Virchow-Robin space dilatation may predict resistance to antidepressant monotherapy in elderly patients with depression

BACKGROUND: Late-life depressive disorders have been linked to cerebrovascular disease (the vascular depression hypothesis). Treatment resistance may be associated with vascular-based lesions in the white matter and basal ganglia. Virchow-Robin spaces (VRS) are cerebrospinal fluid spaces associated with microangiopathy of small cerebral vessels. This study tested the hypothesis that dilation of Virchow-Robin spaces seen on Magnetic Resonance Imaging (MRI) is associated with treatment resistance in elderly depressed individuals. METHODS: 50 patients with late-onset (age over 60 years) major depressive disorder (29 responders to monotherapy, 21 non-responders to monotherapy) and 35 normal volunteers were recruited. Assessment of deep white matter lesions [WML] and periventricular hyperintensities [PVH] (both with the Scheltens rating scale score, [Scheltens, P., Barkhof, F., Leys, D., et al. (1993) A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci;114(1):7-12.]) and the severity of VRS dilatation (using a new scale) were scored from MRI images. Statistical group comparisons and multiple regression analyses were performed to quantify the relationship between imaging features and clinical outcome. RESULTS: There was a trend for greater WML Scheltens scores in the monotherapy resistant group compared to responders and control subjects, but only using the basal ganglia VRS score was there a statistically significant difference. A score of 2 or greater on the VRS score was 80% sensitive and 62% specific in predicting non-response to antidepressant monotherapy. The VRS score accounted for 38% of the variance in the multiple regression model and the PVH score, which was an independent predictor of outcome, contributed another 6%. LIMITATIONS: Numbers are small and type II errors possible, especially for the Scheltens ratings. Treatment response was limited to response or non-response to monotherapy and was retrospectively derived. The VRS scale was originally designed for use in patients with vascular dementia and has not been used before in affective disorders. Although all depressed subjects were late-onset, it is possible that depression led to vascular disease rather than vice versa. CONCLUSION: VRS dilatation is common in diseases associated with microvascular abnormality, which is the presumed basis of vascular depression in the elderly. VRS score may be useful in determining which patients are less likely to respond to antidepressant monotherapy. Prospective studies of patients with a wider range of treatment responses are indicated.     

Neuropsychological assessment of young people at high genetic risk for developing schizophrenia compared with controls: preliminary findings of the Edinburgh High Risk Study (EHRS)

BACKGROUND: Finding risk indicators for schizophrenia among groups of individuals at high genetic risk for the disorder, has been the driving force of the high risk paradigm. The current study describes the preliminary results of a neuropsychological assessment battery conducted on the first 50% of subjects from the Edinburgh High Risk Study. METHODS: One hundred and four high risk subjects and 33 normal controls, age and sex matched, were given a neuropsychological assessment battery. The areas of function assessed and reported here include intellectual function, executive function, perceptual motor speed, mental control/ encoding, verbal ability and language, learning and memory measures, and handedness. RESULTS: The high risk subjects performed significantly more poorly than the control subjects in the following domains of neuropsychological function: intellectual function, executive function, mental control/encoding and learning, and memory. Controlling for IQ, high risk subjects made significantly more errors on the Hayling Sentence Completion Test (HSCT), took longer to complete section A of the HSCT, had lower scores on the delayed recall condition of the visual reproductions subtest of the Wechsler Memory Scale-Revised, and had significantly poorer Rivermead Behavioural Memory Test (RBMT) standardized scores. The presence of significant group by IQ interactions for the RBMT and time to complete section A of the HSCT suggested that differences among the groups were more marked in the lower IQ range. Performance on the HSCT was found to be related to the degree of family history of schizophrenia. CONCLUSIONS: High risk subjects performed more poorly than controls on all tests of intellectual function and on aspects of executive function and memory.     

Cognitive profiles of mild cognitive impairment with and without vascular disease

This study examined whether the cognitive profile of subjects with mild cognitive impairment (MCI) with vascular disease differs from that of MCI subjects with no vascular disease. Consecutive MCI subjects with vascular disease (n=60) and matched MCI subjects with no vascular disease (n=60) were included in the study and were compared with healthy control subjects (n=60). The neuropsychological assessment comprised tests of speed and attention, episodic memory, visuospatial function, language, and executive function. Control subjects performed significantly better than did both MCI groups on the neuropsychological battery. MCI subjects with no vascular disease performed better overall than did MCI subjects with vascular disease, most clearly on tests of speed and attention, visuospatial function, and executive function. MCI subjects with and without vascular disease exhibited differences, both in terms of overall performance and of cognitive profiles. These differences can be largely explained by deficits in speed and attention and in executive function of the MCI subjects with vascular disease.     

Periventricular white matter alterations,dementia, and binswanger's disease

Although periventricular white matter alterations (PWMA) are commonly reported on magnetic resonance imaging (MRI) scans of elderly individuals, a consistent pattern of neuropsychological deficits has yet to be found. However, there are some findings suggesting that executive functions (Luria, 1980) are more impaired than other areas of neuropsychological functioning. We undertook a prospective study of two groups of elderly, demented patients with and without PWMA as measured by MRI. The results demonstrated that subjects with greater white matter alterations performed worse on some executive function tests (e.g., Trail Making Test‐Part B and competing programs/go‐no‐go), whereas there were no differences in other areas of neuropsychological functioning. There were no between‐group differences on the Modified Ischemic Scale (Rosen, Terry, Fuld, Katzman, & Peck, 1980) or on measures of depression. Other pertinent clinical and methodological issues related to the clinical presentation of PWMA, as well as Binswanger's disease, are discussed.     

Dementia associated with periventricular and deep white matter alterations: a subtype of subcortical dementia.

This research examined the neuropsychological functioning of demented patients with periventricular and deep white matter alterations. Thirty-three outpatients with NINCDS-ADRDA probable Alzheimer's disease (AD) and 27 outpatients with probable/ possible ischaemic vascular dementia (IVD, Chui et al., 1992) associated with periventricular and deep white matter alterations matched for age, education, level of dementia, and functional disability were studied. White matter alterations were measured using a 40-point scale previously described by Junque et al. (1990). Subjects with cortical CVAs were excluded. On executive control tests, IVD subjects made more preservations on tests of mental control and response set, and produced fewer responses on phonemic controlled oral word association tests (letters: F,A,S). IVD subjects also made more preservations and graphomotor errors on clock drawings. On the California Verbal Learning Test the IVD group performed better than AD subjects on the short delay free recall test condition, the recognition discriminability index, and made fewer intrusion errors on both free and cued recall conditions. We conclude that neuropsychological assessment can differentiate AD from IVD associated with white matter alterations, and that the neuropsychological profile of demented subjects with significant periventricular and deep white matter alterations is similar to other subcortical dementing illnesses.     

Impaired implicit sequence learning in depression: a probe for frontostriatal dysfunction?

BACKGROUND: Implicit learning through motor sequencing tasks is sensitive to basal ganglia dysfunction. Consequently, it is ideally suited for testing elements of the frontostriatal model of major depression and performance can be related to key clinical, neuropsychological, vascular and biochemical data. METHOD: Twenty-one subjects with moderate to severe unipolar depression and 21 age-, sex- and education-matched controls were recruited. Clinical, vascular and biochemical data were recorded. Subjects were administered a battery of neuropsychological tests that assessed speed of processing, working memory, learning, memory, language, perceptual organization and executive functioning. Additionally, subjects were administered a motor sequencing implicit learning task. Implicit learning is assumed when reaction times improve during the sequenced condition as compared to the pseudo-random baseline condition. RESULTS: The rate of implicit learning in persons with depression was only half that of control subjects (3.6% v. 7.3%). Lower rates of implicit learning in patients were associated with poorer performance on neuropsychological tests of visuomotor speed and mental flexibility, longer duration of depressive episode and severity of acute stress. In a small number of subjects, poorer performance was also related to past suicide attempt. CONCLUSIONS: Impaired implicit learning in persons with depression is consistent with frontostriatal dysfunction. Performance is related to some clinical characteristics and to neuropsychological functioning on tests of visuomotor speed and mental flexibility.     

Anoxic versus traumatic brain injury: amount of tissue loss, not etiology, alters cognitive and emotional function

Research in neuropsychology suggests that the etiology of a neurologic injury determines the neuropathological and neuropsychological changes. This study compared neuropsychological outcome in subjects who had traumatic brain injury (TBI) with subjects who had anoxic brain injury (ABI), who were matched for age, gender, and ventricle-to-brain ratio. There were no group differences for morphologic or neuropsychological measures. Both groups exhibited impaired memory, attention, and executive function, as well as slowed mental processing speed. Intelligence correlated with whole brain volume, and measures of memory correlated with hippocampal atrophy. There was no unique contribution of hippocampal atrophy on neuropsychological outcome between the groups. In the absence of localized lesions, the amount of neural tissue loss, rather than etiology, may be the critical factor in neuropsychological outcome.     

Enhanced motor cortex facilitation in patients with vascular cognitive impairment-no dementia

Data on Transcranial Magnetic Stimulation (TMS) derived measures of cortical excitability and intracortical circuits in age-related white matter changes are scarce. We aimed to assess early changes of motor cortex excitability in nondemented elderly patients with subcortical ischemic vascular disease (SVD). Ten SVD elderly and ten age-matched controls underwent paired-pulse TMS for the analysis of intracortical inhibition (ICI) and facilitation (ICF). All subjects performed neuropsychological assessment and brain magnetic resonance imaging. SVD patients showed abnormal executive control function. No statistically significant differences were found for resting motor threshold, cortical silent period between SVD patients and controls or between the two hemispheres, in patients. A significant enhancement of mean ICF was observed in SVD patients. This study provides the first evidence of functional changes in intracortical excitatory neuronal circuits in patients with SVD and clinical features of vascular cognitive impairment-no dementia. Further studies are required to evaluate whether the observed change of ICF might predict cognitive and/or motor impairment in a population at risk for subcortical vascular dementia.     

Verbal fluency dysfunction in euthymic bipolar patients: a controlled study

OBJECTIVE: To study the executive functioning in euthymic bipolar patients in comparison to healthy controls and to examine the relationship between neuropsychological deficits and clinical variables. METHODS: Twenty-five euthymic bipolar patients and 31 controls underwent a battery of executive tasks including mental flexibility, inhibitory control and verbal fluency tests. RESULTS: There were no significant differences between bipolar patients and controls in relation to mental flexibility and inhibitory control. However, patients performed worse than controls on verbal fluency tests. Poor performances on the Stroop Test and the Hayling and Brixton Tests--part A were associated to lifetime occurrence of psychotic symptoms, prior number of episodes, and previous hospitalizations. CONCLUSIONS: In our study, only verbal fluency tests differentiated bipolar euthymic patients from healthy controls. Patients who showed deficits in information processing speed and inhibitory control had more episodes and hospitalizations and lifetime occurrence of psychotic symptoms.     

Brain-derived neurotrophic factor gene Val66Met polymorphism and cognitive function in obsessive-compulsive disorder

In the present study, we have tested the hypothesis that brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism is associated with obsessive-compulsive disorder (OCD) and also investigated the association between the BDNF Val66Met polymorphism and the performance on tests measuring executive functions in a sample of patients with OCD. A total of 100 patients diagnosed with OCD according to DSM-IV criteria and 110 control subjects were included in this study. Single nucleotide polymorphism (G/A) leading to Val to Met substitution at codon 66 in BDNF was screened in the DNA samples of all participants. The genotype frequencies of BDNF Val66Met polymorphism were compared in OCD patients and healthy controls. The four subgroups of OCD and healthy control subjects, determined according to being Val homozygous or carrying a Met allele, were also compared according to their performance in a battery of neuropsychological tests of executive functions and verbal memory. There was no significant difference for the allele and genotype distributions of BDNF Val66Met polymorphism between the OCD and healthy control groups. Compared to the other three subgroups, OCD-Met carriers were slower on Trail-Making Test part A (TMT A), part B (TMT B) score and its speed-corrected score (TMT B-A). OCD-Met carriers had also poor performance on verbal fluency tasks and several CVLT measures compared only to the healthy control-Met carriers. These results demonstrate that the BDNF Val66Met polymorphism does not appear to be a risk factor for OCD. However, the presence of a BDNF Met allele, which is a known attenuator of BDNF activity, may be associated with a poorer executive functioning in OCD. ? 2012 Wiley Periodicals, Inc.     

Association study between plasma GDNF and cognitive function in late-onset depression

Objective

Improving evidence suggest that neurotrophic growth factor systems might be involved in the pathophysiology of major depressive disorder (MDD). The glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor from the transforming growth factor-β-family, which plays a role in the development and function of hippocampal cells. This study was aimed to test whether GDNF in plasma was abnormal in late-onset depression (LOD), and whether it was associated with the cognitive impairment of LOD.

Methods

The plasma GDNF levels in LOD patients (n = 27) before antidepressant treatment and normal control subjects (n = 28) were measured with the ELISA method. All subjects were assessed by neuropsychological tests and Hamilton Depression Rating Scale (HDRS).

Results

The performance of neuropsychological tests of the LOD group except TMT-B was significantly poorer than those of the control group. The plasma GDNF levels in LOD patients were significantly increased compared to control subjects (P < 0.05). Furthermore, the increase of plasma GDNF level was significantly positively correlated with Digit Span Test backward score in LOD patients, and negatively associated with TMT-B performance.

Conclusions

The findings suggest that LOD patients in acute phase have extensive impairments of cognitive function, and higher plasma GDNF might be involved in the pathogenesis of LOD, which may be associated with the cognitive dysfunction in LOD.     

Neuropsychological change in young people at high risk for schizophrenia: results from the first two neuropsychological assessments of the Edinburgh High Risk Study

BACKGROUND: Studies of groups of individuals who have a genetically high risk of developing schizophrenia, have found neuropsychological impairments that highlight likely trait markers of the schizophrenic genotype. This paper describes the change in neuropsychological function and associations with psychiatric state of high risk participants during the first two assessments of the Edinburgh High Risk Study. METHODS: Seventy-eight high risk participants and 22 normal controls, age and sex matched completed two neuropsychological assessments 18 months to 2 years apart. The areas of function assessed include intellectual function, executive function, learning and memory, and verbal ability and language. RESULTS: The high risk participants performed significantly worse on particular tests of verbal memory and executive function over the two assessments than matched controls. Those high risk participants who experienced psychotic symptoms were found to exhibit a decline in IQ and perform worse on tests of verbal memory and executive function than those without symptoms. An increase in psychotic symptoms between the two assessments in the high risk group was found to be associated with an apparent decline in IQ and memory. CONCLUSIONS: The results suggest that the development of psychotic symptoms is preceded by a decline in IQ and memory. This may reflect a general and a more specific disease process respectively.     

The neuropsychological phenotype of velocardiofacial syndrome (VCFS): relationship to psychopathology.

Children with velocardiofacial syndrome (VCFS; N=14) and a comparison group of siblings (N=8) underwent comprehensive neuropsychological assessment to examine the relationship between cognitive functioning and psychopathology. Significant group differences were obtained on tests of full scale and verbal intellectual functioning and perceptual-motor skills. With the exception of performance on tests of attention and executive functioning, children with VCFS displayed a profile consistent with nonverbal learning disability (NLD). However, within group comparisons revealed significantly poorer visuospatial intellectual and nonverbal memory functioning in sibling controls as well. No significant group differences were obtained on tests of motor speed, academic, language, attention, memory, or executive functioning, with significant variability in children with VCFS frequently accounting for the lack of robust differences. Parent-report measures revealed profiles consistent with ADHD. No clinically significant symptoms of psychosis, depression or anxiety were noted on either self- or parent-report measures. Wisconsin Card Sorting Test performance was found to be highly and negatively correlated with the Thought Problems subscale of the Child Behavior Checklist (CBCL) for VCFS children only, suggesting a possible at-risk indicator for later onset psychopathology.     

Long-term neuropsychological sequelae of fever associated with amnesia.

It has been well established that high fever can cause substantial damage to the cerebellum and also cause multiple small vascular lesions in neocortex and subcortical white matter. Beyond acute effects, the neuropsychological sequelae of these latter cortical and subcortical lesions have not been studied. The investigation reported involved 36 VA patients with a history of serious febrile illness. The febrile illnesses of the pyrexic subjects did not cause febrile seizures and resulted from diseases that did not directly involve the brain (e.g., encephalitis, meningitis, malaria). Control subjects were combat veterans who had suffered gunshot wounds, but who had no history of febrile illness. Pyrexic patients performed worse than controls on a variety of measures including language, memory, concentration, and word finding as well as failing a test of dichotic listening for words. Results demonstrate that hyperpyrexia can have lasting neuropsychological sequelae, and suggest that history of serious febrile illness be considered as an exclusionary criterion for participation in neuropsychological research concerning other topics or disorders.     

Long-term naturalistic treatment of depressive symptoms in bipolar illness with divalproex vs. lithium in the setting of minimal antidepressant use

OBJECTIVE: Risks have been associated with the long-term use of antidepressant in the treatment of bipolar disorder. We review our naturalistic experience with divalproex versus lithium in treating depressive symptoms of bipolar illness. METHOD: All patients with bipolar disorder treated with lithium or divalproex were identified in a university outpatient psychiatry clinic sample over one year (n=38 patients, 41 treatment trials). Treatment response was based on standard prospective symptom rating scales. Mean duration of follow-up was 90 weeks. RESULTS: Lithium and divalproex were equally effective and tolerated in the total sample. Antidepressant effects were noted despite sparing use of standard antidepressant agents (19% received them). Lithium non-responders responded well to divalproex (50%), and vice versa (44%). Divalproex monotherapy (24%) was more common than lithium monotherapy (7%, P=0.07) and was notably effective in treating depressive symptoms, with a 7/10 response on the CGI-BP and improvement on the HDRS (14.8+/-9.2 to 7.6+/-7.8, P=0.003, duration of prospective follow up 26.7 weeks). CONCLUSIONS: Lithium and divalproex were equally effective and tolerated in this naturalistic sample, but responders may represent distinct subgroups. Both agents, but particularly divalproex, demonstrated long-term antidepressant effects, with limited adjunctive standard antidepressant use.     

Brain tissue volumes in relation to cognitive function and risk of dementia

We investigated in a population-based cohort study the association of global and lobar brain tissue volumes with specific cognitive domains and risk of dementia. Participants (n=490; 60-90 years) were non-demented at baseline (1995-1996). From baseline brain MRI-scans we obtained global and lobar volumes of CSF, GM, normal WM, white matter lesions and hippocampus. We performed neuropsychological testing at baseline to assess information processing speed, executive function, memory function and global cognitive function. Participants were followed for incident dementia until January 1, 2005. Larger volumes of CSF and WML were associated with worse performance on all neuropsychological tests, and an increased risk of dementia. Smaller WM volume was related to poorer information processing speed and executive function. In contrast, smaller GM volume was associated with worse memory function and increased risk of dementia. When investigating lobar GM volumes, we found that hippocampal volume and temporal GM volume were most strongly associated with risk of dementia, even in persons without objective and subjective cognitive deficits at baseline, followed by frontal and parietal GM volumes.     

Neuropsychological disturbance in schizophrenia: a diffusion tensor imaging study

Patients with schizophrenia and healthy control subjects underwent both neuropsychological evaluation and magnetic resonance diffusion tensor imaging, during which the cingulum bundle (CB) and the uncinate fasciculus (UF) were defined with fiber tractography and their integrity was quantified. On the basis of prior findings, it was hypothesized that neuropsychological disturbance in schizophrenia may be characterized, in part, by 2 dissociable functional neuroanatomical relationships: (a) executive functioning-CB integrity and (b) episodic memory-UF integrity. In support of the hypothesis, hierarchical regression results indicated that reduced white matter of the CB and the UF differentially and specifically predicted deficits in executive functioning and memory, respectively. Neuropsychological correlates of the CB also extended to lower generalized intelligence, as well as to reduced visual memory that may be related to failures of contextual monitoring of to-be-remembered scenes. Reduced white matter of the CB and the UF may each make distinct contributions to neuropsychological disturbance in schizophrenia.     

Executive dysfunction in medicated, remitted state of major depression

BACKGROUND: Past neuropsychological studies on depression have documented executive dysfunction and it has been reported that some dysfunction persists even after depressive symptoms disappear. Studies have shown a correlation between cerebrovascular lesions and executive dysfunction in depression among the elderly. The aim of the present study was to focus on executive functions in remitted major depressive disorder (MDD) patients, and to investigate whether remitted young and elderly patients show different patterns of executive dysfunction, and to ascertain the relationships with vascular lesions. METHODS: Subjects were 79 inpatients with MDD and 85 healthy controls. Each subject received Wisconsin Card Sorting Test (WCST), Stroop test, and Verbal Fluency Test (VFT) in a remitted state. Both the MDD and control groups were divided into young and elderly groups, and the performances between 4 groups were compared. RESULTS: For Stroop test, the scores of the MDD group were significantly lower than controls. In addition, as for VFT, the scores for the elderly MDD group were significantly lower than the other groups. Multiple regression analysis showed that VFT scores were affected by the presence of vascular lesions. CONCLUSIONS: The results of the present study demonstrated that executive dysfunction remained even in a remitted state in MDD patients, but the patterns of impairment were different between young and elderly patients. The results also suggested that vascular lesions affect executive dysfunction, particularly in elderly depressive patients.     

Brain atrophy associated with baseline and longitudinal measures of cognition

The overall goal was to identify patterns of brain atrophy associated with cognitive impairment and future cognitive decline in non-demented elders. Seventy-one participants were studied with structural MRI and neuropsychological testing at baseline and 1-year follow-up. Deformation-based morphometry was used to examine the relationship between regional baseline brain tissue volume with baseline and longitudinal measures of delayed verbal memory, semantic memory, and executive function. Smaller right hippocampal and entorhinal cortex (ERC) volumes at baseline were associated with worse delayed verbal memory performance at baseline while smaller left ERC volume was associated with greater longitudinal decline. Smaller left superior temporal cortex at baseline was associated with worse semantic memory at baseline, while smaller left temporal white and gray matter volumes were associated with greater semantic memory decline. Increased CSF and smaller frontal lobe volumes were associated with impaired executive function at baseline and greater longitudinal executive decline. These findings suggest that baseline volumes of prefrontal and temporal regions may underlie continuing cognitive decline due to aging, pathology, or both in non-demented elderly individuals.     

Pattern of cognitive dysfunction in depressive patients during maintenance electroconvulsive therapy

BACKGROUND: Objective data regarding adverse cognitive deficits associated with maintenance electroconvulsive therapy (M-ECT) are lacking. This study examined the cognitive state of depressive patients during M-ECT. METHOD: A cross-sectional study was carried out in 11 depressive patients in remission, all with a DSM-IV diagnosis of major depressive disorder. The mean number of previous ECT sessions was 36.1, and the mean intersession interval was 52.7 days. A group of 11 patients who had not received ECT was selected for comparison and matched for diagnosis, sex, age and years of schooling. All subjects were assessed using a complete neuropsychological battery including memory, attention and frontal function tests. RESULTS: Groups did not present differences in long delay verbal recall. Encoding of new information and results on the frontal function tests were significantly lower in the M-ECT patients. CONCLUSION: Depressed patients preserve long-term memory, but suffer short-term memory impairment and frontal function alteration during M-ECT. Further longitudinal studies are necessary to determine the influence of M-ECT on non-memory functions and different memory subtypes.