Elka Stefanova

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

The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimers 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, Parkinsons disease dementia, Huntingtons 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.

Therapeutic efficacy of bilateral prefrontal slow repetitive transcranial magnetic stimulation in depressed patients with Parkinson's disease: an open study.

Recent studies have suggested that both high‐ and low‐frequency repetitive transcranial magnetic stimulation (rTMS) have antidepressant effects in patients with major depression. We conducted an open study to assess the effects of slow rTMS on mood changes in patients with depression associated with Parkinsons disease (PD). Ten depressed patients with PD (four with major depression and six with dysthymia) received daily sessions of rTMS (frequency, 0.5 Hz; pulse duration, 0.1 msec; field intensity, 10% above the motor threshold) over both prefrontal regions (a total of 100 stimuli per prefrontal region daily) over 10 consecutive days. This treatment resulted in a moderate but significant decrease in scores of the Hamilton Depression Rating Scale (33–37%) and the Beck Depression Inventory (24–34%), which persisted 20 days after finishing the stimulation. In parallel, we observed mild improvement (18–20%) of motor symptoms. No significant adverse effects were reported. These preliminary results suggest the therapeutic potential of daily prefrontal low‐frequency rTMS (0.5 Hz) in depression associated with PD.

Glucose Homeostasis in Huntington Disease: Abnormalities in Insulin Sensitivity and Early-Phase Insulin Secretion

BACKGROUND Patients with Huntington disease (HD) develop diabetes mellitus more often than do matched healthy controls. Recent studies in neurodegenerative diseases suggested that insulin resistance constitutes a metabolic stressor that interacts with a preexisting neurobiological template to induce a given disorder. OBJECTIVE To investigate possible changes in insulin sensitivity and secretion, major determinants of glucose homeostasis, in a group of consecutive normoglycemic patients with HD. DESIGN Metabolic investigations. PARTICIPANTS Twenty-nine untreated, nondiabetic patients with HD and 22 control participants matched by age, sex, and socioeconomic background. MAIN OUTCOME MEASURES Glucose tolerance, assessed by means of the glucose curve during oral glucose challenge; insulin sensitivity, assessed using homeostasis model assessment and minimal model analysis based on frequent sampling of plasma glucose and plasma insulin during the intravenous glucose tolerance test; and insulin secretion, determined by means of the acute insulin response and the insulinogenic index. RESULTS The evaluation of insulin sensitivity using homeostasis model assessment demonstrated higher homeostasis model assessment insulin resistance indices, and a lower sensitivity index when the minimal model approach was used, in patients with HD compared with controls (P = .03 and P = .003, respectively). In the assessment of early-phase insulin secretion, the acute insulin response and the insulinogenic index were lower in patients with HD compared with controls (P = .02). The number of CAG repeats correlated significantly only with acute insulin response (P = .003). CONCLUSIONS Besides impairment in insulin secretion capacity, a simultaneous decrease in insulin sensitivity, with an increase in the insulin resistance level, was found in normoglycemic patients with HD compared with controls. These data imply that progression of the insulin secretion defect in HD may lead to a failure to compensate for insulin resistance.

Pattern of brain tissue loss associated with freezing of gait in Parkinson disease

Objective: To investigate whether a specific pattern of gray matter (GM) tissue loss is associated with freezing of gait (FOG) in patients with Parkinson disease (PD). Methods: Seventeen patients with PD with FOG (PD-FOG), 20 patients with PD with no FOG (PD-noFOG), and 34 healthy control subjects were recruited. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and Hoehn and Yahr stage. Patients were also administered a comprehensive neuropsychological battery focused on executive functions. The extent and distribution of GM atrophy were assessed using voxel-based morphometry. Results: In patients with PD, the severity of FOG correlated with frontal executive deficits. Compared with healthy control subjects, PD-FOG patients showed a distributed pattern of GM atrophy including the dorsolateral prefrontal, medial, and lateral temporal, inferior parietal, and occipital cortices. PD-noFOG patients showed only small regions of GM atrophy in the bilateral frontal and temporal cortex. The left inferior frontal gyrus, left precentral gyrus, and left inferior parietal gyrus were more atrophic in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients. In PD-FOG patients, the severity of FOG was associated with GM volumes of the frontal and parietal cortices bilaterally. Conclusions: GM frontal and parietal atrophy occur in PD-FOG patients. FOG in PD seems to share with executive dysfunction and perception deficits a common pattern of structural damage to the frontal and parietal cortices.

Mild cognitive impairment in Parkinson's disease is associated with a distributed pattern of brain white matter damage

This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinsons disease and mild cognitive impairment (PD‐MCI) compared with healthy controls and cognitively unimpaired PD patients (PD‐Cu). Three‐dimensional T1‐weighted and diffusion tensor (DT) magnetic resonance imaging (MRI) scans were obtained from 43 PD patients and 33 healthy controls. Cognition was assessed using a neuropsychological battery. Tract‐based spatial statistics was applied to compare DT MRI indices between groups on a voxel‐by‐voxel basis. Voxel‐based morphometry was performed to assess GM atrophy. Thirty PD patients were classified as MCI. Compared with healthy controls, PD‐Cu and PD‐MCI patients did not have GM atrophy. No region of WM damage was found in PD‐Cu patients when compared with healthy controls. Relative to healthy controls and PD‐Cu patients, PD‐MCI patients showed a distributed pattern of WM abnormalities in the anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto‐occipital, uncinate, and superior longitudinal fasciculi, bilaterally. Subtle cognitive decline in PD is associated with abnormalities of frontal and interhemispheric WM connections, and not with GM atrophy. DT MRI might contribute to the identification of structural changes in PD‐MCI patients prior to the development of dementia. Hum Brain Mapp 35:1921–1929, 2014.

Dystonia in Wilson's disease.

The frequency and type of dystonic movements, as well as brain abnormalities, as depicted with magnetic resonance imaging (MRI), which might correlate with dystonia, were studied in 27 consecutive patients with a neurologic form of Wilsons disease (WD) and optimized treatment. Dystonia was found in 10 patients (37%), being generalized in half of them, while two patients had segmental, two patients multifocal dystonia, and one patient bilateral foot dystonia. Dystonia was a presenting sign in four patients and developed later in the course of the disease in six patients, despite the administered therapy for WD. Putamen was the only structure significantly more frequently lesioned in dystonic (80%) in comparison to WD patients without dystonia (24%), suggesting a relation between abnormalities in this brain region and dystonic movements in WD.

The effect of stage of Parkinson's disease at the onset of levodopa therapy on development of motor complications

The aim of this study was to ascertain whether the stage of Parkinson’s disease (PD) (according to the Hoehn and Yahr staging system) would affect the length of time between the introduction of levodopa therapy and appearance of levodopa‐associated motor complications. Forty patients with clinically definite PD were studied. In all, clinical and therapeutic data were collected from the time of diagnosis to the time of levodopa‐associated motor complications (i.e. dyskinesia, motor fluctuations). In 17 patients, levodopa could be started in Hoehn and Yahr stage I (H&Y‐I; 16.2 months after the onset of PD), whilst in 13 patients levodopa could be started in H&Y‐II (19.6 months after the onset of the disease) and in 10 in H&Y‐III (45.1 months after the onset of PD). Cox proportional hazard regression model shows that the PD patients in whom the initial levodopa treatment was introduced at stage III develop both dyskinesias and motor fluctuations significantly earlier than the patients whose levodopa started in stage I and II of PD. The median interval to develop dyskinesias was 66, 72 and 24 months for patients in whom levodopa was introduced in stage I, II and III, respectively. These values were 64, 55 and 14 months for motor fluctuations. These findings add to the clinical arguments that favour an essential role of severity of PD at levodopa initiation as a risk factor for the development of levodopa‐associated motor complications.

The in vivo distribution of brain tissue loss in Richardson’s syndrome and PSP-parkinsonism: a VBM-DARTEL study

In this study, we wished to test, using magnetic resonance imaging and voxel‐based morphometry (VBM), whether specific cortical and subcortical patterns of brain grey (GM) and white matter (WM) tissue loss can be detected in patients with Richardson’s syndrome (PSP‐RS) and progressive supranuclear palsy‐parkinsonism (PSP‐P), and possibly account for their clinical heterogeneity. Twenty patients with PSP, classified as PSP‐RS (10 patients) or PSP‐P (10 patients), and 24 healthy controls were studied. The Statistical Parametric Mapping (SPM5) and the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra method were used to perform a VBM analysis. Compared with controls, both patient groups showed GM loss in the central midbrain, cerebellar lobes, caudate nuclei, frontotemporal cortices and right hippocampus. WM loss was detected in both conditions in the midbrain, left superior cerebellar peduncle, internal capsulae, and left premotor and bilateral prefrontal regions. Compared with PSP‐P, patients with PSP‐RS showed additional regions of GM loss in the midbrain, left cerebellar lobe and dentate nuclei. PSP‐RS was also associated with a more severe WM loss in the midbrain, internal capsulae, and orbitofrontal, prefrontal and precentral/premotor regions, bilaterally. Patients with PSP‐P showed a more pronounced GM loss only in the frontal cortex, bilaterally. This study shows that, albeit the overall pattern of brain atrophy associated with PSP appears remarkably consistent across the spectrum of clinical features recorded in life, major anatomical differences between these two conditions do exist. Such a different topographical distribution of tissue damage may account for the clinical differences between PSP‐RS and PSP‐P.

Visuomotor skill learning on serial reaction time task in patients with early Parkinson's disease

This study tested the role of basal ganglia in visuomotor skill learning. Thirty‐nine patients early in the course of Parkinsons disease (PD) and 30 patients after operation for an aneurysm of the anterior communicating artery (ACoA) were compared with 31 matched control subjects on a Serial Reaction Time test (SRTt). The patients with PD showed impaired visuomotor skill learning across the repeating blocks, in the presence of preserved declarative knowledge of embedded sequences, in contrast to the ACoA group in whom the reverse pattern was observed. The significant correlation in patients with PD between the standard neuropsychological and motor measures and the performance observed in the skill acquisition test, in the ACoA group and control subjects was not observed. The suggestion that this learning impairment could not be attributed to a motor deficit per se was also confirmed more directly for patients with PD. Accuracy of performance after the initial learning phase on the SRTt in patients with PD was associated predominantly with visual span capacity measures. Declarative knowledge of the embedded sequence of the SRTt was correlated to general cognitive and verbal span abilities in the PD group. The impairment observed in the PD group was not the result of a general decline in cognitive functioning, mood disturbances, or the severity of the motor symptoms.

Depression predicts the pattern of cognitive impairment in early Parkinson's disease

OBJECTIVE To estimate the pattern of cognitive impairment in early Parkinsons disease (PD) associated with depression. Also, the prediction of potentially relevant demographic/clinical factors in early PD on cognitive functioning was tested. METHOD The study comprised 80 consecutive early PD patients (16 with major depression (PDMD), 10 PD patients with dysthimic disorder (PDDD), and 54 nondepressed PD patients (PDND)). Thirty_seven healthy subjects matched for age, gender and education were also included in the study. The cognitive evaluation included the comprehensive classical neuropsychological battery and the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS The two different patterns of cognitive impairment in early PD patients were obtained even when the confounding influences of general cognitive abilities and motor slowness were taken in account. One pattern was common to all PD patients either they were depressed or not, and it is conceived etiologically as dysexecutive. The PDDD group presented only the quantitative increment of the common deficit observed in PD. The second pattern was present in PDMD patients, involved episodic/working memory and language deficits alongside with background executive impairment. Depression was extensively associated with the cognitive dysfunction in early PD, whereas severity of the disease, age at onset and treatment were less favorable as predictors. CONCLUSIONS This study provides evidence that the pattern of cognitive impairment in early PD may be predicted by depression severity. Therefore, the recognition and treatment of depressive disorder in early PD is important.