Ingo Uttner

Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy

This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinsons disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.

Heterozygous R1101K mutation of the DCTN1 gene in a family with ALS and FTD.

A heterozygous R1101K mutation of the p150 subunit of dynactin (DCTN1) is reported in a family with amyotrophic lateral sclerosis (ALS) and co‐occurrence of frontotemporal dementia (FTD). Two members of our kindred were affected with motor neuron disease and two with dementia in an autosomal dominant pattern of inheritance. We excluded the involvement of the ALS and FTD‐linked genes for copper/zinc superoxide dismutase (SOD1) and tau. The R1101K sequence alteration of the DCTN1 gene may predispose subjects to ALS and FTD. Ann Neurol 2005;58:777–780

Cognitive function in bulbar- and spinal-onset amyotrophic lateral sclerosis. A longitudinal study in 52 patients.

AbstractWe performed a longitudinal study of frontal and temporal lobe functions in patients with amyotrophic lateral sclerosis (ALS) and compared the evolution of cognitive performance with that of motor deficits in patients with spinal and bulbar–onset of the disease. Fifty two patients suffering from sporadic ALS according to the El Escorial criteria were examined; 37 patients had a spinal, 15 a bulbar onset of the disease. The data profile included examinations at entry (E1), every four months at follow–up (E2, E3, E4) and after 18 months (E5), if possible. Neuropsychological testing covered the domains of executive functions, memory and attentional control. ALS patients showed executive dysfunctions that were most prominently represented by deficits of non–verbal and verbal fluency and concept formation. Memory–related deficits were also present but less expressed. The same held true for phasic and tonic alertness and divided attention. In contrast to motor functions declining concomitantly with disease progression, cognitive deficits appeared in early disease, were essentially present at initial testing and did not substantially decline on follow–up. A subgroup analysis revealed that bulbar–onset ALS patients performed consistently poorer in many cognitive tests than spinalonset ones with special reference to verbal and non–verbal fluency and interference control. This subgroup difference persisted or even increased throughout follow–up. We conclude that there is a fronto–temporal pattern of cognitive dysfunction in ALS expressing itself early in the course of the disease and mainly with bulbar forms. The cognitive deficits do not progress in synchrony with motor decline, but distinctly more slowly. We suggest that cognitive dysfunctions reflect functional and possibly morphological deficits outside the primary motor system that is specific for the nature and evolution of the disease and might also give clues to etiopathogenesis.

TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

BACKGROUND Recently, TAR DNA-binding protein 43 (TDP-43) was identified as the major component of ubiquitin-positive tau-negative neuronal and glial inclusions in the most common form of frontotemporal lobar degeneration (FTLD) and in amyotrophic lateral sclerosis (ALS). It was demonstrated that different TDP-43 profiles correspond to clinical phenotypes of FTLD or ALS subgroups, and the differential diagnostic potential of TDP-43 was suggested. OBJECTIVES To examine TDP-43 in cerebrospinal fluid (CSF) and to analyze whether it could serve as a diagnostic marker. DESIGN We characterized CSF TDP-43 by immunoblot using different TDP-43 antibodies and determined the relative TDP-43 levels in CSF samples from patients. SETTING Academic research. PATIENTS Twelve patients with FTLD, 15 patients with ALS, 9 patients with ALS plus FTLD, 3 patients with ALS plus additional signs of frontal disinhibition, and 13 control subjects. MAIN OUTCOME MEASURES Results of TDP-43 immunoblot. RESULTS Polyclonal TDP-43 antibodies recognized a 45-kDa band in all analyzed samples. Two monoclonal and N-terminus-specific antibodies did not detect any specific bands, but C-terminus-specific antibodies detected a 45-kDa band and additional bands at approximately 20 kDa in all CSF samples. Relative quantification of 45-kDa bands revealed significant differences among the diagnostic groups (P =.046). Specifically, patients with ALS (P =.03) and FTLD (P =.02) had higher TDP-43 levels than controls but with a prominent overlap of values. CONCLUSION Although there is no evidence of pathologically altered TDP-43 proteins in CSF, TDP-43 levels in CSF might aid in characterizing subgroups of patients across the ALS and FTLD disease spectrum.

Cognitive function in bulbar– and spinal–onset amyotrophic lateral sclerosis

AbstractWe performed a longitudinal study of frontal and temporal lobe functions in patients with amyotrophic lateral sclerosis (ALS) and compared the evolution of cognitive performance with that of motor deficits in patients with spinal and bulbar–onset of the disease. Fifty two patients suffering from sporadic ALS according to the El Escorial criteria were examined; 37 patients had a spinal, 15 a bulbar onset of the disease. The data profile included examinations at entry (E1), every four months at follow–up (E2, E3, E4) and after 18 months (E5), if possible. Neuropsychological testing covered the domains of executive functions, memory and attentional control. ALS patients showed executive dysfunctions that were most prominently represented by deficits of non–verbal and verbal fluency and concept formation. Memory–related deficits were also present but less expressed. The same held true for phasic and tonic alertness and divided attention. In contrast to motor functions declining concomitantly with disease progression, cognitive deficits appeared in early disease, were essentially present at initial testing and did not substantially decline on follow–up. A subgroup analysis revealed that bulbar–onset ALS patients performed consistently poorer in many cognitive tests than spinalonset ones with special reference to verbal and non–verbal fluency and interference control. This subgroup difference persisted or even increased throughout follow–up. We conclude that there is a fronto–temporal pattern of cognitive dysfunction in ALS expressing itself early in the course of the disease and mainly with bulbar forms. The cognitive deficits do not progress in synchrony with motor decline, but distinctly more slowly. We suggest that cognitive dysfunctions reflect functional and possibly morphological deficits outside the primary motor system that is specific for the nature and evolution of the disease and might also give clues to etiopathogenesis.

Evaluation of cognition, structural, and functional MRI in juvenile myoclonic epilepsy

Purpose:  Previous studies using advanced imaging techniques have suggested subtle structural and functional changes in patients with juvenile myoclonic epilepsy (JME), mainly associated with the frontal lobes. In addition, it has been reported that these patients show neuropsychological deficits, often summarized as frontal lobe dysfunction. The aim of this study was a comprehensive analysis of neuropsychological parameters, and functional and structural magnetic resonance imaging (MRI) in an independent cohort of patients with JME.

The Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen: A cross-sectional comparison of established screening tools in a German-Swiss population

Abstract The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) has recently been developed as a fast and easy cognitive screening tool specifically designed for patients with motor impairments in routine clinical use. The German/Swiss-German version of the ECAS was validated in a German-Swiss consortium. One hundred and thirty-six non-demented ALS patients and 160 healthy controls were included in the study. In addition, the Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MoCA) and Consortium to Establish a Registry for Alzheimers Disease plus Scale (CERAD plus) were administered to subgroups of patients. Results showed that administration of ECAS was fast (mean 24 min). Similar to the population in the UK version, ALS patients performed significantly worse in the ALS-specific functions (p < 0.001), specifically in the domain of language (p < 0.001), verbal fluency (p = 0.005) and executive functions (p = 0.02), but not for the non-ALS-specific functions. Carers reported behavioural abnormalities in about 30% and psychotic symptoms in 6% of the patients. Compared to ECAS, FAB, MoCA and CERAD were more generic and performance was not adjusted to motor speed. We conclude that the German/Swiss-German version of the ECAS is a fast and easy to administer cognitive screening instrument sensitive for ALS-specific dysfunctions and behaviour change.

McLeod phenotype without the McLeod syndrome

BACKGROUND: McLeod neuroacanthocytosis syndrome is a late‐onset X‐linked multisystem disorder affecting the peripheral and central nervous systems, red blood cells (RBCs), and internal organs. A variety of mutations have been found in the responsible gene (XK) including single nonsense and missense mutations, nucleotide mutations at or near the splice junctions of introns of XK, and different deletion mutations. To date no clear phenotype‐genotype correlation is apparent. The clinical details of one case of McLeod phenotype without apparent neuromuscular abnormalities have been reported. Here the clinical details of two additional cases are presented, of which the genetic details have previously been published.

Emotional adjustment in amyotrophic lateral sclerosis (ALS)

Despite the devastating motor impairment, a significant number of patients with amyotrophic lateral sclerosis (ALS) maintain a good psychosocial adjustment. Here we investigated whether this is specific for ALS or a more general characteristic of terminal disease. Psychosocial adjustment was investigated in 30 ALS patients, 29 cancer patients in palliative treatment and 29 age-, gender- and level of education-matched healthy controls. Subjective quality of life (sQoL), degree of depressive symptoms and coping were evaluated as measures of psychosocial adjustment. Personality factors were described. ALS and cancer patients showed a good psychosocial adjustment. Subjective QoL and depression did not differ significantly. Both patient groups presented a good sQoL. The level of mild depressive symptoms in both patient groups was similar and none showed clinically relevant depression. ALS patients expressed fewer active coping strategies than cancer patients which were explained by gender differences. Both patient groups showed comparable psychosocial adjustment to their disease. Overall, in terminally ill patients the psychological response to the prognosis is not associated with neurobiological changes (e.g., associated with subclinical deficits in ALS) or with physical decline.

Prosopagnosia after unilateral right cerebral infarction

Sirs: Recently, there have been substantial contributions of functional imaging methods to the delineation of face responsive regions in the human brain, particularly in the fusiform gyrus (FFA, fusiform face area) [1]. There is, however, still no agreement upon the exact pathoanatomical correlates of prosopagnosia, the acquired inability to recognize familiar persons by the mere sight of their faces [2]. A widely accepted view claims that damage to both hemispheres is its necessary precondition [3]. Reports of prosopagnosia following isolated right-hemispheric lesions are still regarded as controversial.We wish to add two new case observations to this discussion.We argue that unilateral, right temporo-occipital infarction is in fact sufficient to cause the syndrome and will propose a unifying hypothesis. The first patient, a 85-year-old right-handed former manager, was admitted with a slight left hemiparesis, left hemisensory loss and a left homonymous hemianopia which were due to an ischemic infarct in the right posterior cerebral artery territory. Neuropsychological examination two weeks later showed left hemineglect on reading, letter cancellation, line bisection, and object drawing from memory. Oculomotor exploration of the left hemispace was reduced, and the patient’s head was continuously, albeit slightly turned to the right. Visual and tactile identification of real objects was within normal limits, but the patient was severely impaired in the recognition of line drawings, particularly if presented in an unconventional view (8 out of 30 correct in the silhouettes subtest of the “Visual Object and Space Perception Battery (VOSP)” [4]; normal range: ≥15). The patient primarily focused on local object features, while he was hardly able to integrate the single details into a whole. Most striking, however, was his impairment in face recognition. An inability to recognize the hospital staff was noticed on the ward. On formal testing with famous faces, he only recognized two out of ten. A portrait of the German head of government was mistaken for an image of the clinical investigator “at a younger age” (the age relation of the two, in fact, being the converse). When confronted with photographs showing his wife amidst other persons, he failed to identify her. Moreover, out of two photographs of himself he took one as showing his wife and only succeeded in correctly interpreting the second picture because of a peculiar detail of clothing. Although able to identify a face as such, he failed to integrate its features into a whole that represented a specific individual. A striking example was his misinterpretation of a laughing face as sad after the photograph had been inverted. He had focused on the corners of the mouth only and whether they were directed upwards or downwards. Magnetic resonance imaging (MRI) revealed a right-sided infarction that included the occipitotemporal region with the FFA and also affected parts of the thalamus and the internal capsule as well as the splenium. The left hemisphere was spared (Fig. 1). The second patient, retired as a railway engineer eight years previously after myocardial infarction, presented to the emergency room at the age of 57 because of sudden dizziness and the inability to recognize his wife’s face. He had homonymous left upper quadrantanopia and left lower quadrant dyschromatopsia in association with hemianopic dyslexia, corresponding to an acute ischemic infarction in the right posterior cerebral artery territory as delineated on neuroimaging. He was seen for formal neuropsychological examination three days later. There was no hemineglect, no memory disorder or other cognitive deficits. However, the severe impairment in face recognition was confirmed. In spite of his ability to differentiate between faces and non-faces, the patient failed to recognize the staff on the ward. Looking at his own face in a mirror he experienced it as surprisingly alien. He had the same impression of absent familiarity if he saw photographs of his wife or of relatives. Out of 27 photographs of famous faces he identified only 8, all of which were characterized by specific features such as the bushy eyebrows of a certain politician or other characteristic paraphernalia that he used for analysis. His tendency towards a piece meal approach was corroborated by the difficulties he displayed in differentiating the gender, age and emotional expression of the faces presented, particularly if they were inverted. In addition, he had the impression that two photographs depicted two different people, if in fact it was the same person, but with a different facial expression. This patient, just as the first, displayed a substantial deficit in identifying line drawings that were presented in a non-canonical view (VOSP-silhouettes: 6/30). Identification of real objects and phoLETTER TO THE EDITORS