Validation of the new consensus criteria for the diagnosis of corticobasal degeneration.

BACKGROUND: Corticobasal degeneration (CBD) is a complex neurodegenerative disorder. Accurate diagnosis is increasingly important, with the advent of clinical trials of drugs aimed at modifying the underlying tau pathology. CBD often presents with a 'corticobasal syndrome' including impairments of movement and cognition. However, patients with similar corticobasal syndromes can have neurodegenerative pathologies that are not CBD. In addition, patients with CBD may present with aphasia or behavioural change. The clinical diversity of CBD and mimicry by non-CBD pathologies hinders accurate diagnosis. METHODS: We applied the new consensus criteria of Armstrong and colleagues et al 1 to a cohort of patients with detailed longitudinal clinical evaluation and neuropathology. RESULTS: In patients with pathologically confirmed CBD, accuracy of diagnosis was similar under the new and previous criteria: 9/19 (47%) met criteria for probable CBD at presentation, 13/19 (68%) at last clinical assessment. Patients with a corticobasal syndrome but without CBD pathology all (14/14) met the new diagnostic criteria of probable or possible CBD, demonstrating that the new criteria lacks the necessary specificity for an accurate ante mortem clinical diagnosis of CBD. None of the clinical features used in the new criteria were more common in the patients with CBD pathology (n=19) than without (n=14). CONCLUSIONS: The Armstrong criteria usefully broadens the recognised clinical phenotype of CBD but does not sufficiently improve the specificity of diagnosis to increase the power of clinical trials or targeted applications of tau-based disease-modifying therapies. Further work is required to show whether biomarkers could be more effective than clinical signs in the diagnosis of CBD.

Emotion recognition in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome characterised by akinesis, rigidity, falls, supranuclear gaze palsy and cognitive, particularly executive, dysfunction. This study examined the extent to which emotion recognition is affected by PSP. Although deficits in the recognition of emotion have been reported in several diseases which share clinicopathological characteristics with PSP, it has never been studied systematically in PSP. Twenty-four patients with probable or definite PSP and matched healthy controls were studied using tests of facial identity and facial emotion recognition. Patients were not impaired in recognising famous faces, but they showed significant deficits in the recognition of emotions, particularly negative emotions. Moreover, emotion recognition was strongly correlated with the severity of other cognitive deficits in PSP, but not disease duration. Deficits in emotion recognition form an integral part of the cognitive spectrum of the disease. The findings point to the pathological involvement of key regions necessary for the processing of emotions and to a subtype of PSP with cognitive and emotion recognition impairments. The acknowledgement of deficits in emotion recognition is important for management of both patients and their carers.

Visuospatial functions in atypical parkinsonian syndromes.

OBJECTIVES: Visuospatial deficits have been occasionally reported but never systematically studied in atypical parkinsonian syndromes. The interpretation of existing studies is complicated by the possible influence of motor and frontal executive deficits. Moreover, no attempt has been made to distinguish visuoperceptual from visuospatial tasks. The aim of the present study was to assess visuoperceptual and visuospatial abilities in three atypical parkinsonian syndromes while minimising the influence of confounding variables. METHODS: Twenty patients with multiple system atrophy (MSA), 43 with progressive supranuclear palsy (PSP), and 25 with corticobasal degeneration (CBD) as well as 30 healthy age matched controls were examined with the Visual Object and Space Perception Battery (VOSP). RESULTS: Visuospatial functions were intact in MSA patients. PSP patients showed mild deficits related to general cognitive decline and the severity of oculomotor symptoms. The CBD group showed the most pronounced deficits, with spatial tasks more impaired than object based tasks. Performance on object based, but not spatial, tasks was related to general cognitive status. The extent of the visuospatial impairment could not be predicted from disease duration or severity. CONCLUSION: Visuospatial functions are not consistently impaired in atypical parkinsonian syndromes. The degree and pattern of impairment varies across the diseases, suggesting that the observed deficits could have a different neural basis in each condition. The distinction between the object based ("ventral stream") and the space oriented ("dorsal stream") processing might be useful in the interpretation of visuospatial deficits in parkinsonian syndromes, especially in CBD.

Ubiquitin-positive inclusions and progression of pathology in frontotemporal dementia and motor neurone disease identifies a group with mainly early pathology.

Frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions has been a topic of major interest in recent years, with this group now accounting for the majority of tau-negative cases of frontotemporal degeneration. The severity of neurodegeneration in FTLD is dependent on the stage of disease and is substantial even in the earliest stages. Elucidating the pathogenesis of FTLD requires evaluation of changes during the earliest possible stage of disease. However, the long survival of most frontotemporal dementia cases means that cases with early neuropathology are not frequently encountered. Cases of FTLD with the shortest survival are those with coexisting motor neurone disease (FTLD + MND), making these the ideal group for studying early FTLD pathology. It is not clear, however, what the pathological contribution of MND is in these cases. This study evaluates the pathology of 20 cases of FTLD (11 with no clinical signs of MND and nine with FTLD + MND) as well as 10 cases of MND without dementia. Our findings indicate that the deposition of ubiquitin does not play a key role in the neurodegenerative process in FTLD, and that the severity of neurodegeneration in FTLD is similar in cases with and without clinical MND.

Subcortical dementia revisited: similarities and differences in cognitive function between progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA).

To examine the similarities and differences in cognitive function between three predominantly subcortical dementing disorders associated with parkinsonism we compared the profiles of cognitive performance in 39 patients with Progressive Supranuclear Palsy (PSP), 26 patients with Multiple System Atrophy (MSA) and 25 with Corticobasal Degeneration (CBD) with those of 30 patients with classic cortical dementia, Alzheimer's Disease (AD), using two different cognitive screening tests: Dementia Rating Scale (DRS) and Addenbrooke's Cognitive Examination (ACE). The cognitive profile on ACE and DRS subtests distinguished subcortical diseases from each other as well as from AD. All parkinsonian syndromes were characterized by a disproportionate impairment in verbal fluency, particularly letter fluency. The three diseases differed, however, in the degree of language, memory and visuospatial impairment. We conclude that similarities, as well as differences, between PSP, MSA and CBD can be detected using a brief, clinically applicable cognitive screening test. The pattern of cognitive impairment is likely to reflect a different distribution of pathology, in particular a higher degree of cortical involvement in PSP and CBD.

Cognitive bedside assessment in atypical parkinsonian syndromes.

BACKGROUND: Despite the growing recognition of the importance of cognitive symptoms for the diagnosis and management of atypical parkinsonian syndromes, the cognitive assessment of the patients in clinical practice often remains very limited. OBJECTIVES: To examine the ability of a brief and simple cognitive screening test to detect cognitive deficits in atypical parkinsonian syndromes. METHODS: Addenbrooke's cognitive examination (ACE), the mini-mental state examination (MMSE), and the dementia rating scale (DRS) were applied to 26 patients with multiple system atrophy (MSA), 39 with progressive supranuclear palsy (PSP), and 25 with corticobasal degeneration (CBD). The results were then compared with those obtained in 30 healthy age matched volunteers and 30 patients with Alzheimer's disease. RESULTS: In all four diseases the rate of detection of cognitive impairment on ACE was higher than on MMSE and comparable with DRS. The severity of cognitive impairment was most pronounced in the CBD group, which showed a similar degree of impairment to the Alzheimer group. In contrast, MSA patients were the least cognitively impaired. The PSP group took an intermediate position. CONCLUSIONS: Cognitive impairment in atypical parkinsonian syndromes can be detected using a brief and clinically applicable bedside test such as ACE.

Memory lost, memory regained: neuropsychological findings and neuroimaging in two cases of paraneoplastic limbic encephalitis with radically different outcomes.

OBJECTIVE: To report two cases of paraneoplastic limbic encephalitis (PNLE) with similar clinical presentation, but dramatically different outcome and to highlight the role of neuropsychological and radiological evaluation in PNLE. METHODS: Both patients underwent an extensive battery of neuropsychological tests designed to document general intellectual function, anterograde verbal and visual memory, naming, knowledge and executive ability. In addition, structural (CT and MRI) and functional (HMPAO-SPECT) brain scans were performed. RESULTS: Both patients presented with fairly sudden onset of profound and persistent memory loss in the absence of other neurological symptoms. Their subsequently diagnosed small cell lung cancer was treated with a combination of radiotherapy and chemotherapy, leading to remission of the tumour. The memory of patient 1 recovered fully and he died from an unrelated cause 1 year later; neuropsychological testing showed a severe, but isolated, anterograde amnesia, brain MRI was normal and HMPAO-SPECT showed left medial temporal hypoperfusion. Patient 2 remained densely amnesic despite regression of her lung tumour; neuropsychological testing disclosed both anterograde and extensive retrograde amnesia together with more generalised cognitive deficits including anomia and executive impairments, MRI showed gross atrophy of the hippocampus and amygdala bilaterally, and HMPAO-SPECT showed pronounced frontal and temporal hypoperfusion. CONCLUSION: Complete remission from PNLE may occur and seems to be associated with pure anterograde amnesia without evidence of structural hippocampal damage in MRI. By contrast, cognitive deficits beyond severe anterograde amnesia and evidence of destructive medial temporal lobe pathology on MRI seem to be poor prognostic features.

Motor neurone disease, dementia and aphasia: coincidence, co-occurrence or continuum?

Cognitive, and particularly aphasic, symptoms associated with motor neurone disease (MND) are still frequently described as rare and "recently discovered". This review demonstrates that the association between MND and dementia was described and recognised as an entity as early as 1929, and its close relationship to Pick's disease was postulated in 1932. Changes in language production and comprehension were also observed by early authors, although they were rarely described as aphasia. The striking similarity to the contemporary descriptions is, however, sometimes obscured by diverging terminology. The syndromes of MND/dementia and MND/aphasia are well established but represent a comparatively small subgroup of MND. In addition, subtle cognitive alterations have also been reported in non-demented MND patients; most studies have found evidence of frontal-executive dysfunction, similar in pattern, but much milder than in patients with frank MND/dementia. These findings are strengthened further by post-mortem studies demonstrating pathological changes in the frontal lobes, and functional neuroimaging studies, showing reduced frontal activation. The issue of whether memory, visuospatial skills and language are affected in non-demented subjects remains, however, controversial. Further studies are required to establish whether MND/dementia and MND/aphasia form separate disease entities or can be viewed as extreme forms of a cognitive deficit characteristic of MND in general.

Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neurone disease-dementia-aphasia syndrome.

We report six patients with clinically diagnosed and electrophysiologically confirmed motor neurone disease (MND), in whom communication problems were an early and dominant feature. All patients developed a progressive non-fluent aphasia culminating in some cases in complete mutism. In five cases, formal testing revealed deficits in syntactic comprehension. Comprehension and production of verbs were consistently more affected those that of nouns and this effect remained stable upon subsequent testing, despite overall deterioration. The classical signs of MND, including wasting, fasciculations and severe bulbar symptoms, occurred over the following 6-12 months. The behavioural symptoms ranged from mild anosognosia to personality change implicating frontal-lobe dementia. In three cases, post-mortem examination has confirmed the clinical diagnosis of MND-dementia. In addition to the typical involvement of motor and premotor cortex, particularly pronounced pathological changes were observed in the Brodmann areas 44 (Broca's area) and 45. The finding of a selective impairment of verb/action processing in association with the dementia/aphasia syndrome of MND suggests that the neural substrate underlying verb representation is strongly connected to anterior cortical motor systems.

Cognition, language and behaviour in motor neurone disease: evidence of frontotemporal dysfunction.

Cognitive symptoms accompanying motor neurone disease (MND) have been recognized and described since the late 19th century. Numerous reports from Europe, North America and Japan suggest existence of a syndrome that can be described as MND/dementia. Typically, psychiatric and cognitive changes, strongly reminiscent of frontotemporal dementia, precede the occurrence of the classical signs and symptoms of MND by several months. In a small number of patients a similar picture can be heralded by a progressive aphasia leading ultimately to mutism. While the syndromes of MND/dementia and MND/aphasia constitute a comparatively small group, subtle but consistent cognitive alterations have also been observed in the majority of nondemented MND patients. Although generally much less pronounced, their pattern, affecting mostly frontal-executive functions, resembles that of MND/dementia. Postmortem examination results, describing pathological changes in the frontal lobes, and functional neuroimaging studies, showing abnormal pattern of frontal activation, add more weight to the hypothesis linking MND to the frontotemporal dementia.

Myoclonus in patients treated with clozapine: a case series.

BACKGROUND: Various types of movement disorder have been reported to occur rarely in patients treated with clozapine. This paper describes five cases in which these phenomena appeared to be clearly associated with clozapine medication and discusses possible pharmacologic mechanisms and treatment options. METHOD: Inpatients receiving clozapine were investigated for the presence of movement disorders. We present five patients with clozapine-induced myoclonus, describe their patterns, and compare clinical features. RESULTS: Five patients treated with clozapine developed a similar pattern of movement disorder that can be described as myoclonus. The neurologic symptoms improved after the treatment was discontinued, the clozapine dose reduced, or concomitant carbamazepine administered. CONCLUSION: Clozapine can induce dose-dependent myoclonus. However, these symptoms can be relieved by reducing the dose of clozapine or giving carbamazepine so that discontinuation of clozapine treatment can be avoided.

Effects of parabrachial opioid antagonism on stimulation-induced feeding.

The pontine parabrachial nucleus (PBN) contains gustatory relay neurons and a high concentration of opioid receptors. To investigate the involvement of PBN opioid activity in feeding behavior, antagonists were infused into the PBN bilaterally and effects on stimulation-induced feeding were determined. Naloxone, a mu-preferring antagonist, increased the lateral hypothalamic stimulation threshold for eliciting feeding behavior while nor-binaltorphimine, a kappa-selective antagonist, did not. Neither antagonist increased threshold when infused into dorsal pontine sites outside of the PBN or the fourth ventricle. In as much as PBN contains mu and kappa but no detectable delta receptors, the present results suggest that mu opioid activity within the PBN is involved in the mediation of feeding behavior.

Rostral and caudal ventricular infusion of antibodies to dynorphin A(1-17) and dynorphin A(1-8): effects on electrically-elicited feeding in the rat.

Lateral ventricular injection of antibodies to dynorphin A(1-13) was previously shown to elevate lateral hypothalamic stimulation frequency threshold for eliciting feeding behavior. The antibodies utilized in that study cross-react completely with dynorphin A(1-17) and, to a lesser extent, dynorphin A(1-8). In the present study, highly specific antibodies to dynorphin A(1-17) and dynorphin A(1-8) were infused into the lateral ventricle and mesopontine aqueduct to determine which biologically active dynorphin A fragment mediates feeding and at what level of the CNS this activity is likely to occur. Both antibodies were found to elevate the feeding threshold. Dynorphin A(1-8) antibodies were effective at both injection sites while dynorphin A(1-17) antibodies were only effective at the lateral ventricular site. These findings suggest that feeding-related dynorphin A(1-17) activity may occur predominantly within the forebrain, while dynorphin A(1-8) activity occurs within the brainstem. Only the dynorphin A(1-8) antibodies, infused into the aqueduct, produced a naloxone-like pattern of progressive elevation in serially determined thresholds; this pattern was previously interpreted to reflect a reduction in consummatory reward. Dynorphin A(1-8) activity within some brainstem structure(s) may therefore contribute prominently to the opioid mechanism whose mediation of the hedonic response to food was previously inferred from naloxone antagonism.

Effects of the selective kappa opioid antagonist, nor-binaltorphimine, on electrically-elicited feeding in the rat.

Lateral ventricular injections of the 'nonspecific' opioid antagonist naloxone (100 micrograms) and the kappa-selective opioid antagonist nor-binaltorphimine (50 micrograms) elevated the electrical brain stimulation frequency threshold for eliciting feeding behavior. Mesopontine aqueductal injections of nor-binaltorphimine, on the other hand, lowered the feeding threshold while naloxone still elevated threshold. These findings suggest the existence of forebrain kappa receptors at which endogenous opioid activity results in a facilitation of feeding while kappa receptors in the brainstem seem to mediate an inhibitory effect.

Medial thalamic injection of opioid agonists: mu-agonist increases while kappa-agonist decreases stimulus thresholds for pain and reward.

Selective agonists for mu- and kappa-opioid receptor types were infused, bilaterally, into the intralaminar central lateral nucleus of the rat. Subcataleptic doses of the mu-agonist, DAGO (0.25 and 1.0 microgram), elevated tailshock threshold for eliciting pain vocalization and motor responses. The hyperalgesic effect of U50,488 is not likely to be the result of antagonist action at a mu 2-isoreceptor; the general mu-antagonist, naloxone, and its less lipophilic quaternary analogue, both failed to produce a significant reduction in pain thresholds. Paralleling their effects on pain, DAGO and U50,488 elevated and reduced, respectively, lateral hypothalamic electrical stimulation threshold for positive reinforcement. These results suggest that medial thalamic opioid mechanisms are not exclusively involved in pain modulation but may generally regulate the responsiveness of the organism to motivating stimuli. Moreover, mu- and kappa-receptors may mediate opposite behavioral effects of opioid peptides.

Antibodies to dynorphin A(1-13) but not beta-endorphin inhibit electrically elicited feeding in the rat.

Highly specific antibodies to dynorphin A(1-13), infused into the lateral ventricle, elevated brain stimulation threshold for eliciting feeding behavior. Antibodies to beta-endorphin had little or no effect. Temporal analysis of the anorectic action indicated a striking similarity to the effect of systemically administered naloxone. These findings suggest that central dynorphin is involved in the control of ingestive behavior and that the anorectic action of naloxone may result from antagonism of dynorphinergic transmission.

Lateral hypothalamic stimulation-produced analgesia: inferred refractory period of directly stimulated neurons and resistance to pimozide antagonism.

Electrical stimulation in lateral hypothalamic sites (ESLH) supporting appetitive behavior and reward also diminishes pain and aversion responses that are organized high in the neuraxis. A paired-pulse stimulation technique was used, in two different behavioral paradigms, to infer the absolute refractory periods of LH neurons that mediate this apparent supraspinal analgesia. In both paradigms, recovery from refractoriness--reflected by increased analgesic action--was evident at intrapair intervals of 0.8 msec and greater. This finding suggests that the overlap, if any, between first stage neurons mediating analgesia and appetitive/reward behavior may be restricted to the 'heterogeneous slow population' distinguished by Gratton and Wise. The dopamine antagonist pimozide, at doses known to diminish ESLH-induced feeding and reward (0.25 and 0.5 mg/kg), failed to affect analgesia. Thus, the dopaminergic second stage neurons deemed critical to feeding and reward may not play an important role in analgesia. Finally, ESLH-induced ameliorative action as a case of 'aversion-gating' or a dimension of classical somatosensory analgesia is discussed.