Chronic obsessive-compulsive disorder: prognostic factors.

BACKGROUND: The course of illness in obsessive-compulsive disorder (OCD) varies significantly between patients. Little is known about factors predicting a chronic course of illness. The aim of this study is to identify factors involved in inducing and in maintaining chronicity in OCD. METHODS: The present study is embedded within the Netherlands Obsessive Compulsive Disorder Association (NOCDA) study, an ongoing multicenter naturalistic cohort study designed to identify predictors of long-term course and outcome in OCD. For this study, 270 subjects with a current diagnosis of OCD were included. Chronicity status at 2-year follow-up was regressed on a selection of baseline predictors related to OCD, to comorbidity and to stress and support. RESULTS: Psychotrauma [odds ratio (OR) 1.98, confidence interval (CI) 1.22-3.22, p = 0.006], recent negative life events (OR 1.42, CI 1.01-2.01, p = 0.043), and presence of a partner (OR 0.28, CI 0.09-0.85, p = 0.025) influenced the risk of becoming chronic. Longer illness duration (OR 1.46, CI 1.08-1.96, p = 0.013) and higher illness severity (OR 1.09, CI 1.03-1.16, p = 0.003) increased the risk of remaining chronic. CONCLUSIONS: External influences increase the risk of becoming chronic, whereas the factors involved in maintaining chronicity are illness-related. As the latter are potentially difficult to modify, treatment should be devoted to prevent chronicity from occurring in the first place. Therapeutic strategies aimed at alleviating stress and at boosting social support might aid in achieving this goal.

Perceptions of free will in obsessive-compulsive disorder: a quantitative analysis.

BACKGROUND: The aim of this study was to explore perceptions of free will in the repetitive behaviors of patients with obsessive-compulsive disorder (OCD) and to explore their relation with core clinical characteristics. METHODS: Experiences of free will were assessed with the Symptomatology And Perceived Free will rating scale (SAPF) in 295 subjects with a lifetime diagnosis of OCD. Patients' scores on the SAPF were subjected to an explorative principal axis factor analysis (PAF). Factor scores were regressed on five OCD symptom dimensions and on seven clinical variables: illness duration, severity of OCD, insight, anxiety and depression, suicidal ideation and quality of life. RESULTS: The PAF revealed three factors: the perceived ability to control and change one's course of action when faced with an obsession or compulsion (the "alternative possibilities" factor); the experience of obsessions or compulsions as intentional (the "intentionality" factor); and the experience of being the source or owner of the obsessions or compulsions (the "ownership" factor). Lower scores on the "alternative possibilities" factor were associated with lower scores on the washing dimension (ß = 0.237, p = 0.004) and higher scores on the precision dimension (ß = - 0.190, p = 0.025) and independently associated with longer illness duration (ß = - 0.134, p = 0.039), higher illness severity (ß = - 0.298, p < 0.001) and lower quality of life (ß = 0.172, p = 0.046). Lower scores on the "intentionality" factor were independently associated with lower quality of life (ß = 0.233, p = 0.027). Higher scores on the "ownership" factor were associated with higher scores on the precision dimension (ß = 0.207, p = 0.023) and independently associated with poorer insight (ß = 0.170, p = 0.045). CONCLUSIONS: The most notable finding of this study is that a diminished experience of free will in OCD is associated with core clinical characteristics: illness duration and severity, insight and quality of life.

Diffusion tensor imaging and cognition in cerebral small vessel disease: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) is very common in elderly and related to cognition, although this relation is weak. This might be because the underlying pathology of white matter lesions (WML) is diverse and cannot be properly appreciated with conventional FLAIR MRI. In addition, conventional MRI is not sensitive to early loss of microstructural integrity of the normal appearing white matter (NAWM), which might be an important factor. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity and we have used this to investigate the relation between white matter integrity, in both WML and NAWM, and cognition among elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study among 503 independently living, non-demented elderly with cerebral SVD aged between 50 and 85 years. All subjects underwent MRI and DTI scanning. WML were segmented manually. We measured mean diffusivity (MD) and fractional anisotropy (FA), as assessed by DTI in both WML and NAWM. RESULTS: Inverse relations were found between MD in the WML and NAWM and global cognitive function (ß=-.11, p<0.05; ß=-.18, p<0.001), psychomotor speed (ß=-.15, p<0.01; ß=-.18, p<0.001), concept shifting (ß=-.11, p<0.05; ß=-.10, p<0.05) and attention (ß=-.12, p<0.05; ß=-.15, p<0.001). The relation between DTI parameters in both WML and NAWM and cognitive performance was most pronounced in subjects with severe WML. CONCLUSION: DTI parameters in both WML and NAWM correlate with cognitive performance, independent of SVD. DTI may be a promising tool in exploring the mechanisms of cognitive decline and could function as a surrogate marker for disease progression in therapeutic trials. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Clinical predictors of seizure threshold in electroconvulsive therapy: a prospective study.

At the start and during the course of electroconvulsive therapy (ECT), estimation of the seizure threshold (ST) is useful in weighing the expected effectiveness against the risks of side effects. Therefore, this study explores clinical factors predicting initial ST (IST) and levels of ST during the ECT course. This prospective observational study included patients aged ≥18 years receiving ECT without contraindications for dose titration. At the first and every sixth consecutive ECT session, ST level was measured. Using multivariate linear regression and multilevel models, predictors for IST and change in ST levels were examined. A total of 91 patients (mean age, 59.1 ± 15.0 years; 37 % male; 97 % diagnosis of depression) were included. In multivariable analysis, higher age (ß = 0.24; P = 0.03) and bifrontotemporal (BL) electrode placement (ß = 0.42; P < 0.001) were independent predictors for higher IST, explaining 49 % of its variation. Also, these two variables independently predicted higher ST levels at different time points during the course. Using multilevel models, absence of a previous ECT course(s) predicted a steeper rise in ST during the course (P = 0.03 for the interaction term time*previous ECT). The age-adjusted dose-titration method is somewhat crude, resulting in some measurement error. Concomitant medication use could have influenced ST levels. Increasing age and BL electrode placement predicted higher (I)ST, which should be taken into account when selecting ECT dosage. Previous ECT course(s) may avoid an increase in ST during the course of ECT.

Patient, treatment, and anatomical predictors of outcome in electroconvulsive therapy: a prospective study.

OBJECTIVES: Baseline predictors of effectiveness and cognitive adverse effects of electroconvulsive therapy (ECT) were prospectively examined. METHODS: Before and after ECT, the Montgomery-Åsberg Depression Rating Scale (MADRS) and Mini Mental State Examination (MMSE) were assessed. Before ECT, a magnetic resonance imaging of the head was performed. Outcome predictors were investigated using multivariable regression analyses. RESULTS: Of 83 patients (mean ± SD age, 59.2 ± 15.3 years; 39% men), 28% had a psychotic depressive disorder, 16% had a bipolar depression, 30% had had previous ECT course(s), and 66% used concomitant antipsychotics. Presence of psychotic depression (ß = -0.25; P = 0.04) and having had previous ECT (ß = -0.35; P = 0.003) predicted lower post-ECT MADRS score. Baseline magnetic resonance imaging characteristics were not predictive of post-ECT MADRS and MMSE scores. The use of concomitant antipsychotics predicted a lower post-ECT MMSE score (ß = -0.21; P = 0.02), whereas the presence of bipolar depression at baseline predicted higher post-ECT MMSE score (ß = 0.23; P = 0.01). The post-ECT MADRS score seemed to be a confounder for the post-ECT MMSE score (ß = -0.20; P = 0.02). CONCLUSIONS: Effectiveness of ECT was better in the patients with a baseline psychotic depression and those who had had ECT before. Cognitive outcome was better in the patients with baseline bipolar depression but worse in those who used antipsychotics during ECT and those who showed more persistent depressive symptoms after ECT.

Diffusion tensor imaging of the hippocampus and verbal memory performance: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) and hippocampal atrophy are related to verbal memory failures and may ultimately result in Alzheimer's disease. However, verbal memory failures are often present before structural changes on conventional MRI appear. Changes in microstructural integrity of the hippocampus, which cannot be detected with conventional MRI, may be the underlying pathological substrate. With diffusion tensor imaging (DTI), we investigated the relation between the microstructural integrity of the hippocampus and verbal memory performance in 503 nondemented elderly with SVD. METHODS: The Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study is a prospective cohort study among 503 nondemented elderly with cerebral SVD aged between 50 and 85 years. All participants underwent T1 MPRAGE, fluid-attenuated inversion recovery, DTI scanning and the Rey Auditory Verbal Learning Test. After manual segmentation of the hippocampi, we calculated the mean diffusivity (MD) and fractional anisotropy in both hippocampi. The relation between memory performance and hippocampal DTI parameters was adjusted for age, sex, education, depressive symptoms, hippocampal, and white-matter lesions volume and lacunar infarcts. RESULTS: We found inverse relations between hippocampal MD and verbal memory performance (ß = -0.22; P < 0.001), immediate recall (ß = -0.22; P < 0.001), delayed recall (ß = -0.20; P < 0.001), and forgetting rate (ß = -0.13; P = 0.025), most pronounced in participants with a normal hippocampal volume. CONCLUSION: Microstructural integrity of the hippocampus assessed by DTI is related to verbal memory performance in elderly with SVD, also in participants with an intact appearing hippocampus. Changes in hippocampal microstructure may be an early marker of underlying neurodegenerative disease, before macrostructural (i.e., volumetric) changes occur.

Cigarette smoking is associated with reduced microstructural integrity of cerebral white matter.

Cigarette smoking doubles the risk of dementia and Alzheimer's disease. Various pathophysiological pathways have been proposed to cause such a cognitive decline, but the exact mechanisms remain unclear. Smoking may affect the microstructural integrity of cerebral white matter. Diffusion tensor imaging is known to be sensitive for microstructural changes in cerebral white matter. We therefore cross-sectionally studied the relation between smoking behaviour (never, former, current) and diffusion tensor imaging parameters in both normal-appearing white matter and white matter lesions as well as the relation between smoking behaviour and cognitive performance. A structured questionnaire was used to ascertain the amount and duration of smoking in 503 subjects with small-vessel disease, aged between 50 and 85 years. Cognitive function was assessed with a neuropsychological test battery. All subjects underwent 1.5 Tesla magnetic resonance imaging. Using diffusion tensor imaging, fractional anisotropy and mean diffusivity were calculated in both normal-appearing white matter and white matter lesions. A history of smoking was associated with significant higher values of mean diffusivity in normal-appearing white matter and white matter lesions (P-trend for smoking status = 0.02) and with poorer cognitive functioning compared with those who never smoked. Associations with smoking and loss of structural integrity appeared to be strongest in normal-appearing white matter. Furthermore, the duration of smoking cessation was positively related to lower values of mean diffusivity and higher values of fractional anisotropy in normal-appearing white matter [ß = -0.004 (95% confidence interval -0.007 to 0.000; P = 0.03) and ß = 0.019 (95% confidence interval 0.001-0.038; P = 0.04)]. Fractional anisotropy and mean diffusivity values in normal-appearing white matter of subjects who had quit smoking for >20 years were comparable with subjects who had never smoked. These data suggest that smoking affects the microstructural integrity of cerebral white matter and support previous data that smoking is associated with impaired cognition. Importantly, they suggest that quitting smoking may reverse the impaired structural integrity.

Diffusion tensor imaging and gait in elderly persons with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Although cerebral small vessel disease, including white matter lesions (WML) and lacunar infarcts, is associated with gait disturbances, not all individuals with small vessel disease have these disturbances. Identical-appearing WML on MRI could reflect different degrees of microstructural integrity. Moreover, conventional MRI does not assess the integrity of normal-appearing white matter (NAWM). We therefore investigated the relation between white matter integrity assessed by diffusion tensor imaging in WML, NAWM, several regions of interest, and gait. METHODS: A total of 484 nondemented elderly persons between 50 and 85 years old with cerebral small vessel disease were included in this analysis and underwent MRI and diffusion tensor imaging scanning. Mean diffusivity and fractional anisotropy within WML, NAWM, and regions of interest were related to quantitative and semiquantitative gait parameters. RESULTS: Mean diffusivity in the WML was inversely related with gait (velocity ß=-0.15; P=0.002). For the fractional anisotropy, this relation was less evident. The same was found in the NAWM (velocity ß=-0.21; P<0.001) and for some parameters also after additional adjustment for WML and lacunar infarcts. CONCLUSIONS: This study indicates that integrity of both WML and NAWM, beyond the detection limit of conventional MRI, is associated with gait disturbances.

Hypertension and cerebral diffusion tensor imaging in small vessel disease.

BACKGROUND AND PURPOSE: Hypertension is a risk factor for cerebral small vessel disease, which includes white matter lesions (WML) and lacunar infarcts. These lesions are frequently observed on MRI scans of elderly people and play a role in cognitive decline. Preferably, one would like to evaluate the effect of hypertension before fluid-attenuated inversion recovery visible macrostructural lesions occur, possibly by investigating its effect on the microstructural integrity of the white matter. Diffusion tensor imaging provides measures of structural integrity. METHODS: In 503 patients with small vessel disease, aged between 50 and 85 years, we cross-sectionally studied the relation between blood pressure, hypertension, and hypertension treatment status and diffusion tensor imaging parameters in both normal-appearing white matter (NAWM) and WMLs. All of the subjects underwent 1.5-T MRI and diffusion tensor imaging scanning. Fractional anisotropy and mean diffusivity were calculated in both NAWM and WMLs. RESULTS: Increased blood pressure and hypertension were significantly related to lower fractional anisotropy in both NAWM and WMLs and to higher mean diffusivity in WMLs. For hypertensives, odds ratios for the risk of impaired microstructural integrity (fractional anisotropy) were 3.1 (95% CI: 1.8 to 5.7) and 2.1 (95% CI: 1.2 to 3.5) in NAWM and WMLs, respectively, compared with normotensives. Fractional anisotropy odds ratios for treated uncontrolled subjects were 6.5 (95% CI: 3.3 to 12.7) and 2.7 (95% CI: 1.5 to 5.1) in NAWM and WMLs, respectively, compared with normotensives. CONCLUSIONS: Our data show that diffusion tensor imaging may be an appropriate tool to monitor the effect of blood pressure and the response to treatment on white matter integrity, probably even before the development of WMLs on fluid-attenuated inversion recovery.

Gait in elderly with cerebral small vessel disease.

BACKGROUND AND PURPOSE: Gait disorders are common in the elderly and are related to loss of functional independence and death. White matter lesions (WMLs) may be related, but only a minority of individuals with WMLs has gait disorders. Probably other factors are involved, including location and the independent effect of frequently coinciding lacunar infarcts, the other aspect of cerebral small vessel disease. The aim of our study was to investigate the effect of both the severity and location of both WMLs and lacunar infarcts on gait. METHODS: Four hundred thirty-one independently living, nondemented elderly aged between 50 and 85 years with cerebral small vessel disease were included in this analysis and underwent MRI scanning. The number and location of lacunar infarcts were rated and WML volume was assessed by manual segmentation with automated delineating of different regions. Gait was assessed quantitatively with an electronic walkway as well as the semiquantitatively Tinetti and Timed-Up-and-Go test. RESULTS: WMLs and lacunar infarcts were both independently associated with most gait parameters with stride length as the most sensitive parameter related to WMLs. WMLs in the sublobar (basal ganglia/internal capsule) and limbic areas and lacunar infarcts in the frontal lobe and thalamus were related to a lower velocity. CONCLUSIONS: Cerebral small vessel disease is related to gait disturbances. Because small vessel disease may, in part, be preventable, it should be regarded as a potentially important target for postponing gait impairment.

Patterns of cortical degeneration in an elderly cohort with cerebral small vessel disease.

Emerging noninvasive neuroimaging techniques allow for the morphometric analysis of patterns of gray and white matter degeneration in vivo, which may help explain and predict the occurrence of cognitive impairment and Alzheimer's disease. A single center prospective follow-up study (Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort study (RUN DMC)) was performed involving 503 nondemented elderly individuals (50-85 years) with a history of symptomatic cerebral small vessel disease (SVD). Age was associated with a global reduction in cortical thickness, and this relationship was strongest for ventrolateral prefrontal cortex, auditory cortex, Wernicke's area, superior temporal lobe, and primary visual cortex. Right and left hemispheres differed in the thickness of language-related areas. White matter (WM) lesions were generally negatively correlated with cortical thickness, primarily in individuals over the age of 60, with the notable exception of Brodmann areas 4 and 5, which were positively correlated in age groups 50-60 and 60-70, respectively. The observed pattern of age-related decline may explain problems in memory and executive functions, which are already well documented in individuals with SVD. The additional gray matter loss affecting visual and auditory cortex, and specifically the head region of primary motor cortex, may indicate morphological correlates of impaired sensory and motor functions. The paradoxical positive relationship between WM lesion volume and cortical thickness in some areas may reflect early compensatory hypertrophy. This study raises a further interest in the mechanisms underlying cerebral gray and white matter degeneration in association with SVD, which will require further investigation with diffusion weighted and longitudinal MR studies.

Classification of comorbidity in obsessive-compulsive disorder: A latent class analysis.

OBJECTIVE: Patients with OCD differ markedly from one another in both number and kind of comorbid disorders. In this study, we set out to identify and characterize homogeneous subgroups of OCD patients based on their comorbidity profile. METHODS: In a cohort of 419 adult subjects with OCD, the lifetime presence of fifteen comorbid disorders was assessed. Latent class analysis was used to identify comorbidity-based subgroups. Groups were compared with regard to core clinical characteristics: familiality, childhood trauma, age at onset, illness severity, OCD symptom dimensions, personality characteristics, and course of illness. RESULTS: The study sample could be divided in a large group (n = 311) with a low amount of comorbidity that could be further subdivided into two subgroups: OCD simplex (n = 147) and OCD with lifetime major depressive disorder (n = 186), and a group (n = 108) with a high amount of comorbidity that could be further subdivided into a general anxiety-related subgroup (n = 49), an autism/social phobia-related subgroup (n = 27), and a psychosis/bipolar-related subgroup (n = 10). Membership of the high-comorbid subgroup was associated with higher scores on childhood trauma, illness severity, and the aggression/checking symptom dimension and lower scores on several personality characteristics. CONCLUSION: Grouping OCD patients based on their comorbidity profile might provide more homogeneous, and therefore, more suitable categories for future studies aimed at unraveling the etiological mechanisms underlying this debilitating disorder.

MRI characteristics predicting seizure threshold in patients undergoing electroconvulsive therapy: a prospective study.

BACKGROUND: In electroconvulsive therapy (ECT), the electrical current must pass the scalp, skull, cerebrospinal fluid (CSF) and brain tissues, to sufficiently exceed the seizure threshold (ST). OBJECTIVE: To investigate the relationship between these anatomical strata of the head and the level of the ST, in both right unilateral (RUL) and bifrontotemporal (BL) ECT. METHODS: Observational prospective study among 74 mainly depressed patients. STs were measured at the 1st (initial ST), 6th, 12th, 18th and 24th session. MRI scans were acquired before the 1st session. Scalp and skull thickness at electrode sites were measured on T2-weighted images. Volumes of intracranial space (ICV), CSF, gray and white matter, and white matter hyperintensities were estimated using whole brain isovoxel T1-weighted images. Separate multivariate regression analyses for RUL (n = 55) and BL (n = 19) treated groups were used to estimate the predictive values of the MRI variables. RESULTS: The patients had a mean age of 57.7 ± 14.8 years, and 39% were men. After adjustment for age, gender and ICV, CSF volume strongly and independently predicted initial ST in both RUL (ß = 0.31; P = 0.049) and BL ECT (ß = 0.64; P = 0.007). Using multilevel regression analysis, CSF volume was associated with ST during the remaining RUL ECT course (ß = 0.20; P = 0.02). CONCLUSIONS: Taking into account the limitations in the titration method and MRI analysis, volume of CSF strongly and independently predicted initial ST. Therefore, the exclusive use of age-based ECT dosing methods may result in suboptimal electrical stimulus dosage in patients with CSF volumes that are not within the average range.

Diffusion tensor imaging and mild parkinsonian signs in cerebral small vessel disease.

Although the role of cerebral small vessel disease (SVD), including white matter lesions (WMLs) and lacunar infarcts, in mild parkinsonian signs (MPS) is increasingly being recognized, not all individuals with SVD have MPS. Using diffusion tensor imaging (DTI), we investigated whether the presence of MPS was dependent on the microstructural integrity underlying WMLs, the early loss of integrity of the normal-appearing white matter (NAWM) and location of this damage. We examined 483 elderly subjects with SVD and without parkinsonism. Subjects with severe loss of integrity within their WMLs had a higher risk of MPS, regardless of WML volume (fractional anisotropy odds ratios = 1.9; 95% confidence interval, 1.1-3.4). The same was found in the normal-appearing white matter, but this association disappeared after adjustment for WMLs and lacunar infarcts. The integrity of the periventricular frontal regions-of-interest was significantly lower in subjects with MPS than without, independent of WMLs and lacunar infarcts. This study indicates that integrity of WMLs, especially in the frontal lobe, is associated with MPS. Diffusion tensor imaging may be of added value in investigating the underlying mechanisms of parkinsonian signs in subjects with SVD.

Hypertension is related to the microstructure of the corpus callosum: the RUN DMC study.

Vascular factors play a role in the etiology of Alzheimer's disease (AD), presumably due to emergence of white matter lesions. However, important white matter structures involved in the etiology of AD, including the corpus callosum (CC), remain invariably free from macroscopical white matter lesions, although loss of microstructural integrity assessed with diffusion tensor imaging (DTI) has been described in the CC. Vascular factors have been related to these microstructural white matter changes too, but little is known about their effect on the CC. In 499 subjects with cerebral small vessel disease, aged 50-85 years, we cross-sectionally investigated the relation between hypertension, hypertension treatment status, the microstructural integrity of the CC using DTI, and the attendant cognitive performance. Fractional anisotropy and mean diffusivity were calculated in four substructures of the CC (genu, anterior body, posterior body, and splenium). Differences between groups were calculated with analysis of variance, adjusted for age, gender, and cardiovascular risk factors. Compared with normotensive subjects, hypertensive subjects had a lower fractional anisotropy in the splenium and a significant higher mean diffusivity in both the anterior body and the splenium; this was most noticeable in treated uncontrolled hypertensive subjects. Furthermore we found that microstructural integrity of the CC was related to global cognition. Of this relation, 14 to 60% was explained by the mediating effect of small vessel disease elsewhere in the white matter. Our findings indicate that adequate blood pressure treatment might postpone these changes and the attendant cognitive dysfunction.