Depression in multiple sclerosis: effect of brain derived neurotrophic factor Val66Met polymorphism and disease perception.

BACKGROUND AND PURPOSE: Depression is common amongst subjects with multiple sclerosis (MS), and several investigations have explored different determinants of this condition, including physical disability, psychological and psychosocial factors. The brain derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with depression. The aim of this study was to analyze the influence of disease-related factors, BDNF Val66Met polymorphism and perception of disease on the severity of depression in MS. METHOD: In total, 136 MS patients (88 women) were recruited and genotyped for BDNF rs6265 polymorphism at nucleotide 196 (G/A) using 'high resolution melting'. Depressive symptoms were assessed by the Multiple Sclerosis Depression Rating Scale. Perception of health status was assessed using the SF-36 questionnaire. RESULTS: A multivariable linear regression model showed that the best predictors of depression were the SF-36 General health (ß = -0.209; P = 0.013), Mental health (ß = -0.410; P < 0.001) and Social activity (ß = -0.195; P = 0.035) scores; physical disability (assessed by the Extended Disability Status Scale score) was directly correlated to depression severity on univariate analysis, but it was not a relevant predictor of depression on multivariate analysis; other variables directly related to the disease (treatment, annual relapsing rate) and the BDNF Val66Met polymorphism were not significantly associated with depression. CONCLUSION: Perception of the health status is the principal predictor of depressive symptoms in our sample. This result supports the hypothesis that the subjective interpretation of the disease's consequences is one of the main factors in determining depression in MS.

Familiarity for famous faces and names is not equally subtended by the right and left temporal poles. Evidence from an rTMS study.

The aims of the present experiment was to investigate: (a) if transient disruption of neural activity in the right (RTP) or left temporal pole (LTP) can interfere with the development of a familiarity feeling to the presentation of faces/written names of famous/unknown people; and (b) if this interference specifically affects the familiarity for faces after inhibition of the RTP and for names after inhibition of the LTP. Twenty healthy volunteers took part in the study. Repetitive transcranial magnetic stimulation (rTMS) was administered online; it disrupted the neural activity of the right or left TP in concomitance with the presentation of each face and name whose familiarity had to be assessed. Furthermore, in a control group, each participant was submitted to a single experimental session in which rTMS was delivered to the vertex in association with the presentation of faces and written names. Since previous rTMS studies have shown that the temporary inactivation of the right and left TP influences the response latencies, but not the number of correct responses, in this study we took into account both the number of correct responses obtained in different experimental conditions and the corresponding response latencies. A three-way factorial ANOVA carried out on the Response Scores showed only a general effect of the Type of Stimuli, due to better performances on names than on faces. This greater familiarity of names is consistent with previous data reported in the literature. In the three-way factorial ANOVA carried out on the Latency Scores, post-hoc analyses showed an increased latency of responses to faces after right stimulation in Latency Total, Latency on Correct responses and Latency on Unfamiliar faces. None of these results were obtained in the control group. These data suggest that rTMS at the level of the RTP preferentially affects the development of familiarity feelings to the presentation of faces of famous people.

The Multiple Features Target Cancellation (MFTC): an attentional visual conjunction search test. Normative values for the Italian population.

Several studies, showing that attention disorders during encoding reduce later memory performance, have stressed the critical role of attention for the formation of durable memory traces. Accordingly, some studies suggest that attentive disturbances, together with declarative memory defects, can constitute the earliest cognitive disorders in Alzheimer's disease. Therefore, the analysis of these disorders can contribute to identify different forms of dementia and to detect demented patients characterized by a faster cognitive decline. In this study, we report the normative data (gathered in a large Italian population) of a short test that assess the ability to detect stimuli characterized by a conjunction of features: the 'Multiple Features Targets Cancellation' task (MFTC). Our sample of 465 subjects was composed by urban and rural people. Multiple linear regression analyses revealed significant relation of false alarms with age and educational level, and of time of execution with age, educational level and gender. Regression analyses on accuracy scores did not show any significant correlation with demographics variables. Based on non-parametric techniques, cutoff scores were obtained on the corrected scores of the patients, and equivalent scores were derived for each measure. The MFTC task represents a useful tool that explores attentional disorders (and in particular conjunction search disturbances) and that could be helpful both in discriminating different forms of dementia and to detect mild cognitive impairment patients at risk of conversion to dementia.

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia.

BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.

False alarms during recognition of famous people from faces and voices in patients with unilateral temporal lobe resection and normal participants tested after anodal tDCS over the left or right ATL.

Data gathered in the field of the experimental social psychology have shown that it is more difficult to recognize a person through his/her voice than through his/her face and that false alarms (FA) are produced more in voice than in face recognition. Furthermore, some neuropsychological investigations have suggested that in patients with damage to the right anterior temporal lobe (ATL) the number of FA could be higher for voice than for face recognition. In the present study we assessed FA during recognition of famous people from faces and voices in patients with unilateral ATL tumours and in normal participants tested after anodal transcranial direct current stimulation (tCDS), over the left or right ATL. The number of FA was significantly higher in patients with right than in those with left temporal tumours on both face and voice familiarity. Furthermore, lesion side did not differentially affect patient's sensitivity or response criterion when recognizing famous faces, but influenced both these measures on a voice recognition task. In fact, in this condition patients with right temporal tumours showed a lower sensitivity index and a lower response criterion than those with left-sided lesions. In normal subjects, the greater right sided involvement in voice than in face processing was confirmed by the observation that right ATL anodal stimulation significantly increased voice but only marginally influenced face sensitivity. This asymmetry between face and voice processing in the right hemisphere could be due to the greater complexity of voice processing and to the difficulty of forming stable and well-structured representations, allowing to evaluate if a presented voice matches or not with an already known voice.

Correlations between peripheral blood mononuclear cell production of BDNF, TNF-alpha, IL-6, IL-10 and cognitive performances in multiple sclerosis patients.

The aim of this study was to investigate the role of Brain Derived Neurotrophic Factor (BDNF) and inflammatory factors in the development of cognitive dysfunctions in Multiple Sclerosis (MS). We correlated peripheral blood mononuclear cell (PBMC) production of BDNF, Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin (IL)-6 and IL-10 with performances on specific neuropsychological tasks in a selected series of MS patients. We studied a sample of 30 patients with relapsing-remitting (RR)MS, segregated by gender and matched for age, education, disease duration, type of immunomodulating therapy, degree of disability and overall cognitive status. We found that low BDNF levels were correlated with increased time of execution on a divided attention and visual scanning task whereas high levels of IL-6 were correlated with low Mini Mental State Examination scores. We did not observe any significant correlations between IL-10, TNF-alpha levels and cognitive performances in our patients. In conclusion our study shows a correlation between low BDNF and high IL-6 production by PBMCs and poorer performances in cognitive tasks in RRMS patients suggesting a possible role of these factors in cognitive impairment in MS.

EFNS guidelines for the diagnosis and management of Alzheimer's disease.

BACKGROUND AND OBJECTIVES: In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer's disease (AD) and other disorders associated with dementia, published in early 2007. The aim of this revised international guideline was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD. Mild cognitive impairment and non-Alzheimer dementias are not included in this guideline. METHODS: The task force working group reviewed evidence from original research articles, meta-analysis, and systematic reviews, published before May 2009. The evidence was classified and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS: The recommendations for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of AD, behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers were all revised as compared with the previous EFNS guideline. CONCLUSION: A number of new recommendations and good practice points are made, namely in CSF, neuropsychology, neuroimaging and reviewing non-evidence based therapies. The assessment, interpretation, and treatment of symptoms, disability, needs, and caregiver stress during the course of AD require the contribution of many different professionals. These professionals should adhere to these guideline to improve the diagnosis and management of AD.

In vivo functional evaluation of central cholinergic circuits in vascular dementia.

OBJECTIVE: Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of motor cortex. This test, named short latency afferent inhibition (SAI) has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in Alzheimer disease (AD) patients, a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. The objective of present study was to evaluate central cholinergic circuits in patients with Vascular Dementia (VaD). METHODS: We evaluated SAI in a group of patients with VaD and compared the data with those from a group of AD patients and a control group of age-matched healthy individuals. RESULTS: Mean SAI was normal in VaD patients while it was significantly reduced in AD patients. The analysis of individual data showed abnormal SAI in 75% of AD and in only 25% of VaD. CONCLUSIONS: SAI is normal in most of VaD patients in contrast with AD patients. This test might be used for the functional evaluation of central cholinergic circuits in VaD patients. SIGNIFICANCE: SAI testing may represent a useful additional tool for the evaluation of patients with VaD however, further studies are required in order to evaluate whether this method can be used for the differential diagnosis between pure VaD and different forms of dementia.

Defective recognition and naming of famous people from voice in patients with unilateral temporal lobe tumours.

Twenty-nine patients who underwent surgery for a temporal glioma, either in the left (16 patients) or right (13 patients) hemisphere, were administered standardized tests of unknown voice discrimination (UVD) and of famous voice recognition (VO-REC), which included tasks of familiarity evaluation, semantic identification and naming of famous voices. The UVD consisted of twenty stimuli, in which two audio files were consecutively presented; the subject was requested to judge whether the voices belonged to the same or different persons. In the VO-REC, patients were requested to recognize the voices of 40 very well known people; these voices were intermingled with the voices of 20 unknown people for a familiarity check, followed by identification and naming of persons recognized as familiar. We aimed at verifying the effect of laterality and intra-temporal site of lesion on familiarity assessment, false alarms, identification and naming of familiar people. As for the effect of lesion side, our results showed that patients with right temporal gliomas were significantly more impaired in voices discrimination and produced more false alarms than patients with a left glioma, who, in turn, were significantly more impaired in name retrieval than patients with a right temporal glioma. The high number of false alarms in patients with a right temporal glioma suggests that familiarity judgment was impaired. Regarding the neuroanatomical correlates of these different patterns of impairment, MRI data suggested that: (a) UVD disorders are due to lesions involving the whole right anterior temporal lobe and extending to lateral portions of the temporal and frontal lobes; (b) familiarity judgments (testified by an increased number of false alarms) are impaired in lesions restricted to the right anterior temporal lobe; (c) name retrieval deficits are found only in patients with left temporal lesions. UVD disorders were interpreted, at least in part, as due to an impairment of executive functions, resulting from a disconnection of the right temporal lobe from the frontal lobe control. A partly unexpected finding was that some patients with a right temporal tumour had a normal performance in famous voice recognition and identification, in spite of having severe voice discrimination disturbances. These unexpected results, in agreement with previous observation made in the visual (face) modality, are inconsistent with strictly hierarchical models of voice processing.

Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease.

AIM: To assess the long-term cognitive and behavioural outcome after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients affected by Parkinson's disease, with a 5-year follow-up after surgery. METHODS: 11 patients with Parkinson's disease treated by bilateral DBS of STN underwent cognitive and behavioural assessments before implantation, and 1 and 5 years after surgery. Postoperative cognitive assessments were carried out with stimulators turned on. RESULTS: A year after surgery, there was a marginally significant decline on a letter verbal fluency task (p = 0.045) and a significant improvement on Mini-Mental State Examination (p = 0.009). 5 years after surgery, a significant decline was observed on a letter verbal fluency task (p = 0.007) and an abstract reasoning task (p = 0.009), namely Raven's Progressive Matrices 1947. No significant postoperative change was observed on other cognitive variables. No patient developed dementia 5 years after surgery. A few days after the implantation, two patients developed transient manic symptoms with hypersexuality and one patient developed persistent apathy. CONCLUSION: The decline of verbal fluency observed 5 years after implantation for DBS in STN did not have a clinically meaningful effect on daily living activities in our patients with Parkinson's disease. As no patient developed global cognitive deterioration in our sample, these findings suggest that DBS of STN is associated with a low cognitive and behavioural morbidity over a 5-year follow-up, when selection criteria for neurosurgery are strict.

Lateralization of brain mechanisms underlying automatic and controlled forms of spatial orienting of attention.

Unilateral Spatial Neglect (USN) can be considered as a defect in spatial orienting of attention toward the half space contralateral to the damaged hemisphere. Since the classical work of Brain, W.R. Brain 64:224-272 (1941), several authors have emphasized that this defect is definitely more frequent and severe in patients with right brain damage, but the reason for this hemispheric asymmetry has remained controversial. Several investigations conducted with different experimental paradigms in different laboratories have shown that only automatic orienting of attention toward stimuli arising in the half space contralateral to the damaged hemisphere is disrupted in USN, whereas controlled, volitional orienting can be more or less completely spared. The hypothesis that at the level of the right hemisphere, spatial orienting of attention may be mainly prompted by automatic mechanisms may, therefore, be advanced. By contrast, the left hemisphere might play a leading role in mechanisms underlying volitional orienting of attention. According to this model, recovery from USN could be due to substitution of the lost automatic orienting mechanisms with the spread volitional orienting mechanisms subserved by the intact left hemisphere.

Sexual behavior and hemispheric laterality of the focus in patients with temporal lobe epilepsy.

Various studies have described an unusually common incidence of sexual and reproductive dysfunction in patients affected by temporal lobe epilepsy (TLE). The purpose of the present study was to further investigate, by means of an ad hoc questionnaire, the relationship between sexual disorders and the hemispheric laterality of the epileptic focus in men and women with right (R) TLE and left (L) TLE. The results suggest a reduction of sexual interest in patients with R-TLE as compared with L-TLE in both men and women. This effect was fundamentally observed when sexual interest was implicitly explored. No significant difference was found between R-TLE and L-TLE groups concerning most aspects of sexual performance. Various hypotheses are discussed to interpret this effect of hemispheric lateralization on sexual interest.

The relationship between visuospatial and representational neglect.

Using a quantitative measure, we analyzed the relationship between visuospatial and representational neglect in right- and left-brain-damaged patients and found signs of representational neglect only in right-brain-damaged patients. Although representational neglect was always associated with visuospatial neglect, suggesting that the two forms share a common underlying mechanism, the most frequent finding in right-brain--damaged patients was that of visuospatial neglect in isolation. A strong influence of the phenomenon of attentional attraction toward space ipsilateral to the lesion in visuospatial, as opposed to imaginal, tasks can account for this finding.

Choline acetyltransferase (ChAT) activity differs in right and left human temporal lobes.

Choline acetyltransferase (ChAT) activity was studied in different areas and in sequential sections of the cortical layers in the first temporal gyrus of left and right hemispheres of four human brains. The ChAT activity values obtained in all the samples from left hemisphere were significantly higher than in the right hemisphere. Furthermore, the study of ChAT activity in the cortical layers in Brodmann area 22 shows a greater left prevalence of enzymatic activity in cortical layers II and IV. The biochemical data seem to suggest a possible morphologic and/or functional difference between the two hemispheres.

Dissociation between knowledge of living and nonliving things in dementia of the Alzheimer type.

Patients who survive herpes simplex encephalitis (HSE) sometimes present a category-specific disorder for living things. Since HSE specifically involves the temporolimbic structures of both hemispheres, these structures could play a critical role in processing and storing information about living things. If this were the case, a category-specific disorder for the same items should also be observed in the early stages of dementia of the Alzheimer type (DAT) as the temporolimbic structures are often severely affected in this condition. To test this hypothesis, we administered to 15 DAT patients and to 10 normal controls a confrontation-naming task and a verbal associates recognition task, with both living and nonliving items as stimuli. The hypothesis was confirmed, since DAT patients performed worse with living than with nonliving items, and scored worse than normal controls on the living but not the nonliving items.

Laterally directed arm movements and right unilateral neglect after left hemisphere damage.

Signs of unilateral neglect for events occurring in one hemispace most often result from right hemisphere lesions. Right unilateral neglect after left hemisphere damage is much rarer, and has received less attention. The present study explores the relationships between right unilateral neglect and asymmetries in producing laterally directed arm movements in the horizontal plane in left brain-damaged (LBD) patients. Participants produced right- or left-directed arm movements with their left arm in response to centrally located visual stimuli. Results showed that LBD patients with signs of right unilateral neglect were consistently slowed when producing arm movements toward the right (neglected) side, as compared to left-directed movements. Taking into account patients with and without signs of neglect, this directional asymmetry positively correlated with a reaction-time measure of perceptual spatial bias. These findings stand in contrast with previous results obtained with the same experimental paradigm in right brain-damaged patients, in whom a consistent slowing of leftward-directed movements was rare and apparently unrelated to the presence and severity of left neglect. These conflicting results are discussed with respect to the hypothesis that different mechanisms may underlie left and right unilateral neglect.

Constructive disabilities in focal brain-damaged patients. Influence of hemispheric side, locus of lesion and coexistent mental deterioration.

The performance of 185 focal brain-damaged patients on two non-verbal constructive tasks ('Copying Drawings' and 'Copying Drawings with Landmarks') was evaluated with regard to three variables: laterality of cerebral lesion, intrahemispheric locus of lesion, and coexistence of mental deterioration. The aim of the study was to assess the relationships between each of these variables and both the incidence and severity of constructional apraxia. Different evaluations were carried out in order to partial-out the possible interference of unilateral spatial neglect. Results showed that, regardless of whether faults attributable to unilateral spatial neglect were penalized or not: right brain-damaged patients performed slightly worse and showed a higher percentage of pathologic performances than left brain-damaged patients; subjects with parietal--and particularly with right parietal--damage obtained the poorest mean scores and exhibited the highest incidence of apraxic performances; and coexistence of mental deterioration was the most relevant variable associated with global decay of constructive scores and incidence of constructional apraxia.

Evidence for a possible neuroanatomical basis for lexical processing of nouns and verbs.

Neuropsychological studies have revealed that brain-damaged patients may show impairments of specific word categories. This study reports the performance of three patients with impairments of the categories noun and verb. The first and second patients, with left frontal lobe atrophy, were impaired in naming and comprehension of verbs. The third patient, with striking atrophy of the left temporal lobe, was disproportionately impaired in naming and comprehension of nouns. These findings suggest that anatomically distinct neural systems in the temporal and frontal lobes of the dominant hemisphere might play a critical role in lexical processing of nouns and verbs, respectively.

Early rightwards orienting of attention on simple reaction time performance in patients with left-sided neglect.

A specific disruption in the ability to automatically disengage attention from its previous focus has been hypothesized to account for the extinction phenomenon often observed in the unilateral spatial neglect syndrome. Recent literature, however, also brings out the role played in neglect by an imbalance in the attentional orienting systems, resulting in an early shift of attention towards the side of space ipsilateral to the brain lesion. In the present study we hypothesized that this attentional bias in orienting of attention might be demonstrated in a paradigm of simple reaction time to lateralized visual stimuli by contrasting the presence vs the absence on the computer screen of the square boxes used to facilitate position expectancy. A main prediction was made that patients with neglect would show a significant increase in reaction time to contralateral visual stimuli in the presence of bilateral reference boxes as compared to conditions in which no boxes were displayed. The right-sided box was in fact expected to exert an early attraction on the patient's attention, thus modifying the pattern of reaction times to the proper targets. This prediction was confirmed in right brain-damaged patients with moderate to severe neglect.

The production of morphological and lexical opposites in aphasia.

Four unselected groups of Broca's, Wernicke's, conduction, amnesic aphasic patients and a group of normal controls were asked to produce the best opposite of 60 adjectives. For half of the stimuli the expected opposite was morphologically related to the stimulus word (e.g. "formal"/"informal"), for the other half it could be obtained only by selecting a new base-form within the lexicon (e.g. "good"/"bad"). Following some neurolinguistic observations by Hécaen et al., it was predicted that amnesic patients should produce mainly morphological opposites, whereas conduction aphasics should produce mainly lexical antonyms. Results confirmed the predictions, since amnesic aphasics showed a prevalent impairment in the selection lexical opposites, whereas conduction aphasics showed a selective impairment in the production of morphological antonyms.