Johanne Somme

Initial neuropsychological impairments in patients with the E46K mutation of the α-synuclein gene (PARK 1).

INTRODUCTION In 2004 we described the mutation E46K of the α-Synuclein (SNCA). These patients show Parkinsons disease with early cognitive impairment, sleep disorders and autonomic dysfunction. OBJECTIVE The main objective is to identify early neuropsychological impairments in patients with the E46K mutation. METHODS This is a longitudinal neuropsychological study of 4 of the 5 surviving patients with E46K mutation by semi-structured interviews and the following scales: Mattis Dementia Rating Scale (MDRS), semantic and phonemic verbal fluency tests (VFT), Benton Visual Retention Test (BVRT), Stroop Test (STROOP), Clock drawing test (CLOCK), WAIS III Letter and Number sequencing (WAIS III LN), Rey Auditory Verbal Learning Test (RAVLT) and Benton Judgement of Line Orientation Test (BJLOT). Motor status was assessed by UPDRS III. RESULTS Motor status: Patients 1, 2 and 3 present mild to moderate Parkinson disease of 7, 8 and 3years of evolution respectively, patient 4 is asymptomatic. Cognitive status: Patient 2 and 3 both refer cognitive decline while patient 1 presents no cognitive complaints, however they all show a progressive cognitive decline across various tasks. Tests of frontal function showed the first alterations in all patients but fluctuate. The first cognitive complaints coincide with deterioration of tasks of posterior cortical basis. Patient 4 presents a normal performance on all tests. Patient 1, 2 and 3 have all presented visual hallucinations. CONCLUSIONS A fluctuating frontal impairment is observed at early stages. Prominent visuospatial alterations and visual hallucinations suggest that posterior cortical dysfunction might be a distinct early feature of the cognitive impairment observed in patients with this mutation.

Cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K mutation in the α synuclein gene

OBJECTIVE The aim of this study was to analyze autonomic function and cardiac sympathetic innervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene (SNCA) mutation. PATIENTS AND METHODS Autonomic function tests were performed in six patients, four of whom were symptomatic carriers (ages: 46, 59, 52 and 28-years) and two who were asymptomatic carriers (ages: 52 and 29 years). Autopsy studies were performed on an additional two symptomatic carriers not eligible for autonomic testing. Patients completed the SCOPA autonomic questionnaire, and underwent the head-up tilt test accompanied by measurements of plasma norepinephrine. Valsalva maneuver and deep breathing tests, along with recording of sympathetic skin response (SSR) and cardiac MIBG scintigraphy were carried out. Myocardial tissue sections removed from the two autopsied cases were subjected to routine histological staining and immunohistochemical processing with monoclonal antibodies against tyrosine hydroxylase and alpha-synuclein. RESULTS Both the four symptomatic and the older asymptomatic carriers reported abnormalities in the SCOPA questionnaire and had markedly diminished cardiac MIBG uptake. Plasma norepinephrine in the supine and tilted positions was normal in all subjects. Only one patient had significant orthostatic hypotension. There was a complete absence of tyrosine hydroxylase immunostaining in the myocardium of the two autopsied cases. INTERPRETATION We have found imaging and histological evidence of cardiac sympathetic denervation in symptomatic and asymptomatic carriers of the E46K alpha-synuclein gene mutation. The sympathetic denervation appears to be organ-specific, with selective affectation of the heart given that plasma norepinephrine levels and blood pressure were normal.

Neuropsychiatric Symptoms in Amnestic Mild Cognitive Impairment: Increased Risk and Faster Progression to Dementia

Introduction. Neuropsychiatric symptoms (NPS) are common in mild cognitive impairment (MCI) but its role as a predictive factor for the progression to dementia is still not clear. The objective of this study is to identify NPS that predict the progression from amnestic MCI (a-MCI) to dementia using an easy to administer screening tool for NPS. Material and Methods. 132 patients with a-MCI were assessed for NPS by the Neuropsychiatric Inventory (NPI) and followed to detect progression to dementia. Results. The mean follow-up time was 3.5±2.9 years and rate of progression to dementia 28.8%. Two items of NPI were found to be independent risk factors for progression, nighttime behavioural disturbance (hazard ratio(HR)=2.2, 95%CI=1.10-4.43), anxiety (HR=2.5, 95%CI=1.01-6.20) and apathy (HR=2.2, 95%CI=1.003-4.820). The risk of progression increased with higher score on NPI (HR=1.046 per point, 95%CI=1.019- 1.073), and with a higher number of items of NPI affected (HR=3.6 per item, 95%CI=2.0-6.4). Faster progression to dementia was observed in patients with either nighttime behavioural disturbance, apathy or anxiety (4.6 vs. 8.3 years, 5.3 vs. 8.4 years and 3.0 vs. 7.7 years respectively, p 3 items = 2.9 years, p<0.001). Conclusions. Assessing a broad spectrum of NPS can help identify patients with a-MCI presenting a higher risk for progression to dementia. This can be useful to select patients for closer follow-up, clinical trials and future therapeutic interventions.

Cerebrospinal fluid Aβ levels correlate with structural brain changes in Parkinson's disease.

ParkWest is a large Norwegian multicenter study of newly diagnosed drug‐naïve subjects with Parkinsons disease (PD). Cognitively normal PD subjects (PDCN) and PD subjects with mild cognitive impairment (PDMCI) from this cohort have significant hippocampal atrophy and ventricular enlargement, compared to normal controls. Here, we aimed to investigate whether the same structural changes are associated with cerebrospinal fluid (CSF) levels of amyloid beta (Aβ)38, Aβ40, Aβ42, total tau (t‐tau), and phosphorylated tau (p‐tau). We performed three‐dimensional radial distance analyses of the hippocampi and lateral ventricles using the MRI data from ParkWest subjects who provided CSF at baseline. Our sample consisted of 73 PDCN and 18 PDMCI subjects. We found significant associations between levels of all three CSF Aβ analytes and t‐tau and lateral ventricular enlargement in the pooled sample. In the PDCN sample, all three amyloid analytes showed significant associations with the radial distance of the occipital and frontal horns of the lateral ventricles. CSF Aβ38 and Aβ42 showed negative associations, with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and a negative association with the occipital horns in PDMCI. CSF Aβ levels in early PD correlate with ventricular enlargement, previously associated with PD dementia. Therefore, CSF and MRI markers may help identify PD patients at high risk for developing cognitive decline and dementia in the course of their illness. Contrary to Alzheimers disease, we found no associations between CSF t‐tau and p‐tau and hippocampal atrophy.

SCOPA-AUT scale in different parkinsonisms and its correlation with (123) I-MIBG cardiac scintigraphy.

INTRODUCTION Our objective was to assess the usefulness of the Scales for Outcomes in Parkinsons disease - Autonomic (SCOPA-AUT) in the differential diagnosis of Parkinsonisms and clarify its relation with 123-I-MIBG cardiac scintigraphy. METHODS A total of 112 patients with Parkinsons disease (PD), 12 with multiple system atrophy parkinsonian variant (MSA-P) and 20 with progressive supranuclear palsy (PSP) participated in the study. The following variables were collected: age, sex, age at onset, length of illness, type and dose of anti-Parkinson medication, and score on the Unified Parkinsons Disease Rating Scale. The Unified Multiple System Atrophy Rating Scale was administered to patients with MSA and the Progressive Supranuclear Palsy Rating Scale to those with PSP. Finally, the SCOPA-AUT was administered to all the patients. Cardiac 123I-MIBG SPECT scans were performed on a subset of patients (25 with PD and 5 with MSA-P). RESULTS Statistically significant differences were observed (p < 0.01) in the SCOPA-AUT scores between patients with PD (14.75+/-8.09) and those with MSA (21.07+/-5.56), the latter having higher scores on the bowel function (20.07+/-13.40 vs 34.92+/-14.91) and urinary domains (30.21+/-21.55 vs 49.26+/-21.40) (p < 0.01). No correlation was found between the SCOPA-AUT score and anti-Parkinsons medication and heart:mediastinum (H/M) MIBG uptake ratio in the cardiac SPECT (at 4 h). DISCUSSION Severity of dysautonomia as measured by the SCOPA-AUT was not correlated with clinical severity, time since onset or the H/M ratio. In the patients with PD, the only variable associated with the H/M ratio was age at onset of the disease.

Application of depression criteria (DSM-IV) in patients with Parkinson's disease

INTRODUCTION The aim of this study is to analyze the clinical differences between Parkinsons disease patients with major (MD) and minor depression (md) and to see how both affect the quality of life. MATERIAL AND METHODS 118 patients diagnosed with Parkinsons disease. The mean age of onset was 60.4+/-11.2 years with a mean duration of 8.5+/-6.2 years. Depression was diagnosed according to DSM-IV-TR criteria. Scores on the Hamilton depression inventory, MMSE, PDQ-39, NPI-10, UPDRS III, and UPDRS IV were recorded. RESULTS Twenty-one patients (17.8%) met the criteria of major depression (MD) and 33 (28.0%) those of minor depression (md). The scores on the PDQ-39 and NPI-10 of patients with MD were higher than in patients with md, and control group. The MMSE scores were lower in patients with MD. In 52.2% of the patients with MD, the diagnosis of depression was made prior to that of PD, this occurred only in 24.2% of the patients with md (p<0.001). The presence of anhedonia was related to cognitive impairment and the presence of neuropsychiatric symptoms. DISCUSSION MD is probably a part of the disease process of PD; it is associated with cognitive impairment and may precede motor symptoms.

Factors influencing the symmetry of Parkinson's disease symptoms

INTRODUCTION The presence of asymmetry in symptoms and clinical signs favours the diagnosis of Parkinsons disease (PD). The aim of this study is to analyse this symptom asymmetry as a function of different variables and compare it with other parkinsonisms. MATERIALS AND METHODS 201 Patients with PD were studied. The sample was supplemented with 29 patients diagnosed with MSA-P (according to the criteria established by the American Academy of Neurology) and 17 with PSP (according to the criteria established by the NINDS-SPSP International Workshop). The symmetry was evaluated, based on items 20-23, 25 and 26 of the Unified Parkinsons Disease Rating Scale, by subtracting the motor score for the left side from that for the right side. Those patients with a difference of one point or more were designated as being asymmetric. RESULTS Around 16.4% of patients presented symmetrical clinical symptoms. There were no differences between those patients with or without family history of the disease. Those patients with symmetric symptoms were found to have longer symptomatic disease duration (10.8 vs. 7.9 years), a worse mental state (UPDRS I: 3.9 vs. 3.2), a higher incidence of complications (UPDRS IV: 4.5 vs. 3.2) and had their activities of daily living (ADL) affected to a greater degree (UPDRS II: 13.0 vs. 11.0). Around 48.3% of the MSA-P patients and 52.9% of the PSP patients showed symmetric symptoms. CONCLUSIONS The degree of symmetry is not useful in differentiating between sporadic and familial PD. However, the observation of highly symmetrical symptoms in a patient with short evolution time indicates that an atypical parkinsonism should be suspected.

The applause sign and neuropsychological profile in progressive supranuclear palsy and Parkinson's disease

BACKGROUND The applause sign has been associated with various neurodegenerative diseases. We investigate its validity in the differential diagnosis of progressive supranuclear palsy and Parkinsons disease, and its relationship with neuropsychological tests. PATIENTS AND METHODS 23 patients with progressive supranuclear palsy and 106 patients with Parkinsons disease were included and administered the following scales: progressive supranuclear palsy rating scale, unified Parkinsons disease rating scale (UPDRS), mini-mental state examination (MMSE), frontal assessment battery (FAB), neuropsychiatric inventory and three-clap test. RESULTS 73.9% with progressive supranuclear palsy and 21.7% with Parkinsons disease showed a positive applause sign. Only a positive applause sign, UPDRS II score and disease duration were found to be predictors of progressive supranuclear palsy. Both patient-groups showed statistically significant correlations between the applause sign and neuropsychological tests: in progressive supranuclear palsy patients MMSE correlation coefficient: 0.62 (p: 0.002) and FAB correlation coefficient: 0.48 (p: 0.02), and in Parkinsons disease patients MMSE correlation coefficient: 0.47 (p<0.001) and FAB correlation coefficient: 0.43 (p<0.001). Verbal fluency and inhibitory control (FAB) and writing and orientation in time (MMSE) discriminated between patients with normal and positive applause sign. CONCLUSIONS A positive applause sign is not specific to progressive supranuclear palsy and may also be observed in Parkinsons disease patients with altered cognition, and its related to cortical frontal abnormalities such as language disorders and inhibitory control.

Neuroleptic malignant syndrome and serotonin syndrome in a female patient: a clinicopathologic case.

We report the case of a 24-year-old female patient who initially developed a neuroleptic malignant syndrome after haloperidol exposure and experienced 6 years later a serotonin syndrome after repeated fluoxetine exposure. The patient did not respond to symptomatic treatment and died in this latter episode. At necropsy, no gross or microscopic changes were seen with conventional histological stains, and immunohistochemical stains were negative. This is the first clinicopathologic case of a patient who experienced both neuroleptic malignant and serotonin syndromes. We speculate that this case argue in favor that both syndromes share some fundamental pathogenetic mechanisms.

Automated and manual hippocampal segmentation techniques: Comparison of results, reproducibility and clinical applicability

Background Imaging techniques used to measure hippocampal atrophy are key to understanding the clinical progression of Alzheimers disease (AD). Various semi-automated hippocampal segmentation techniques are available and require human expert input to learn how to accurately segment new data. Our goal was to compare 1) the performance of our automated hippocampal segmentation technique relative to manual segmentations, and 2) the performance of our automated technique when provided with a training set from two different raters. We also explored the ability of hippocampal volumes obtained using manual and automated hippocampal segmentations to predict conversion from MCI to AD. Methods We analyzed 161 1.5 T T1-weighted brain magnetic resonance images (MRI) from the ADCS Donepezil/Vitamin E clinical study. All subjects carried a diagnosis of mild cognitive impairment (MCI). Three different segmentation outputs (one produced by manual tracing and two produced by a semi-automated algorithm trained with training sets developed by two raters) were compared using single measure intraclass correlation statistics (smICC). The radial distance method was used to assess each segmentation techniques ability to detect hippocampal atrophy in 3D. We then compared how well each segmentation method detected baseline hippocampal differences between MCI subjects who remained stable (MCInc) and those who converted to AD (MCIc) during the trial. Our statistical maps were corrected for multiple comparisons using permutation-based statistics with a threshold of p < .01. Results Our smICC analyses showed significant agreement between the manual and automated hippocampal segmentations from rater 1 [right smICC = 0.78 (95%CI 0.72–0.84); left smICC = 0.79 (95%CI 0.72–0.85)], the manual segmentations from rater 1 versus the automated segmentations from rater 2 [right smICC = 0.78 (95%CI 0.7–0.84); left smICC = 0.78 (95%CI 0.71–0.84)], and the automated segmentations of rater 1 versus rater 2 [right smICC = 0.97 (95%CI 0.96–0.98); left smICC = 0.97 (95%CI 0.96–0.98)]. All three segmentation methods detected significant CA1 and subicular atrophy in MCIc compared to MCInc at baseline (manual: right pcorrected = 0.0112, left pcorrected = 0.0006; automated rater 1: right pcorrected = 0.0318, left pcorrected = 0.0302; automated rater 2: right pcorrected = 0.0029, left pcorrected = 0.0166). Conclusions The hippocampal volumes obtained with a fast semi-automated segmentation method were highly comparable to the ones obtained with the labor-intensive manual segmentation method. The AdaBoost automated hippocampal segmentation technique is highly reliable allowing the efficient analysis of large data sets.