Is age at symptom onset associated with severity of memory impairment in adults with obsessive-compulsive disorder?

OBJECTIVE: Age at onset is a potentially important marker for neurobiological features of obsessive-compulsive disorder (OCD). This study examined the relationship between age at symptom onset and memory impairment in adults with OCD. METHOD: The authors used the Rey-Osterrieth Complex Figure Test and the California Verbal Learning Test to compare memory functioning of 37 adult OCD patients with self-reported childhood onset of symptoms (onset at less than 18 years of age) with that of 31 patients with adult-onset symptoms. RESULTS: No differences were found between the two groups on any of the verbal and nonverbal memory measures. CONCLUSIONS: Self-reported age at symptom onset is not associated with memory performance in adult patients with OCD according to tests previously found to be sensitive to frontal-striatal system dysfunction and impairment in OCD. Such dysfunction appears to be a consistent feature of OCD in adults, regardless of age at initial symptom onset.     

Increase of Ki-67+ natural killer cells in multiple sclerosis patients treated with interferon-β and interferon-β combined with low-dose oral steroids

Interferon-β (IFN-β) is known to expand regulatory CD56(bright) natural killer (NK) cells in multiple sclerosis (MS). In this cross-sectional study we show that MS patients treated with IFN-β alone or in combination with low-dose prednisolone displayed increased proportion of all NK cell subsets in the active phase of the cell cycle (Ki-67+). There was no difference in NK cell apoptosis markers. In vitro experiments showed that both IFN-β and IFN-β in combination with corticosteroids increased the proportion of Ki-67(+) NK cells. This study, although limited, shows that treatment with IFN-β affects NK cell cycle without altering NK cell apoptosis in MS patients.     

Sleep quality is associated with the severity of clinical symptoms in Parkinson’s disease

Sleep disorders are very common in Parkinson’s disease (PD), being associated with several other conditions, mainly psychiatric disorders. The present study was designed to assess sleep quality in Brazilian patients with PD and to evaluate whether sleep changes are associated with clinical variables, especially neuropsychiatric symptoms in PD. Patients diagnosed with PD were subjected to a comprehensive clinical evaluation that included the assessment of motor, cognitive and psychiatric symptoms. Our study showed that sleep complaints are frequent in PD and worse sleep quality is associated with depressive and anxious symptoms, poorer cognitive performance and greater severity of PD symptoms. In the multivariate analysis, older age, greater severity of anxiety and PD remained as significant predictors of worse sleep quality. In conclusion, sleep complaints, depressive and anxiety symptoms are frequent in PD patients. Older age, disease severity and anxiety symptoms are significant predictors of poorer sleep quality in PD patients.     

Pyroglutamylated amyloid-β is associated with hyperphosphorylated tau and severity of Alzheimer’s disease

Pyroglutamylated amyloid-β (pE(3)-Aβ) has been suggested to play a major role in Alzheimer’s disease (AD) pathogenesis as amyloid-β (Aβ) oligomers containing pE(3)-Aβ might initiate tau-dependent cytotoxicity. We aimed to further elucidate the associations among pE(3)-Aβ, full-length Aβ and hyperphosphorylated tau (HP-τ) in human brain tissue. We examined 41 post mortem brains of both AD (n = 18) and controls. Sections from frontal and entorhinal cortices were stained with pE(3)-Aβ, HP-τ and full-length Aβ antibodies. The respective loads were assessed using image analysis and western blot analysis was performed in a subset of cases. All loads were significantly higher in AD, but when using Aβ loads as independent variables only frontal pE(3)-Aβ load predicted AD. In frontal and entorhinal cortices pE(3)-Aβ load independently predicted HP-τ load while non-pE(3)-Aβ failed to do so. All loads correlated with the severity of AD neuropathology. However, partial correlation analysis revealed respective correlations in the frontal cortex only for pE(3)-Aβ load only while in the entorhinal cortex respective correlations were seen for both HP-τ and non-pE(3)-Aβ loads. Mini Mental State Examination scores were independently predicted by entorhinal HP-τ load and by frontal pE(3)-Aβ load. Here, we report an association between pE(3)-Aβ and HP-τ in human brain tissue and an influence of frontal pE(3)-Aβ on both the severity of AD neuropathology and clinical dementia. Our findings further support the notion that pE(3)-Aβ may represent an important link between Aβ and HP-τ, and investigations into its role as diagnostic and therapeutic target in AD are warranted.     

Plasma β-endorphin levels and natural killer cells in two cases of congenital indifference to pain

We have investigated plasma -endorphin (-E), ACTH, and cortisol in two cases of congenital indifterence to pain (CIP), a rare syndrome characterized by unresponsiveness to painful stimuli. As the two patients had frequent skin infections, we also studied lymphocyte response to mytogens in the absence or presence of -E. In addition, we explored a series of lymphocyte membrane antigens related to different aspects of the immune response, such as CD3⁺, CD4⁺, CD8⁺, B, NK Leu 7, Leu 9, and Leu 19, anti-interleukin-2 receptor (anti-TAC). Plasma -E levels in the two patients were significantly higher than in controls, whereas plasma ACTH and cortisol levels were normal. Lymphocyte response to the mitogen phytohemagglutinin was normal. The expression of Leu 7, Leu 9, and Leu 19, three antigens related to natural killer cells, was decreased by about 50%. The results indicate that in the two cases of CIP studied, high plasma -E levels are associated with a reduction in the expression of natural killer cells. This suggests that the two phenomena are specifically related to each other. These data represent further evidence of the possible pathophysiological relevance of the neuroendocrine-immune feedback.     

TNIP2 mediates GRβ-promoted inflammation and is associated with severity of major depressive disorder

In depression, continual activation of the hypothalamic–pituitaryadrenal (HPA) axis with excess cortisol release leads to impair sensitivity of the glucocorticoid receptor (GR) and increase activity of the pro-inflammatory immune responses. Aberrant expression of GR has been associated with inflammation in patients with major depressive disorder (MDD). Our previous studies showed that the aberrant expression of TNFAIP3 gene, which encodes the NF-κB regulatory protein A20, TNFAIP3-associated proteins and Toll-like receptors (TLRs) are involved in inflammation-associated depression. However, the link between desensitization of GR actions and negative regulation of the TLRs-mediated inflammatory pathway in MDD is yet to be established. Here, we examined the association of depression severity, measured via the 17-item Hamilton Depression Rating Scale (HAMD-17), with the mRNA expression profiling of GRα, GRβ, TNFAIP3-interacting proteins (TNIP), including TNIP1, TNIP2, and TNIP3, and TNFAIP3-like proteins, such as cezanne1, cezanne2, trabid, and valosin-containing protein p97/p47 complex-interacting protein p135 (VCIP135), in monocytes from 69 patients with MDD and 42 healthy controls. Herein we found the mRNA expressions of GRβ and TNIP2 were significantly higher in monocytes from patients with MDD. Notably, TNIP2 level was positively correlated with the GRβ expression and severity of depression, as determined via Pearson's correlation analysis. Mechanistically, we demonstrated that overexpression of GRβ promotes the mRNA levels of TNIP2 and tumor necrosis factor alpha (TNF-α) in human monocytes. The promoting effect of GRβ on TNF-α expression was partially attenuated upon depletion of TNIP2, suggesting that TNIP2 was required for GRβ-mediated enhancement of TNF-α levels. Together, these results suggest that activation of GRβ/TNIP2/TNF-α axis may induce inflammation in MDD patients and targeting this newly identified pathway may help in the development of better therapeutic approaches to reduce the development of MDD.     

Thyroid hormone level is associated with the frequency and severity of Guillain–Barré syndrome

Objective: Guillain–Barré syndrome (GBS) is a neurodegenerative and inflammatory demyelination disorder, and oxidative stress is concerned with the pathogenesis of the disease. Also, we found that thyroid hormone level is correlated to the oxidative and antioxidant status in previous studies. Our study was aimed to find the possible relationship between the frequency and severity of GBS and thyroid hormone levels. Materials and methods: We measured serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT₄) and free triiodothyronine (FT₃) in 238 individuals, including 90 GBS, 44 multiple sclerosis and 104 healthy controls. Results: Our findings demonstrate that the patients with GBS had lower TSH and higher FT_4, FT₄/FT₃ than healthy controls in the normal range. Furthermore, it was also shown in our study that TSH levels in patients with GBS were correlated with disease severity measured by the Hughes Functional Grading Scale. Conclusion: Lower TSH, higher FT₄ and FT₄/FT₃ stand for the oxidative status and are associated with the incidence and severity of GBS.     

β-Adrenergic receptor mediated increases in activation and function of natural killer cells following repeated social disruption

Natural killer (NK) cells are specialized innate lymphocytes important in the early defense against tumor and virus bearing cells. Many factors influence the immune system’s effectiveness against pathogens, including stress. Social disruption (SDR) “primes” macrophages/monocytes and dendritic cells thereby enhancing their anti-microbial function. What remains unclear is whether similar responses are evident in NK cells. Current studies investigated the cellular distribution and activation/inhibitory phenotypes of NK cells in the spleen, lung, and blood of C57BL/6 male mice following SDR. Furthermore, cytolytic activity and anti-viral cytokine production of splenic NK cells were determined. Lastly, β-adrenergic receptor (β-AR) signaling was investigated to determine possible mechanisms behind the SDR-induced NK cell alterations. Results indicated NK cells from SDR mice have increased expression of CD16 and CD69 and reduced NKG2a and Ly49a expression on splenic CD3?/DX5+ NK cells indicative of an activated phenotype, both immediately and 14 h post-SDR. Administration of propranolol (10 mg/kg; non-selective β-adrenergic receptor antagonist) was shown to block these “priming” effects at the 14 h time-point. In the lung, SDR had similar effects on activation and inhibitory receptors 14 h post-SDR, however no alterations were evident in the blood besides increased NK cells directly after SDR. Additionally, splenic NK cells from SDR mice had increased CD107a surface expression, cytolytic activity, and IFN-γ production was increased upon costimulation with IgG and IL-2 ex vivo. Collectively, these data suggest that social stress “primes” NK cells in the spleen and lung to be more proficient in their cytolytic and anti-viral/tumor effecter functions through β-adrenergic receptor dependent signaling.     

Susceptibility to Guillain-Barré syndrome is not associated with CD1A and CD1E gene polymorphisms

Immune responses to microbial glycolipids that cross-react to neural epitopes may trigger the Guillain-Barré syndrome (GBS). CD1 molecules are involved in antigen presentation of glycolipids and variation in CD1 genes was recently reported to confer susceptibility to develop GBS. This hypothesis was tested by comparing single nucleotide polymorphisms (SNPs) of CD1A and CD1E in 312 well defined GBS patients and 212 healthy controls. SNPs in CD1A and CD1E were not associated with GBS susceptibility, specific clinical subgroups, anti-ganglioside antibodies, antecedent infections and prognosis. Based on this study, CD1 polymorphisms are not a susceptibility or disease modifying factor in GBS.     

Decreased sleep quality in Parkinson’s patients is associated with higher anxiety and depression prevalence and severity,and correlates with pain intensity and quality

Objective: Pain, poor sleep quality, restless legs syndrome (RLS), and other symptoms are frequently reported by patients with Parkinson’s disease (PD). However, the impact that pain severity and interference has on non-motor symptoms (NMS) has not been extensively studied. The objective of the present study is to explore the relationship between sleep quality in PD to pain and other NMS that affect quality of life.Methods: The study included 100 PD patients and 100 age and gender-matched controls assessed for pain severity and pain interference using the Brief Pain Inventory and sleep quality using the Pittsburgh Sleep Quality Index. Participants were also evaluated for their subjective levels of anxiety and depression using the Hospital Anxiety and Depression Scale.Results: PD patients with poor sleep quality had greater pain severity and pain interference than controls and PD patients with good or borderline sleep quality. PD patients with poor sleep quality also had the greatest case-ness and severity for depression and anxiety. However, RLS was not significantly correlated with depression, anxiety or pain.Discussion: Poor sleep quality in PD patients is related to greater pain severity, pain interference, and more radiating and paresthestic pain that is independent of RLS. There is a higher prevalence of depression and anxiety in PD patients compared to controls, especially in PD patients with poor sleep quality. Our findings suggest a relationship between poor sleep quality in PD with pain, anxiety and depression. Prospective studies are warranted to investigate the causal relationship.     

Frequency and severity of headache is worsened by Interferon-β therapy in patients with multiple sclerosis

Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and severity of headache is worsened by Interferon‐β therapy in patients with multiple sclerosis.
Acta Neurol Scand: 2012: 125: 91–95.
© 2011 John Wiley & Sons A/S. Background – The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon‐beta (IFNβ) could induce or worsen HA. Objective – To evaluate the impact of IFNβ treatment on HA and the relationship between HA and the various commercial preparations of IFNβ in mildly disabled patients with MS. Methods – A specific questionnaire was administered to 357 relapsing‐remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNβ administration. Results – One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNβ‐1a (Avonex^®), 84 with subcutaneous injections of IFNβ‐1b (Betaferon^®) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNβ‐1a (Rebif^®) 22 mcg or IFNβ‐1a (Rebif^®) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre‐existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNβ therapy; this was more frequently reported by patients treated with Avonex^® and Rebif^® 44. Ninety‐five patients experienced new HA. Conclusion – IFNβ treatment could worsen HA in patients with pre‐existing HA or cause the appearance of new HA. Among different IFNβ preparations, Rebif^® 44 and Avonex^® seemed to be more cephalalgic than the other drugs.     

What factors are associated with the maintenance of PTSD after a motor vehicle accident? The role of sex differences in a help-seeking population

To investigate potential sex differences in factors that are associated with chronic PTSD, data from 223 participants were examined using logistic regression analyses. Each participant had been involved in a serious motor vehicle accident (MVA), which had occurred at least 6 months earlier (range 6mos-37 years). Although men and women did not differ in the rate of diagnosed PTSD, four variables were found to interact significantly with sex in the prediction of chronic PTSD: peritraumatic experiences of helplessness, danger, and the certainty that one would die during the MVA and lack of employment. Follow up analyses indicated that although the peritraumatic experience variables were statistically significant, no notable differences emerged in the odds ratios of men and of women. In contrast, men who were unemployed were 9.94 times more likely to be diagnosed with PTSD, relative to men who were employed, while unemployed women were 2.85 times more likely to be diagnosed with PTSD, relative to women who were employed. Results are discussed in light of the role of functional limitations and their impact on the maintenance of PTSD in men and women.     

Is ADHD severity in adults associated with the lifetime prevalence of comorbid depressive episodes and anxiety disorders?

PurposeThe objective of the present study was to examine the association between ADHD severity and the lifetime prevalence of comorbid depressive episodes and anxiety disorders in adults with ADHD.Subjects/materials and methodsAnalyses were based on data of the Conner's Adult ADHD Rating Scale (CAARS) and a parent study examining the epidemiology of adult ADHD in 17 GP practices in Budapest, Hungary. Subjects between 18 and 60 years were included in the screening phase (n = 3529). Out of 279 positively screened subjects 161 participated in a clinical interview and completed the CAARS to confirm the diagnosis. We applied four diagnostic criteria: “DSM-IV”; “No-onset” (DSM-IV criteria without the specific requirement for onset); “Symptoms-only” (DSM-IV symptom criterion only); and “Reduced symptoms-only” (DSM-IV symptom criterion with a reduced threshold for symptom count). The MINI PLUS 5.0 was used to assess psychiatric comorbidity.ResultsADHD severity, as measured by the CAARS ADHD Index, showed a significant positive association with the prevalence of comorbid depressive episodes in all but the “ADHD_No-onset” group (“DSM-IV”: F[1.23] = 8.39, P = 0.0081; “No-onset”: F(1.27) = 0.97, P = 0.3346; “Symptoms-only”: F[1.55] = 30.79, P < 0.0001; “Reduced symptoms-only”: F(1.62) = 26.69, P < 0.0001).Discussion and conclusionResults indicate that ADHD symptom severity increases in association with lifetime comorbidity with depression.     

FGFR2 is associated with bipolar disorder: A large-scale case–control study of three psychiatric disorders in the Chinese Han population

Objectives. Repetitive linkage analyses have indicated 10q25–q26 as a shared risk region for schizophrenia (SCZ) and bipolar disorder (BPD). A genome-wide association study and follow-up recently identified a significant association between a single nucleotide polymorphism (SNP) of this region (rs17101921) and SCZ. The nearest gene to this SNP is fibroblast growth factor receptor 2 (FGFR2). Methods. We carried out a large scale case–control study to test the association between FGFR2 and three major psychiatric disorders: SCZ, BPD and major depressive disorder (MDD) in the Chinese Han population. Eight tag SNPs were genotyped using Taqman assay in 1139 BPD patients, 1112 SCZ patients, 1119 MDD patients and 1135 shared healthy controls. Results. After correcting the multiple tests by permutation, one SNP (rs11199993), and a haplotype including this SNP, was found to be significantly associated with BPD. Potential population stratification in our samples was analyzed using 70 additional random SNPs dispersed on different chromosomes. No population stratification was detected, so our results could not be affected by this cofounding factor. Limitations of our study include incomplete coverage and insufficient power to detect association for relatively small odds ratio. Conclusions. Association between FGFR2 and BPD is worthy of further confirmation.     

Fatigue in irritable bowel syndrome is associated with plasma levels of TNF-α and mesocorticolimbic connectivity

Irritable bowel syndrome (IBS) is a symptom-based disorder of gut-brain interactions generating abdominal pain. It is also associated with a vulnerability to develop extraintestinal symptoms, with fatigue often reported as one of the most disturbing. Fatigue is related to brain function and inflammation in several disorders, however, the mechanisms of such relations in IBS remain elusive. This study aimed to elucidate fatigue and its association with a resting state network of mesocorticolimbic regions of known importance in fatigue, and to explore the possible role of circulating TNF-α levels in IBS and healthy controls (HC). Resting state functional magnetic resonance imaging (fMRI) was conducted in 88 IBS patients and 47 HC of similar age and gender to investigate functional connectivity between mesocorticolimbic regions. Further, fatigue impact on daily life and plasma levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α), of known relevance to immune activation in IBS, were also measured. The selected mesocorticolimbic regions indeed formed a functionally connected network in all participants. The nucleus accumbens (NAc), in particular, exhibited functional connectivity to all other regions of interest. In IBS, fatigue impact on daily life was negatively correlated with the connectivity between NAc and dorsolateral prefrontal cortex bilaterally (left p = 0.019; right p = 0.038, corrected for multiple comparisons), while in HC, fatigue impact on daily life was positively correlated to the connectivity between the right NAc and anterior middle insula in both hemispheres (left p = 0.009; right p = 0.011). We found significantly higher levels of TNF-α in IBS patients compared to HC (p = 0.001) as well as a positive correlation between TNF-α and fatigue impact on daily life in IBS patients (rho = 0.25, p = 0.02) but not in HC (rho = −0.13, p = 0.37). There was no association between functional connectivity in the mesocorticolimbic network and plasma levels of TNF-α in either group In summary, this novel multimodal study provides the first evidence that the vulnerability to fatigue in IBS is associated with connectivity within a mesocorticolimbic network as well as immune activation. These findings warrant further investigation, both peripherally and potentially with measurements of central immune activation as well.     

Aggregation of α-synuclein in S. cerevisiae is associated with defects in endosomal trafficking and phospholipid biosynthesis

Parkinson’s disease is the most common neurodegenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson’s disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome–Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity.     

Reduced production of IFN-γ and LT-α is associated with successful prednisone therapy in patients with acquired hemophilia A: a pilot study

Glucocorticoids (GC) are a standard treatment for acquired hemophilia A (AH). Although the optimal treatment regimen and duration of GC's is unknown, measurement of sub-clinical immune responses may help direct therapeutic decision making. To study the helpfulness of this approach, three male patients diagnosed with AH were treated with prednisone. The therapy resulted in inhibitor elimination in two out of the three individuals. During the treatment, peripheral mononuclear cells were isolated at different time points and stimulated in vitro. The expression of IFN-γ and LT-α were monitored at both the protein and the mRNA levels. The amount of IFN-γ and LT-α were markedly reduced by the time of inhibitor disappearance in the patients responding to GC therapy but remained high in the non-responder until cyclophosphamide was added. This study suggests that the secretion level of IFN-γ and/or LT-α could be a predictive marker of prednisone responsiveness.