles ALS–FTD, without prominent behavioural disturbances. A higher RMT in PLS than ALS and ALS–FTD is consistent with differential cortical motor neuronal abnormalities and more severe involvement of corticospinal axons while SICI, indicative of inhibitory interneuronal dysfunction was comparable with ALS and ALS–FTD. Overall, while these findings support the notion that PLS lies on the ALS–FTD spectrum, the mechanisms underlying slow disease progression are likely to be distinct in PLS.

     

Association between the growth rate of subependymal giant cell astrocytoma and age in patients with tuberous sclerosis complex

Purpose

The most common neurological complications associated with tuberous sclerosis complex (TSC) include intractable seizures that begin in infancy and subependymal giant cell astrocytoma (SEGA) complicated by hydrocephalus with increasing age. Information on SEGA growth of TSC patients is limited. This study aimed to examine the TSC-SEGA growth rates by periodic neuroimaging.

Methods

This study evaluated the TSC-SEGA growth rates by serial neuroimaging. Fifty-eight patients with TSC underwent systematic evaluation, including a review of medical history and serial brain neuroimaging.

Results

While magnetic resonance imaging was more sensitive in detecting cortical tubers than computed tomography (73.1 vs. 0 %, p?<?0.001), its efficacy in identifying intracranial lesions was comparable to that of computed tomography (96.2 vs. 100 %, p?=?0.658). Significant tumor growth was observed in children (p?=?0.012) and adults (p?=?0.028) during follow-up periods, respectively (median for children 23.5 months, interquartile range 18–40 months and median for adults 23 months, interquartile range 12–34 months). Further, the SEGA growth rate in children was significantly higher than that in adults (75.6 vs. 16.5 %, p?=?0.03).

Conclusions

The results of the study show that SEGA has a significantly higher growth rate in children using serial follow-up brain imaging, suggesting the importance of performing follow-up neuroimaging at yearly intervals in childhood to identify and prevent potential comorbidities.

     

Bone mineral density in pediatric patients with meningomyelocele

Purpose

The aim of this study was to determine the bone mineral density (BMD) and the factors leading to reduction in BMD in children diagnosed with meningomyelocele.

Methods

A total of 31 patients with meningomyelocele (mean (SD) age, 8.5 (3.9) years; 51.6 % were females) and 22 healthy children were included. BMD of femoral neck and spinal L1–L4 levels and markers for bone metabolism were recorded.

Results

BMD of femoral neck (p?=?0.001) and spinal L1–L4 (p?=?0.01), serum calcium (p?=?0.031), and urinary deoxypyridinoline (p?=?0.015) levels were significantly lower in patients than in controls. Mobilization was significantly reduced in lumbar (p?=?0.001) and thoracic (p?=?0.002) level meningomyelocele compared to controls, while a significant positive correlation was noted between BMD of spinal L1–L4 and mobility (r?=?0.58, p?=?0.015).

Conclusions

Our findings suggest a decrease in BMD in meningomyelocele patients being associated with osteoporosis rather than nutritional and hormonal factors and the negative impact of higher levels of lesion on the mobility.

     

Basal ganglia shrinkage without remarkable hippocampal atrophy in chronic aviremic HIV-positive patients

Conventional magnetic-resonance (MR) imaging is not sensitive enough in depicting subtle neurodegenerative changes that occur during chronic HIV infection with good peripheral viral suppression. The aim of this study was to compare brain volumes in HIV-positive subjects with age- and education-matched healthy controls with regard to influence of aging and immunologic parameters. An overall of 65 subjects (40 HIV-positive and 25 age-, gender-, and education-matched healthy subjects) underwent conventional MR imaging with three-dimensional sequence adequate for volumetric measurements. Volumes of specific brain regions were measured and compared between HIV-positive and healthy subjects using Student t test. Correlations between obtained brain volumes and immunologic parameters were determined using Pearson’s correlation test. Influence of age as a covariate was determined using ANCOVA test. Statistical value was set at p?<?0.05. Volumes of nucleus accumbens (p?=?0.003), putamen (p?=?0.003), and thalamus (p?=?0.046) were significantly decreased in HIV-positive subjects compared with healthy, while volumes of lateral ventricles were significantly increased (p?=?0.043). However, influence of age on atrophy was greater than presence of HIV infection in all observed volumes. Positive correlation of nadir CD4+ count and nucleus accumbens volume was obtained, as well as of therapy with lateral ventricle volumes. Volumes of putamen correlated negatively with duration of therapy. HIV-associated atrophic changes are visible in nucleus accumbens, putamen, and thalamus in neurocognitively asymptomatic stage, while no changes can be observed in the hippocampus, affected by other types of dementias. Under therapy, the influence of physiological aging on HIV-associated atrophy is greater than the presence of HIV infection per se.     

Biomarkers of neuronal injury and amyloid metabolism in the cerebrospinal fluid of patients infected with HIV-1 subtypes B and C

Based on prior reports that the HIV-1 Tat protein modulates amyloid-beta (Aβ) metabolism, this study aimed to compare CSF neural injury biomarkers between 27 patients with HIV subtype B, 26 patients with HIV subtype C, 18 healthy HIV-negative controls, and 24 patients with Alzheimer’s disease (AD). Immunoassays were used to measure soluble amyloid precursor protein α and β (sAPPα, sAPPβ), Aβ oligomers 38, 40, 42, and Aβ-total; phosphorylated tau (P-tau₁₈₁), and total tau (T-tau). Comparisons between HIV(+) and HIV(?) (including AD) were adjusted by linear regression for gender and age; HIV subtype comparisons were adjusted for nadir CD4 and plasma viral load suppression. The p values were corrected for multiple testing with the Benjamini-Hochberg procedure. CSF Aβ-42 and Hulstaert (P-tau₁₈₁) index were lower in HIV1-C than B (p = 0.03, and 0.049 respectively); subtypes did not differ on other CSF biomarkers or ratios. Compared to AD, HIV(+) had lower CSF levels of T-tau, P-tau₁₈₁ (p < 0.001), and sAPPα (p = 0.041); HIV(+) had higher CSF Aβ-42 (p = 0.002) and higher CSF indexes: [Aß-42/(240 + 1.18 T-tau)], P-tau₁₈₁/Aβ-42, T-tau/Aβ-42, P-tau₁₈₁/T-tau, sAPPα/β (all p ≤ 0.01) than AD. Compared to HIV(?), HIV(+) had lower CSF Aβ-42, and T-tau (all p ≤ 0.004). As conclusion, amyloid metabolism was influenced by HIV infection in a subtype-dependent manner. Aß-42 levels were lower in HIV1-C than B, suggesting that there may be greater deposition of Aß-42 in HIV1-C. These findings are supported by CSF Hulstaert (P-tau₁₈₁) index. Differences between HIV and AD in the patterns of Aß and Tau biomarkers suggest that CNS HIV infection and AD may not share some of same mechanisms of neuronal injury.     

Suicide risk and prevalence of major depressive disorder (MDD) among individuals infected with HIV-1 subtype C versus B in Southern Brazil

Major depressive disorder (MDD) is among the most prevalent neuropsychiatric disorders associated with HIV infection; however, its risks and neurobiologic correlates in diverse cultures are poorly understood. This study aimed to examine the frequency of MDD among HIV+ participants in southern Brazil. We hypothesized that the frequency and severity of MDD would be higher among individuals with HIV+ compared with HIV? and higher in HIV subtype B compared with C. Individuals with HIV (n?=?39) as well as seronegative controls (n?=?22) were enrolled in a cross-sectional, prospective, observational study. Current and lifetime history of MDD was diagnosed by MINI-Plus; symptom severity was assessed by Beck Depression Inventory-II (BDI-II). Current and past episodes of MDD were significantly more frequent in the HIV+ versus HIV? group: current MDD, 15 (38.5 %) vs. 0 (0 %), p?=?0.0004; past MDD, 24 (61.5 %) vs. 3 (13.6 %), p?=?0.0004. The median BDI-II score in the HIV+ group was significantly higher than that in the HIV? (13 (8–27.5) vs. 2.5 (1–5.5); p?<?0.0001). Current suicide risk, defined as during the last month, was found in 18 % of participants in the HIV-positive and none in the HIV-negative group. Neither current MDD frequency (8 (57.1 %) vs. 6 (40 %), p?=?0.47) nor BDI-II score differed across subtypes B and C. HIV+ group may be more likely to experience current MDD than HIV?. This was the first study to compare the frequency and severity of MDD in HIV subtypes B and C; we found no difference between HIV subtypes B and C.     

Non-motor and Extracerebellar Features in Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant degenerative disease. Pathological studies have demonstrated not only cerebellar and brainstem atrophy, but substantia nigra, motoneurons, basal ganglia, thalamus, and peripheral nerves involvement. These findings may explain non-motor and extra-cerebellar features in SCA2. We accessed the non-motor symptoms and extra-cerebellar signs in SCA2 patients in order to provide a better understanding on pathophysiological mechanisms and natural history of brain degeneration in the disease. Thirty-three SCA2 patients were evaluated and compared with 26 healthy subjects. We investigated the following variables: sleep disorders, cognitive deficit, olfactory impairment, urinary dysfunction, psychiatric symptoms, cramps, pain, movement disorders, and weight loss. SCA2 had a high frequency of REM sleep behavior disorder (48.48 %, N?=?16) as well as excessive daytime sleepiness (42.42 %, N?=?14). Chorea was present in 15.15 % (N?=?5), dystonia in 27.27 % (N?=?9), and parkinsonism in 27.27 % (N?=?9). Slow saccadic pursuit was present in 87.87 % (N?=?29) and ophtalmoparesis in 78.78 % (N?=?26) of patients. Regarding sleep disorders, 18.18 % (N?=?6) of patients had restless leg syndrome. Dysphagia was present in 39.39 % (N?=?13), weight loss 24.24 % (N?=?8), and urinary dysfunction 27.27 % (N?=?9). Cramps was present in only 6 % of patients (N?=?2). This study highlighted the high frequency of non-motor symptoms and extra-cerebellar signs in SCA2. Our findings demonstrate the widespread of nervous system involvement in SCA2 patients and contribute to better understand the natural history of brain degeneration in this genetic condition.     

Determinants of Anxiety and Depression Among University Students of Lahore

Benefits from an improved understanding of mental health of young adults, particularly students, affecting their academic performance are likely to be numerous. Thus, we aimed at evaluating anxiety and depression among annual and semester university students of Lahore, Pakistan. A cross-sectional study of 7 months duration was designed by enrolling a total of 404 students from two private and two public sector universities of Lahore. We found significant differences in frequency distribution with regard to age (p?=?0.003), marital status (p?=?0.01), living status (p?=?0.004), and reasons affecting of mental health (p?=?0.004) between annual and semester system students. Students enrolled in annual system exhibited higher odds of anxiety, mild (OR 2.7, p?=?0.019), and extremely severe (OR 2.6, p?=?0.002), compared to semester students. In overall assessment of university students, after univariate analysis, multivariate analysis demonstrated significant association of depression with male students (OR 2.3, p?=?0.001), age?≤?22 years (OR 2.8, p?=?0.0005) and living status (OR 5.96, p?=?0.0005). Similarly, as for anxiety, only male students demonstrated higher odds of anxiety (OR 2.8, p?=?0.0005). As expected, compared to a single reason, multiple reasons affecting student’s mental health demonstrated significant association with all three determinants of mental health, i.e., stress (OR 0.36, p?=?0.0005), anxiety (OR 0.31, p?=?0.0005), and depression (OR 0.5, p?=?0.0005). Taken together, these data suggested higher prevalence of anxiety among annual system students, mainly because of studies, while in overall assessment male students and students at an early stage of their life at the university were susceptible to anxiety and depression, probably due to multiple reasons affecting their mental health.     

Peripheral neuropathy in HIV patients in sub-Saharan Africa failing first-line therapy and the response to second-line ART in the EARNEST trial

Sensory peripheral neuropathy (PN) remains a common complication in HIV-positive patients despite effective combination anti-retroviral therapy (ART). Data on PN on second-line ART is scarce. We assessed PN using a standard tool in patients failing first-line ART and for 96 weeks following a switch to PI-based second-line ART in a large Randomised Clinical Trial in Sub-Saharan Africa. Factors associated with PN were investigated using logistic regression. Symptomatic PN (SPN) prevalence was 22 % at entry (N?=?1,251) and was associated (p?<?0.05) with older age (OR?=?1.04 per year), female gender (OR?=?1.64), Tuberculosis (TB; OR?=?1.86), smoking (OR?=?1.60), higher plasma creatinine (OR?=?1.09 per 0.1 mg/dl increase), CD4 count (OR?=?0.83 per doubling) and not consuming alcohol (OR?=?0.55). SPN prevalence decreased to 17 % by week 96 (p?=?0.0002) following similar trends in all study groups (p?=?0.30). Asymptomatic PN (APN) increased over the same period from 21 to 29 % (p?=?0.0002). Signs suggestive of PN (regardless of symptoms) returned to baseline levels by week 96. At weeks 48 and 96, after adjusting for time-updated associations above and baseline CD4 count and viral load, SPN was strongly associated with TB (p?<?0.0001). In summary, SPN prevalence was significantly reduced with PI-based second-line therapy across all treatment groups, but we did not find any advantage to the NRTI-free regimens. The increase of APN and stability of PN-signs regardless of symptoms suggest an underlying trend of neuropathy progression that may be masked by reduction of symptoms accompanying general health improvement induced by second-line ART. SPN was strongly associated with isoniazid given for TB treatment.     

Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals

Cell-free mitochondrial DNA (mtDNA) is a highly immunogenic molecule that is associated with several inflammatory conditions and with neurocognitive impairment during untreated HIV infection. Here, we investigate how cell-free mtDNA in cerebrospinal fluid (CSF) is associated with inflammation, neuronal damage, and neurocognitive functioning in the context of long-term suppressive antiretroviral therapy (ART). We quantified the levels of cell-free mtDNA in the CSF from 41 HIV-infected individuals with completely suppressed HIV RNA levels in blood plasma (<50 copies/mL) by droplet digital PCR. We measured soluble CD14, soluble CD163, interferon γ-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), neopterin, and neurofilament light chain (NFL) by immunoassays in CSF supernatant or blood plasma. Higher levels of mtDNA in CSF were associated with higher levels of MCP-1 (r = 0.56, p < 0.01) in CSF and TNF-α (r = 0.43, p < 0.01) and IL-8 (r = 0.44, p < 0.01) in blood plasma. Subjects with a previous diagnosis of AIDS showed significantly higher levels of mtDNA (p < 0.01) than subjects without AIDS. The associations between mtDNA and MCP-1 in CSF and TNF-α in blood remained significant after adjusting for previous diagnosis of AIDS (p < 0.01). Additionally, higher levels of mtDNA were associated with a lower CD4 nadir (r = ?0.41, p < 0.01) and lower current CD4% (r = ?0.34, p = 0.03). Paradoxically, higher levels of mtDNA in CSF were significantly associated with better neurocognitive performance (r = 0.43, p = 0.02) and with less neuronal damage (i.e. lower NFL). Higher cell-free mtDNA is associated with inflammation during treated HIV infection, but the impact on neurocognitive functioning and neuronal damage remains unclear and may differ in the setting of suppressive ART.     

Minocycline for acute stroke treatment: a systematic review and meta-analysis of randomized clinical trials

Background

Various randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke.

Methods

Literature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models.

Results

We identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR?=?1.31; 95% CI 0.98–1.74, p?=?0.06) and 3-month BI (MD?=?6.92; 95% CI ??0.92, 14.75; p?=?0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR?=?1.59; 95% CI 1.19–2.12, p?=?0.002; I²?=?58%) and 3-month BI (MD?=?12.37; 95% CI 5.60, 19.14, p?=?0.0003; I²?=?47%), whereas reduced the 3-month NIHSS (MD ??2.84; 95% CI ??5.55, ??0.13; p?=?0.04; I²?=?86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion.

Conclusions

Although data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients.

     

Neurofilament light chain in blood is negatively associated with neuropsychological performance in HIV-infected adults and declines with initiation of antiretroviral therapy

HIV-associated neurocognitive disorder (HAND) persists in the combination antiretroviral therapy (cART) era and is associated with diminished quality of life. The disorder remains challenging to diagnose given the requirement for comprehensive neuropsychological testing. Blood biomarkers are needed to facilitate the diagnosis of HAND and to gauge neurological response to antiretroviral therapy. We performed a study of plasma neurofilament light chain (NFL) that included 37 HIV-infected and 54 HIV-negative adults. In the univariate mixed-effect model involving HIV-infected participants, there was a statistically significant linear relationship between composite neuropsychological score (NPT-11) and plasma NFL (slope?=???9.9, standard error?=?3.0 with 95% confidence interval ??3.2 to ??16.6 and p?=?0.008 when testing slope?=?0). Similarly, in the multivariate mixed-effect model, higher plasma NFL was significantly associated with worse NPT-11 (slope?=???11.5, standard error?=?3.3 with 95% confidence interval ??3.7 to ??19.0 and p?=?0.01 when testing slope?=?0). The association between NPT-11 and NFL appeared to be driven by the group of individuals off cART. In a subset of participants who had visits before and after 24 weeks on cART (n?=?11), plasma NFL declined over time (median?=?22.7 versus 13.4 pg/ml, p?=?0.02). In contrast, plasma NFL tended to increase over time among HIV-negative participants (median 10.3 versus 12.6 pg/ml, p?=?0.065, n?=?54). Plasma NFL therefore shows promise as a marker of neuropsychological performance during HIV. Larger studies are needed to determine if NFL could serve as a diagnostic tool for HAND during suppressive cART.     

Changes of cerebrospinal fluid Aβ<Subscript>42</Subscript>, t-tau,and p-tau in Parkinson’s disease patients with cognitive impairment relative to those with normal cognition: a meta-analysis

The cerebrospinal fluid (CSF) signature of reduced amyloid beta 1–42 (Aβ₄₂), elevated total tau (t-tau), and phosphorylated tau181 (p-tau) is important for the early diagnosis of Alzheimer’s disease (AD). Aβ₄₂, t-tau, and p-tau have been reported in numerous studies to contribute to predicting cognitive impairment in Parkinson’s disease (PDCI). However, no consistent conclusion can be drawn so far. Literatures regarding Aβ₄₂, t-tau, and p-tau in CSF were systematically reviewed, and a meta-analysis was thus performed to evaluate the changes of these biomarkers in PDCI patients, including PD with mild cognitive impairment (PDMCI) and PD dementia (PDD) patients, relative to PD with normal cognition (PDNC) patients. Databases of “PubMed,” “EBSCO,” and “Springer” were retrieved for articles concerning Aβ₄₂, t-tau, and p-tau in PDCI patients relative to those in PDNC patients published from January 1, 2000 to February 1, 2017. The following keywords were set, namely, “dementia” or “cognitive impairment” or “mild cognitive impairment” and “cerebrospinal fluid” and “Parkinson*.” Sixteen articles comprising 590 PDCI patients and 1182 PDNC patients were included. The results showed that CSF Aβ₄₂ level in PDCI cohort was lower than that in PDNC cohort (pooled Std.MD = ?0.44, 95% CI [?0.61, ?0.26], p < 0.00001). Reduced Aβ₄₂ (pooled Std.MD = ?0.60, 95% CI [?0.75, ?0.45], p < 0.00001) as well as elevated t-tau (pooled Std.MD = 0.21, 95% CI [0.06, 0.35], p = 0.006) and p-tau (pooled Std.MD = 0.36, 95% CI [0.02, 0.69], p = 0.04) could be observed in PDD cohort compared with PDNC cohort. Therefore, amyloid pathology and tauopathy may participate in the development of PDD, which is similar to AD.     

ApoA1, ApoJ and ApoE Plasma Levels and Genotype Frequencies in Cerebral Amyloid Angiopathy

The involvement of apolipoproteins, such as the ApoE4 isoform, in Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) highlights the fact that certain lipid carriers may participate in soluble β-amyloid (Aβ) transport. Our general aim was to characterize the soluble levels of the apolipoproteins apoE, apoA1 and apoJ/clusterin and their genotype status in patients with CAA. We analyzed the genotypes frequency of APOA1 (rs5069, rs670), CLU (rs11136000, rs1532278, rs7012010, rs9331888) and APOE (rs429358, rs7412) in a cohort of patients with CAA-associated intracerebral hemorrhage (ICH) (n = 59) and compared the results with those from hypertension-associated ICH (n = 42), AD patients (n = 73) and controls (n = 88). In a subgroup of patients, we also determined the plasma concentrations of apoE, apoA1 and apoJ/clusterin. We found increased plasma apoJ/clusterin levels in CAA patients compared to AD patients or controls after adjusting for sex and age (CAA vs. controls, p = 0.033; CAA vs. AD, p = 0.013). ApoA1 levels were not altered between groups, although a strong correlation was observed between plasma Aβ(1-40) and apoA1 among CAA patients (r = 0.583, p = 0.007). Regarding plasma apoE concentration, a robust association between circulating levels and genotype status was confirmed (p < 0.001). Whereas the APOE4 frequency was higher in AD (p < 0.001) and CAA (p = 0.013), the APOA1 and CLU genotypes were not different among groups. In the CAA cohort, the risk-linked CLU variant (C) rs11136000 was associated with white matter hyperintensities (p = 0.045) and the presence of lobar microbleeds (p = 0.023) on MRI. In summary, our findings suggest that apoA1 may act as a physiological transporter of Aβ(1-40) and that apoJ/clusterin appears to be a chaperone related to distinctive lesions in CAA brains.     

The Diagnosis and Natural History of Multiple System Atrophy,Cerebellar Type

The objective of this study was to identify key features differentiating multiple system atrophy cerebellar type (MSA-C) from idiopathic late-onset cerebellar ataxia (ILOCA). We reviewed records of patients seen in the Massachusetts General Hospital Ataxia Unit between 1992 and 2013 with consensus criteria diagnoses of MSA-C or ILOCA. Twelve patients had definite MSA-C, 53 had possible/probable MSA-C, and 12 had ILOCA. Autonomic features, specifically urinary urgency, frequency, and incontinence with erectile dysfunction in males, differentiated MSA-C from ILOCA throughout the disease course (p?=?0.005). Orthostatic hypotension developed later and differentiated MSA-C from ILOCA (p?<?0.01). REM sleep behavior disorder (RBD) occurred early in possible/probable MSA-C (p?<?0.01). Late MSA-C included pathologic laughing and crying (PLC, p?<?0.01), bradykinesia (p?=?0.01), and corticospinal findings (p?=?0.01). MRI distinguished MSA-C from ILOCA by atrophy of the brainstem (p?<?0.01) and middle cerebellar peduncles (MCP, p?=?0.02). MSA-C progressed faster than ILOCA: by 6 years, MSA-C walker dependency was 100 % and ILOCA 33 %. MSA-C survival was 8.4?±?2.5 years. Mean length of ILOCA illness to date is 15.9?±?6.4 years. A sporadic onset, insidiously developing cerebellar syndrome in midlife, with autonomic features of otherwise unexplained bladder dysfunction with or without erectile dysfunction in males, and atrophy of the cerebellum, brainstem, and MCP points strongly to MSA-C. RBD and postural hypotension confirm the diagnosis. Extrapyramidal findings, corticospinal tract signs, and PLC are helpful but not necessary for diagnosis. Clarity in early MSA-C diagnosis can prevent unnecessary investigations and facilitate therapeutic trials.     

Elevated C-reactive protein and white blood cell count at admission predict functional outcome after non-aneurysmal subarachnoid hemorrhage

Introduction

Patients with non-aneurysmal subarachnoid hemorrhage (SAH) are considered to have an overall benign course of disease compared to patients suffering from aneurysmal SAH. Nevertheless, a small but significant number of such patients might only achieve unfavorable outcome. Therefore, the purpose of the present study was to determine if routine laboratory markers of acute phase response are associated with unfavorable outcome in patients with non-aneurysmal SAH.

Methods

From 2006 to 2017, 154 patients suffering from non-aneurysmal SAH were admitted to our institution. Patients were stratified according to the distribution of cisternal blood into patients with perimesencephalic SAH (pSAH) versus non-perimesencephalic SAH (npSAH). C-reactive protein (CRP) and white blood cells (WBC) assessments were performed within 24 h of admission as part of routine laboratory workup. Outcome was assessed according to the modified Rankin Scale (mRS) after 6 months and stratified into favorable (mRS 0–2) vs. unfavorable (mRS 3–6).

Results

The multivariate regression analysis revealed “CRP?>?5 mg/l” (p?=?0.004, OR 143.7), “WBC count?>?12.1 G/l” (p?=?0.006, OR 47.8), “presence of IVH” (p?=?0.02, OR 13.5), “poor-grade SAH” (p?=?0.01, OR 45.2) and “presence of CVS” (p?=?0.003, OR 149.9) as independently associated with unfavorable outcome in patients with non-aneurysmal SAH.

Conclusion

Elevated C-reactive protein and WBC count at admission were associated with unfavorable outcome after non-aneurysmal SAH.

     

Clinical Value of Neutrophil to Lymphocyte and Platelet to Lymphocyte Ratio After Aneurysmal Subarachnoid Hemorrhage

Background

Inflammation and thrombosis are associated with the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH) and neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are emerging as novel inflammatory markers in stroke. We aimed to identify the association of NLR and PLR with delayed cerebral ischemia (DCI) and 3-month outcome after aSAH.

Methods

Two hundred and forty-seven patients diagnosed with aSAH within 24 h of symptoms onset were enrolled. Clinical, neuroradiological, laboratory, and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Admission NLR, PLR, and combined NLR-PLR associated with outcomes were evaluated by logistic regression analysis, and we used receiver operating characteristic curves to detect the overall predictive accuracy of these markers.

Results

Fifty-five (22.3 %) patients had unfavorable outcome and 47 (19 %) developed DCI. Both NLR and PLR were correlated with WFNS grade (ρ = 0.35[p < 0.001], ρ = 0.28[p < 0.001]) and modified Fisher grade (ρ = 0.25[p = 0.001], ρ = 0.28[p = 0.003]) and independently related to DCI (OR 2.18, 95 %CI 1.51–3.15, p = 0.016; OR 2.21, 95 %CI 1.61–3.32, p = 0.008) and functional outcome (OR 1.89, 95 %CI 1.52–3.17, p = 0.015; OR 1.77, 95 %CI 1.48–3.21, p = 0.018) at 3 months after aneurysm repair. They had comparable predictive ability in DCI occurrence (area under the curve [AUC] 0.65, 95 %CI 0.55–0.74, p = 0.002; AUC 0.68, 95 %CI 0.60–0.76, p < 0.001) and poor outcome (AUC 0.70, 95 %CI 0.63–0.77, p < 0.001; AUC 0.65, 95 %CI 0.58–0.72, p = 0.001). However, combination of the two indexes showed a better predictive value than each alone (AUC 0.73, 95 %CI 0.66–0.81, p < 0.001 for DCI; AUC 0.76, 95 %CI 0.70–0.83, p < 0.001 for poor outcome).

Conclusions

NLR and PLR as novel inflammatory biomarkers are independent predictors of DCI development and functional outcome after acute aSAH. When combined together, they may help to identify high-risk patients more powerfully.

     

Quality of life and social functioning of former long-stay psychiatric patients transferred into the community: a 10 year follow up study

Purpose

Deinstitutionalisation in Ireland began following the impetus of the successful transfer of psychiatric patients into the community in other countries. This study sought to evaluate the quality of life (QoL) and social functioning (SF) of former long-stay institutionalised patients with severe and enduring mental illness who had been relocated into local community settings and followed up 10 years later.

Method

One month prior to hospital closure, 87 former long-stay psychiatric patients, the majority of whom had a diagnosis of schizophrenia, were assessed on a range of QoL and SF measures. Patients were followed-up 10 years later in the community, to evaluate baseline predictors of quality of life and social functioning.

Results

Study completers (n?=?35) improved significantly on a range of QoL and SF measures over the 10 year period. Specific improvements were noted in domestic skills (t = ? 2.8, p?<?0.0008), community skills (t = ? 4.9, p?<?0.001), as well as the activity and social relations measure (t = ? 4.1, p?<?0.001). Increased social function (t = ? 6.3, p?<?0.001) and improvement on the social behaviour scale (t?=?7.6, p?<?0.001) were noted at follow-up. Linear regression analysis found that less social behaviour problems at baseline predicted QoL 10 years later (t = ? 2.6, p?<?0.02).

Conclusion

This study demonstrated that transfer into the community from an institutional environment was associated with long-term improvements in quality of life and social functioning, even in those who spent many years in the institution. Those who demonstrated the greatest improvement in QoL had less social behavioural problems at baseline assessment, providing further evidence of the success of community living for former long-stay patients.