Kai Stephan Paulus

Longitudinal study of cognitive dysfunction in multiple sclerosis: neuropsychological, neuroradiological, and neurophysiological findings.

Objective: (1) To assess cognitive function and cerebral magnetic resonance imaging (MRI) involvement in relapsing-remitting multiple sclerosis; (2) to monitor disease evolution, cognitive dysfunction, and cerebral lesion burden over time (mean 8.5 year follow up period); (3) to study the relation between clinical, neuropsychological, and MRI data. On follow up assessment, visual and auditory oddball event related potentials (ERPs) were recorded as psychophysiological evaluation of cognitive status. Correlations between neuropsychological, MRI, and ERP data were also analysed. Methods: Neuropsychological study assessed verbal and non-verbal IQ, deterioration index (DI) from WAIS subtests, conceptual reasoning, attention, verbal and visuospatial short-term and long term memory. MRI assessment detected presence of demyelinating lesions by using a semiquantitative method as well as cortical and subcortical atrophy over time. Results: Attention, short-term and long term visuospatial memory were mildly impaired at baseline and remained unaltered longitudinally. At retesting a significant worsening of verbal long term memory (p=0.023), DI presence (p=0.041) and the increase of supratentorial and subtentorial MRI lesions load (p=0.001) emerged. Expanded disability status scale score correlated significantly with total lesion burden at both evaluations (p=0.043 and p=0.024 respectively). Temporal, occipital, and frontal horn lesions as well as cortical atrophy correlated significantly with attention and memory tests at baseline. Follow up assessment revealed significant correlation between cortical atrophy and attention as well as visuospatial short-term memory; spatial long term memory correlated significantly with lesions in body of lateral ventricle and frontal lobe. ERP study showed P300 latency abnormalities in 75% of patients, involving specifically more visual P300 (58.4 % of cases) than auditory wave (41.6 %). Visual P300 latency and amplitude correlated significantly with DI and auditory P300 latency with frontal horn and brain stem lesions. Conclusions: These findings revealed mild cognitive impairment in MS patients particularly consistent with slowing information processing over time. Increased MRI lesions do not correlate with the clinical course of the disease and cognitive deficit evolution. Thus, cognitive dysfunction could be related to disease peculiarity and not to the time course. Correlations between P300, neuropsychological, and MRI findings provide further information about ERP application to examine cognitive impairment in MS and probably to investigate their neural origin.

Visual and auditory event-related potentials in sporadic amyotrophic lateral sclerosis

OBJECTIVES To investigate the relationship between amyotrophic lateral sclerosis (ALS) and cognitive function by means of oddball event-related potentials (ERPs) and to determine the usefulness of this methodology in the cognitive status assessment of physically disabled patients. METHODS Visual and auditory oddball ERPs were recorded in 16 consecutive sporadic ALS patients. A comprehensive battery of neuropsychological (NP) tests assessed intelligence, executive functions, attention, memory, word fluency, visuo-motor and visual-constructive skills. RESULTS All patients performed visual and auditory ERPs and 75% of cases showed abnormal N200 and/or P300 waves. Ten patients (62.5%) carried out the entire psychometric evaluation with significant impairment on tests of executive function and attention. A significant correlation between delayed visual (P<0.04) and auditory (P<0.04) P300 latency and impaired NP tests was found. CONCLUSIONS In agreement with literature data, our findings confirm the hypothesis of cognitive impairment in ALS patients especially on attention and executive functions suggesting a more extensive degeneration beyond the motor areas. ALS causes severe physical disabilities and such a condition may interfere with NP testing. Thus, the P300 seems to be a useful tool for the assessment of cognition and attention when severe physical deficits are present.

Risperidone, neuroleptic malignant syndrome and probable dementia with Lewy bodies.

1. Conflicting reports are available regarding the sensitivity of patients with Dementia with Lewy bodies (DLB) to risperidone. 2. The authors studied a rare familial case of probable DLB, who developed a documented episode of neuroleptic malignant syndrome (NMS) following the exposure to risperidone. Previously, the patient had had an episode of NMS on trifluoperazine. 3. The discontinuance of risperidone, in combination with a mild increase of dopaminergic therapy, led to a complete recovery in few days. 4. In patients with DLB, a continued vigilance for extrapyramidal side effects, including NMS, would be advisable during the use of risperidone.

Paired neurophysiological and clinical study of the brainstem at different stages of Parkinson’s Disease

OBJECTIVE To study brainstem function in Parkinsons Disease (PD) at different stages, through a battery of vestibular-evoked myogenic potentials (VEMPs) and compare the results with scores on clinical scales assessing the presence of symptoms linked to brainstem involvement. METHODS Cervical, masseter and ocular VEMPs were recorded in patients with early PD (n=14, disease duration 1.42±0.7years), advanced PD (n=19, disease duration 7.26±2.9years) and in 27 age-matched controls. In PD, the following clinical scales were administered: Mini-BESTest, REM sleep Behavior Disorder Screening Questionnaire (RBD-SQ), PD Sleep Scale, Epworth Sleepiness Scale and Geriatric Depression Scale. RESULTS Rate of VEMPs alterations was higher (p<0.001) in PD than controls, but similar within PD groups. However, early and advanced PD showed a different pattern of abnormalities (p=0.02), being latency delay prevalent in the former and absence in the latter. VEMP impairment correlated directly with RBD-SQ scores in both PD cohorts and inversely with Mini-BESTest scores in advanced PD. CONCLUSIONS VEMPs displayed progressive severity of alterations at different stages of PD, with remarkable correlations with presence of postural instability and RBD. SIGNIFICANCE The combined use of VEMPs may provide interesting insights into the pathophysiological mechanisms of PD at the earliest and prodromal stage of the disease.

Comparison of two neural network classifiers in the differential diagnosis of essential tremor and Parkinson’s disease by 123 I-FP-CIT brain SPECT

PurposeTo contribute to the differentiation of Parkinson’s disease (PD) and essential tremor (ET), we compared two different artificial neural network classifiers using 123I-FP-CIT SPECT data, a probabilistic neural network (PNN) and a classification tree (ClT).Methods123I-FP-CIT brain SPECT with semiquantitative analysis was performed in 216 patients: 89 with ET, 64 with PD with a Hoehn and Yahr (H&Y) score of ≤2 (early PD), and 63 with PD with a H&Y score of ≥2.5 (advanced PD). For each of the 1,000 experiments carried out, 108 patients were randomly selected as the PNN training set, while the remaining 108 validated the trained PNN, and the percentage of the validation data correctly classified in the three groups of patients was computed. The expected performance of an “average performance PNN” was evaluated. In analogy, for ClT 1,000 classification trees with similar structures were generated.ResultsFor PNN, the probability of correct classification in patients with early PD was 81.9±8.1% (mean±SD), in patients with advanced PD 78.9±8.1%, and in ET patients 96.6±2.6%. For ClT, the first decision rule gave a mean value for the putamen of 5.99, which resulted in a probability of correct classification of 93.5±3.4%. This means that patients with putamen values >5.99 were classified as having ET, while patients with putamen values <5.99 were classified as having PD. Furthermore, if the caudate nucleus value was higher than 6.97 patients were classified as having early PD (probability 69.8±5.3%), and if the value was <6.97 patients were classified as having advanced PD (probability 88.1%±8.8%).ConclusionThese results confirm that PNN achieved valid classification results. Furthermore, ClT provided reliable cut-off values able to differentiate ET and PD of different severities.

Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson's disease, a triggering role in the disease?

Environmental factors are implicated in the development of Parkinsons disease (PD). We have investigated on the role of molecular mimicry between HSV1 and α-synuclein that could foster the progression of PD. The antibody response against homologous peptides in PD patients and healthy controls was evaluated, showing that these antibodies are highly prevalent among PD patients to healthy controls. The competitive assay demonstrated cross-reactivity between HSV1 and human α-synuclein peptides. The results may suggest the hypothesis of the involvement of HSV1 in stimulating the immune cells against the neurons of the substantia nigra as a consequence of the cross reactivity.

Neuropsychophysiological findings in a case of long-standing overt ventriculomegaly (LOVA).

Long-standing overt ventriculomegaly in adults (LOVA) is a clinical entity characterized by chronic hydrocephalus with infant onset, slow evolution and clinical disturbances during adulthood. Few cases are reported in literature describing the evident contrast between the severity of hydrocephalus and the relatively spared neurological functioning and cognitive aspects. The authors describe a 59-year-old man with congenital hydrocephalus complaining of persistent gait impairment. Neurological examination showed a mild paraparesis, severe higher cortical function impairment but relatively sparing of daily living activity. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a very remarkable ventriculomegaly compressing the brain cortex but sparing the cerebellum and the brainstem. Brain Single Photon Emission Computer Tomography (SPECT) showed a prevalent cerebellar perfusion as well. Neuropsychological testing was consistent with severe cognitive deterioration and attention disorders. Language and praxis functions seemed to be preserved. Auditory oddball ERPs (P300) showed morphological abnormalities especially of late components. This case report demonstrates in vivo the level of adaptation to which human brain can reach under chronic mechanic stress conditions. The striking poor cerebral parenchyma representation and the relatively spared language and praxic abilities account for a functional reorganization of residual structures due to the neural plasticity.

Dance therapy improves motor and cognitive functions in patients with Parkinson’s disease

OBJECTIVE To explore the effects of Dance Therapy (DT) and Traditional Rehabilitation (TR) on both motor and cognitive domains in Parkinsons Disease patients (PD) with postural instability. METHODS Sixteen PD patients with recent history of falls were divided in two groups (Dance Therapy, DT and Traditional Rehabilitation, TR); nine patients received 1-hour DT classes twice per week, completing 20 lessons within 10 weeks; seven patients received a similar cycle of 20 group sessions of 60 minutes TR. Motor (Berg Balance Scale - BBS, Gait Dynamic Index - GDI, Timed Up and Go Test - TUG, 4 Square-Step Test - 4SST, 6-Minute Walking Test - 6MWT) and cognitive measures (Frontal Assessment Battery - FAB, Trail Making Test A & B - TMT A&B, Stroop Test) were tested at baseline, after the treatment completion and after 8-week follow-up. RESULTS In the DT group, but not in the TR group, motor and cognitive outcomes significantly improved after treatment and retained after follow-up. Significant changes were found for 6MWT (p = 0.028), TUG (p = 0.007), TMT-A (p = 0.014) and TMT-B (p = 0.036). CONCLUSIONS DT is an unconventional physical therapy for PD patients which effectively impacts on motor (endurance and risk of falls) and non-motor functions (executive functions).

Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson's disease

Environmental factors are implicated in the development of Parkinsons disease (PD). The aim of this study is to investigate the role of cell-mediated immunity upon a specific immune-stimulation with HSV-1 and human alpha-synuclein homologues peptides by using the intracellular cytokine method on Parkinsons patients and healthy controls. The study showed, for the first time, a specific response to TNF-α CD8, CD4 and NK cells after stimulation in PD patients. Our data show a possible role of the immune system in the pathogenesis of Parkinsons disease, and that HSV-1 infections may lead to a progression of the disease.

Is there a role for Mycobacterium avium subspecies paratuberculosis in Parkinson's disease?

In Parkinsons disease (PD) ZnT proteins play an important role. Zinc is a co-factor of numerous enzymes and stabilizes the tertiary structure of several proteins. Nothing is known about previous infections mediated by Mycobacterium avium subsp. paratuberculosis (MAP). We evaluated if a previous infection with MAP could induce the production of antibodies that cross-reacted with the Znt homologous antigenic peptides associated to Parkinson. The humoral response toward MAP3865c peptides, ZnT3 and ZnT10 was evaluated. The hypothesis of cross-reactivity needs to be confirmed; we have observed the presence of MAP in PD patients by PCR, positivity to MAP3865c peptides, therefore MAP infection but not cross-reaction with human homologous Znt proteins.