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ObjectiveTo determine the frequency and characteristics of clinical diagnostic change in frontotemporal dementia (FTD)-spectrum syndromes and Alzheimer's disease (AD)-type dementia.MethodsWe reviewed records and categorized diagnostic changes in patients seen ≥ 2 times with behavioral variant FTD (bvFTD, n = 99), nonfluent and semantic variant primary progressive aphasia (nfvPPA, n = 32; svPPA, n = 59), corticobasal syndrome (CBS, n = 40), progressive supranuclear palsy-Richardson syndrome (PSP-RS, n = 34), and AD-type dementia (n = 49). For bvFTD, we compared patients with and without diagnostic change, and assessed predictors of diagnostic change by logistic regression.ResultsInitial diagnoses changed infrequently at subsequent visits in svPPA (6.8%), PSP-RS (8.8%), and nfvPPA (12.5%), with rare changes largely involving clinicopathological overlap or diagnostic ambiguity. Changes in AD-type dementia (30.6%) and CBS (37.5%) were more common, but reflected greater specificity, predicted co-pathology, or overlapping syndromes. Diagnostic change in bvFTD was also common (32.3%), but more diverse, including motor neuron disease development, alternative neurodegenerative syndromes, and non-neurodegenerative diseases. Diagnostic change occurred more often in those who met possible rather than probable bvFTD criteria (70.6% vs 15.3%, p

To investigate the retina thickness assessed using optical coherence tomography in atypical parkinsonism in comparison with health controls (HC) and patients with Parkinson’s disease (PD). PubMed and EMBASE were searched for potentially eligible studies that reported retina thickness in atypical parkinsonism [including progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal degeneration] in comparison with that of HC and PD patients from their dates of inception to Jan 24, 2021. Mean difference (μm) of the thickness of peripapillary retinal nerve fiber layer (pRNFL) and central macular thickness (CMT) were pooled with random effects model. We included ten studies eligible for inclusion criteria. Average pRNFL thickness and average CMT were thinner in PSP [pooled mean difference (μm) of − 4.71, 95% CI (− 7.15, − 2.27); − 15.12, 95% CI (− 16.93, − 13.30)] and in MSA [− 5.37, 95% CI (− 6.59, − 4.15); − 5.93, 95% CI (− 11.00, − 0.87)] compared with HC, and were thinner in PSP [− 5.81, 95% CI (− 8.92, − 2.69); − 10.63, 95% CI (− 20.29, − 0.98)] and in MSA [− 0.35 μm, 95% CI (− 5.72, 5.01); − 7.42 μm [95% CI (− 12.46, − 2.38)] compared with PD. The pRNFL thickness was thinning in superior, inferior and nasal quadrants, and CMT was thinning in outer sectors in MSA compared with HC. The retina thickness was significantly thinner in PSP and MSA than those in HC and PD. The specific patterns of retina thinning in MSA could be clinical importance for differentiation among atypical parkinsonism.

OBJECTIVES: To determine the clinical, anatomical, genetic and pathological features of dual frontotemporal lobar degeneration (FTLD) pathology: FTLD-tau and FTLD-TDP-43 in a large clinicopathological cohort. METHODS: We selected subjects with mixed FTLD-TDP and FTLD-tau from 247 FTLD cases from the University of California, San Francisco Neurodegenerative Disease Brain Bank collected between 2000 and 2016 and compared their clinical, anatomical, genetic, imaging and pathological signatures with those of subjects with pure FTLD. RESULTS: We found nine cases (3.6%) with prominent FTLD-TDP and FTLD-tau. Six cases were sporadic, whereas one case had a C9ORF72 expansion, another had a TARDBP A90V variant, and the other had an MAPT p.A152T variant. The subtypes of FTLD-TDP and FTLD-tau varied. Mixed FTLD cases were older and tended to show a higher burden of Alzheimer disease pathology (3/9, 33%). The neuroimaging signature of mixed cases, in general, included more widespread atrophy than that of pure groups. Specifically, cases of mixed corticobasal degeneration (CBD) with FTLD-TDP showed more prominent asymmetric left-sided atrophy than did those of pure CBD. However, the clinical phenotype of mixed cases was similar to that seen in pure FTLD. CONCLUSIONS: Although patients with mixed FTLD-TDP and FTLD-tau are rare, in-depth clinical, pathological and genetic investigations may shed light on the genetic and biochemical pathways that cause the accumulation of multiple proteinaceous inclusions and inform therapeutic targets that may be beneficial to each one of these abnormal protein misfoldings.

Corticobasal syndrome is a rare neurodegenerative disorder, which presents with a progressive, asymmetrical, akinetic rigid syndrome and early cortical signs. However, clinical, pathological, and electrophysiological heterogeneity makes the understanding of this syndrome challenging. Corticobasal syndrome can have various pathological substrates including corticobasal degeneration, Alzheimer's disease, Fronto-temporal degeneration with TDP inclusions, Creutzfeldt-Jakob disease, and progressive supranuclear palsy (PSP). Furthermore, tools such as transcranial magnetic stimulation (TMS) and functional neuroimaging techniques like PET and SPECT have not been adequately used to supplement the clinico-pathological heterogeneity. TMS studies in CBS have revealed changes in cortical excitability and transcortical inhibition. Despite the availability of more than 2 decades, its potential in CBS has not been fully utilized in studying the cortical plasticity and effect of Levodopa on central neurophysiology. PET and SPECT studies in CBS have shown abnormalities in regional glucose metabolism, asymmetrical involvement of presynaptic dopaminergic system, and ascending cholinergic connections to the cortex. While most studies have shown normal D2 receptor-binding activity in striatum of CBS cases, the results have not been unanimous. Functional neuroimaging and TMS studies in CBS have shown the involvement of GABAergic, muscarinic, and dopaminergic systems. In this review, we aim to provide the current state of understanding of central neurophysiology and neurochemistry of CBS using TMS and functional neuroimaging techniques. We also highlight the heterogeneous nature of this disorder and the existing knowledge gaps.

Corticobasal degeneration (CBD) was first described by Rebeiz et al. in 1967, and was called corticodentatonigral degeneration with neuronal achromasia [1]. Since then, our knowledge of the clinical features and underlying tau pathology has grown tremendously. Clinical antemortem diagnosis of CBD pathology remains challenging and has led to the development of revised diagnostic criteria. As various clinical phenotypes may have CBD pathology, accurate prevalence studies are lacking. Recently, pooled prevalence of fronto-temporal lobar degeneration, PSP and CBS was reported as 10.6 per 100,000 [2]. Although rare, CBD is an important disease to understand because it provides a model of a specific proteinopathy (tauopathy) and, therefore, opportunity to study pathophysiology of tauopathies and efficacy of tau-directed therapies. In the past few years, identification of tau specific ligands has advanced neuroimaging of tauopathies such as CBD and progressive supranuclear palsy. However, clinical prediction of CBD pathology remains challenging and an active are of research. In this review, we highlight key emerging issues in CBD pathophysiology, genetics and novel neuroimaging techniques with tau ligands.

Pain is common in atypical parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (LBD). In this study, a systematic review and meta-analysis was conducted and peer-reviewed literature was searched to determine the prevalence and types of pain in four atypical parkinsonism syndromes: MSA, PSP, CBD and LBD. The results show that pain was prevalent mainly in MSA patients in comparison to PSP and CBD patients. Pain was reported at an early stage and was found in females, with limb pain being the most common, followed by neck and back pain. In comparison to PSP, pain locations were similar to MSA patients. CBD patients experienced pain the least in comparison to MSA, PSP and LBD patients.

Pathological changes in corticobasal degeneration (CBD) consist of abnormal deposition of the microtubule-associated protein tau. However, the simultaneous accumulation of different misfolded proteins in the brain can be observed in many neurodegenerative diseases with significantly longer disease durations. We encountered a patient with CBD who survived for an extremely long period (18 years) after the diagnosis. We performed an autopsy to elucidate the effect of the longer survival on the pathology of CBD. We observed abnormal aggregation of trans-activating response region DNA-binding protein of 43 kDa (TDP-43) and α-synuclein, as well as phosphorylated tau, in neurons of broader regions of the brain, beyond the amygdala and other limbic areas. We found that phosphorylated tau, α-synuclein, and TDP-43 partially co-existed in the same cellular aggregates. The triple pathologic changes might be related to the longer survival of the patient compared with the typical clinical course of patients with CBD. Further investigations are required to support the hypothesis that tauopathy, synucleinopathy, and TDP-43 proteinopathy might share common pathogenic mechanisms in terms of cross-seeding of the pathologic proteins.

The 4-repeat (4R)-tauopathies can be clinically heterogeneous and difficult to diagnose. An FDG-PET pattern of hypometabolism has been previously reported in clinically suspected 4R-tauopathies. Considering that pathological confirmation has not been used as inclusion criteria in these studies, however, the possibility exists that atypical cases were excluded. We studied pathologically confirmed cases of 4R-tauopathies to determine if FDG-PET patterns of hypometabolism different than those previously described exist. We identified all autopsy confirmed 4R-tauopathies with FDG-PET imaging performed between 2010 and 2013 within the Mayo Clinic database. Clinical features and FDG-PET imaging were compared to a group of normal controls. Ten patients, seven of which had autopsy-confirmed progressive supranuclear palsy (PSP), were identified. We also identified two cases with globular glial tauopathy (GGT) and one case of corticobasal degeneration (CBD). The overall predominant imaging findings included bilateral caudate hypometabolism in nine cases, mild asymmetric thalamic hypometabolism in eight, midbrain hypometabolism in seven, and bilateral hypometabolism in the supplementary motor area in seven. No differences were observed between PSP and GGT. The one CBD case had asymmetric parietal hypometabolism that was not seen in the PSP and GGT cases. As previously described, 4R-tauopathies are associated with frontal, caudate, midbrain and thalamic hypometabolism on FDG-PET. This is the first report of FDG-PET in GGT, and although our series was limited, no features distinguish GGT from PSP. There was some evidence that parietal hypometabolism may be suggestive of CBD.

Sporadic Creutzfeldt-Jakob disease (sCJD) generally manifests itself by cognitive or rapidly progressive motor symptoms. An atypical onset or an unusual evolution may delay the diagnosis. Among patients with a confirmed diagnosis of sCJD following a post-mortem neuropathological examination at the Neuropathology Centre of Lille, France, those who had presented with atypical cognitive disorders at onset were included in the study. Four patients were included. The first patient (64-years-old) presented early language disorders, later accompanied by apathy and behavioral disorders. The prolonged course suggested a diagnosis of progressive primary aphasia. The second patient (68-years-old) presented with aphasia, apraxia, and ataxia of the right upper limb with parkinsonian syndrome, suggesting corticobasal degeneration. In the two last patients (58- and 61-years-old), the onset was marked by an anxiety-depression syndrome, falls, visual hallucinations, extra-pyramidal syndrome, and fluctuating cognitive decline. The diagnosis raised was probable Lewy body dementia. The 14.3.3 protein was found in two of the four cases. The clinical elements found may initially suggest focal atrophy or Lewy body dementia. A very rapid clinical deterioration generally suggests sCJD, but in the last case, the evolution was particularly slow. The diagnosis of sCJD must be considered in cases of rapid-onset dementia, even if all of the clinical criteria are not present. The detection of the 14.3.3 protein and multifold increase in total-Tau with normal or slightly increased phosphorylated-Tau in the CSF are additional arguments to reinforce the diagnosis. The post-mortem neuropathological examination is important to confirm the diagnosis.

A 65-year-old woman developed progressive apraxic agraphia, characterized by poorly formed graphemes, a kanji (Japanese morphograms) recall impairment, relatively preserved oral spelling of kanji characters, and incorrect stroke sequences on writing accompanied by micrographia over a 3-year period. She also showed minor degrees of rigidity, limb-kinetic apraxia, and ideomotor apraxia of the left hand. Although asymmetric rigidity and limb-kinetic apraxia strongly suggested corticobasal degeneration, (11)C-Pittsburgh compound B positron emission tomography (PiB-PET) showed the predominantly right-sided accumulation of amyloid β in the cortices and striatum. (18)F-fluoro-deoxy-glucose PET and single photon emission computed tomography with a (99m)Tc-ethylcysteinate dimer (ECD-SPECT) also revealed predominantly right-sided hypometabolism and hypoperfusion in the primary sensorimotor cortex, posterior cingulate gyrus, temporoparietal cortices, frontal cortices, thalamus, and basal ganglia, a pattern characteristic of both corticobasal degeneration and Alzheimer's disease. The findings suggest that progressive apraxic agraphia with micrographia presenting as corticobasal syndrome can show an Alzheimer's disease pathology. It is also suggested that ideomotor apraxia of the left hand can occur without a callosal lesion, and is caused by hypometabolism or hypoperfusion in the right frontal and parietal cortices, as revealed by PET and SPECT.

There is ample evidence from a large number of clinical and pathological studies of an early involvement of olfactory bulbs and cortex in the Lewy body pathology in idiopathic Parkinson's disease (iPD), the olfactory system being one of the first targets of degeneration in this condition. The olfactory dysfunction may be measurably present at the time of initial presentation and progresses in a proportion of patients as the disease advances. Patients with iPD have a more severe olfactory loss as compared to multisystem atrophy whereas the syndromes of corticobasal degeneration and progressive supranuclear palsy have no olfactory loss. A proportion of drug induced parkinsonism may have olfactory loss indicative of primary pathology of dopaminergic degeneration in these patients. Unlike single photon emission tomography, formal measurement of olfaction would provide a supportive role in diagnosing or excluding iPD depending on the duration of an individual patient's parkinsonian symptoms. Whilst olfaction may be only minimally impaired in early stages and may thus not help to differentiate from other syndromes, an intact olfaction in patients with parkinsonism of few years' duration would indicate a non-iPD pathology. Olfactory measurement is easy, cheap and now easily available in a number of tests, and olfactory assessment at different stages of parkinsonism should be used as a diagnostic aid for idiopathic PD and would enhance the diagnostic accuracy of iPD when used in conjunction with the UK Parkinson's disease society Brain Bank supportive criteria for diagnosis of idiopathic Parkinson's disease.

Dear Sirs, The eye of the tiger sign (EOT), seen on T2 sequences of magnetic resonance imaging (MRI), is considered pathognomonic for neurodegeneration with brain iron accumulation type 1 (NBIA1, previously known as Hallervorden–Spatz syndrome) [1–3]. This sign is described as low signal intensity in both globi pallidi (due to iron accumulation) that surrounds a central region of high signal intensity (caused by gliosis, edema, and neuronal loss with subsequent secondary vacuolization and cavitation) [1–3]. It has been occasionally reported in neurodegenerative disorders other than NBIA1, including neuroferritinopathy, progressive supranuclear palsy, multisystem atrophy, pure akinesia, and corticobasal degeneration [1–3]. Here, we describe the first case of EOT-like MRI appearance in a 41-year-old man with Wilson’s disease. At the age of 24 years, the patient developed dysarthria, oromandibular dystonia, gait disturbances, and positional hand tremor. One year later he was diagnosed with Wilson’s disease, based on the presence of Kayser–Fleischer ring and abnormal copper metabolism [i.e. decreased serum ceruloplasmin (8.2 mg/dL, normal 25–45) and serum copper (30 μg/dL, normal 70–140 μg/dL) combined with increased copper urinary excretion (664 μg/24 h, normal 0–50)]. Genetic examination confirmed compound heterozygosity, with ATP7B mutations in exon 13 (G988R) and in exon 7 (IVS7 + 3A>G). After introduction of 1000 mg/day d-penicillamine, the patient gradually improved. In 2013 his remaining symptoms were only slight dysarthria and oromandibular dystonia (occasionally grimacing). The Kayser–Fleischer rings were no longer present. However, a routine control brain MRI revealed abnormalities very similar to EOT sign (Fig. 1). Fig. 1 The MR image mimicking the “eye of the tiger” sign in T2-weighted magnetic resonance sequences; bilateral hypointensity in both putaminal regions and lateral parts of globi pallidi, with a central hyperintensity (black arrows) The difference was that hypointensity tended to localize in the lateral part of the globus pallidus and putamen instead of the medial part of the globus pallidus. Subsequent MR spectroscopy showed that the mean N-acetyloaspartate/creatine ratio (TE-144mS) in the globus pallidus was 1.55, and the mean choline/creatine ratio (TE-144 mS) was 1.10 (Fig. 2a). In the normal appearing control region, the values were 2.37 and 1.08, respectively (Fig. 2b), which may reflect neuronal loss in the affected area. Noteworthy, the patient has no co-morbidities, does not drink alcohol and had no occupational risk factors for tissue metal accumulation. Normal levels of serum iron metabolism markers (ferritin, iron, total iron binding capacity) combined with the early age of the disease onset, lack of anemia and diabetes allowed to exclude aceruloplasminemia and neuroferritinopathy. The lack of acanthocytosis, pigmentary retinopathy, hypoprobetalipoproteinemia, and good response to d-penicillamine with no subsequent progression over 15 years allowed us to exclude NBIA1. The patient's brother was diagnosed with hepatic Wilson’s disease without any neurological signs at 28 years of age. Fig. 2 The magnetic brain spectroscopy from: a unaffected structures in the right temporal lobe; b central, hyperintensive part of “eye of the tiger” sign showing markedly decreased N-acetyloaspartate in the globus pallidus as a results of reactive ... Wilson’s disease is a treatable, inherited disorder leading to pathological copper accumulation that damages affected organs, especially the liver and brain. It has been suggested that disturbances of iron metabolism occur in the liver of Wilson’s disease patients, as copper-dependent enzymes are also involved in its metabolic pathways [4]. In a recent post-mortem study we demonstrated that iron accumulates also in the brain [5]. As the EOT sign suggests accumulation of iron [2, 3, 6, 7], its increased concentration in the basal ganglia of the reported patient appeared to be particularly pronounced. However, the exact role of iron-metabolism disturbances in Wilson’s disease is still unknown and further studies are needed. Considering that patients with EOT sign may occasionally have conditions other than NBIA1, it is advisable to carry out careful differential diagnosis in order not to miss a condition that can be effectively treated.

The clinical and neuroanatomical correlates of specific apraxias in neurodegenerative disease are not well understood. Here we addressed this issue in progressive nonfluent aphasia (PNFA), a canonical subtype of frontotemporal lobar degeneration that has been consistently associated with apraxia of speech (AOS) and in some cases orofacial apraxia, limb apraxia and/or parkinsonism. Sixteen patients with PNFA according to current consensus criteria were studied. Three patients had a corticobasal syndrome (CBS) and two a progressive supranuclear palsy (PSP) syndrome. Speech, orofacial and limb praxis functions were assessed using the Apraxia Battery for Adults-2 and a voxel-based morphometry (VBM) analysis was conducted on brain MRI scans from the patient cohort in order to identify neuroanatomical correlates. All patients had AOS based on reduced diadochokinetic rate, 69% of cases had an abnormal orofacial apraxia score and 44% of cases (including the three CBS cases and one case with PSP) had an abnormal limb apraxia score. Severity of orofacial apraxia (but not AOS or limb apraxia) correlated with estimated clinical disease duration. The VBM analysis identified distinct neuroanatomical bases for each form of apraxia: the severity of AOS correlated with left posterior inferior frontal lobe atrophy; orofacial apraxia with left middle frontal, premotor and supplementary motor cortical atrophy; and limb apraxia with left inferior parietal lobe atrophy. Our findings show that apraxia of various kinds can be a clinical issue in PNFA and demonstrate that specific apraxias are clinically and anatomically dissociable within this population of patients.

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) has been reported in patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). This imaging approach is a sensitive diagnostic tool that possibly differentiates PD and DLB from other movement disorders and Alzheimer's disease (AD). We recently reported cardiac sympathetic denervation in PD, DLB and PAF, which accounts for the decreased cardiac uptake of MIBG in these disorders. Patients with PD, DLB and PAF have Lewy bodies (LBs) in the nervous system, whereas patients with multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration, AD and parkin-associated PD have no LBs in the nervous system. Even in patients with MSA, cardiac sympathetic denervation was associated with the presence of LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. Taken together, we conclude that the decreased cardiac uptake of MIBG is a potential biomarker for the presence of LBs.We infer that MIBG myocardial scintigraphy is a non-invasive tool that allows us to detect LBs during life.

Dystonia can occasionally be found in idiopathic Parkinson's disease. It is very uncommon in untreated patients and is more frequently seen as a complication of its treatment. In this review, the various types of dystonia occurring in PD, the differential diagnosis with other parkinsonian syndromes associated with dystonia and treatments available are revised. Dystonia unrelated to treatment can be typical (blepharospasm, torticollis), atypical (parkinsonian writer's cramp, camptocormia, anismus), or occurring in earlyonset Parkinson disease (the so-called kinesigenic foot dystonia, considered a hallmark of early-onset Parkinson's disease). Early and prominent dystonia in untreated patients with parkinsonism should raise the suspicion of other entities other than Parkinson's disease, such as progressive supranuclear palsy, multiple system atrophy or corticobasal degeneration. In patients on chronic dopaminergic treatment, peak-dose dystonia, diphasic dystonia and off-dystonia can be seen. The later constitutes the major dystonic feature of chronic levodopa therapy, and a wide variety of strategies are available to manage this complication. Among them, deep brain stimulation of the subthalamic nucleus has proved to be the most effective one. Dystonic reactions (mainly involving oculomotor cranial nerves and limbs) in operated patients (especially carriers of deep brain stimulation (DBS) devices) are increasingly being reported, constituting a new type of dystonia in patients with Parkinson's disease: dystonia linked to surgical treatment.

Reduced cardiac uptake of 123I-metaiodobenzylguanidine (MIBG) is considered to represent dysfunction of the postganglionic neurons of the cardiac sympathetic nervous system. Evidence indicates that cardiac uptake of 123I-MIBG is decreased in patients with idiopathic Parkinson’s disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF), which have common pathological features with Lewy body formation. In the present article, we review previous reports that determined heart-mediastinum (H/M) ratios in early and delayed images of patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) in comparison to those of IPD and controls. The majority of reports suggest that H/M ratios of patients with PSP, CBD and MSA are comparable to those of controls, while H/M ratios of patients with IPD are significantly reduced. This reduction seen in IPD may reflect the loss and/or dysfunction of postganglionic cardiac sympathetic nerve terminals. Several authors reported mild reduction of 123I-MIBG uptake in patients with MSA and PSP. However, no degeneration of postganglionic neurons of the cardiac sympathetic nervous system has been detected in patients with these diseases. These results indicate that cardiac 123I-MIBG uptake is a sensitive tool with which to differentiate IPD from neurodegenerative diseases with extrapyramidal symptoms such as PSP, CBD and MSA.

Functional imaging studies with positron emission tomography (PET) and single photon emission computed tomography (SPECT) have shown alterations in glucose metabolism, perfusion, dopaminergic systems, cholinergic systems and activation of microglia in the brains of patients with Parkinson’s disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA). [18F]fluorodeoxyglucose-PET and perfusion SPECT show characteristic changes in brain glucose metabolism and perfusion, which are useful for differential diagnosis of these disorders. [18F]dopa-PET and SPECT studies of dopamine transporters show marked impairment of nigrostriatal neuronal terminals in PD, PSP, CBD and MSA. PET studies with carbon-11-labeled acetylcholine analogs have shown mild to moderate reduction of acetylcholinesterase (AChE) activity in the cerebral cortex in PD, severe reduction of AChE activity in the thalamus in PSP, and marked reduction of AChE activity in the cerebellum. [11C](R)-PK11195-PET studies have shown an increase in activated microglia in brain regions that mirror the known distribution of neuropathologic changes in PD, CBD and MSA, which provides insight into the pathophysiology of these disorders.

Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA) are manifested as atypical parkinsonism. Both PSP and CBD are considered tauopathies because of the accumulation of tau protein in the brains, and MSA is considered a synucleinopathy owing to accumulation of α-synuclein. Although some pathological changes are found in both PSP and CBD, other changes allow the two conditions to be differentiated. Typical clinical manifestations of PSP and CBD have been described, but unusual clinical manifestations, which complicate clinical diagnosis, have been reported. MSA has been divided into the pathological subtypes of striatonigral degeneration and olivopontocerebellar atrophy, although some cases of MSA have features of both subtypes. Both the substantia nigra and the putamen are initially affected in the striatonigral degeneration subtype. Rare patients have both MSA and PSP.

To characterize the dysarthria in patients with corticobasal degeneration (CBD) and determine if analysis of speech in isolation helps to distinguish CBD patients from patients with Parkinson's disease (PD).60 subjects were assessed by means of perceptual analysis of speech: 15 patients with CBD, 15 patients with PD and 30 control subjects. A detailed profile was furnished with the help of 33 perceptual items. A global perceptual approach was used to classify patients by judges blind to the medical diagnosis. Rating scales were adapted to quantify the degree of spasticity and hypokinesia in the speech of each patient.Dysarthria was frequent in CBD even though it remained mild for a long period of time. Group analysis revealed the importance of temporal errors of speech control in CBD patients while voice disturbances were most frequent in PD patients. However, attempts to classify patients according to global perceptual analysis remained below a reasonable level of clinical acceptability. Finally, even though the widespread neuropathological changes suggest that deviant speech dimensions of several types of dysarthria might be found in CBD, evidence for a mixed dysarthria with presence of spastic elements could not be established.The findings support the view that even though perceptual analysis is mandatory in the management of dysarthric patients, it does not help in the clinical differential diagnosis of CBD.

Prion diseases are inherited in 5–15 % of cases. They are classified according to changes in the prion protein gene (PRNP) or conventionally according to phenotype as Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), or familial Creutzfeldt-Jakob disease (fCJD). Point mutations and insertions within PRNP form the genetic background. We report the results of a systematic analysis of over 500 case reports of patients with PRNP abnormalities. We compare clinical, neuropathological and molecular data in five groups, namely GSS, FFI, fCJD, base pair insertion (BPI), and all cases collectively. Clinical presentation overlaps between mutations, but some have characteristic features (e. g. P105L, D178N–129M, T183A). Some mutations, especially in the lack of sufficient family history, in earlier phases tend to resemble other neurodegenerative disorders like multiple system atrophy, corticobasal degeneration or familial diseases such as late-onset spinocerebellar ataxia, spastic paraparesis, frontotemporal dementia, or Alzheimer's disease. The codon 129 polymorphism has a phenotypic influence in inherited prion diseases, as in non-genetic forms, but additional factors might be considered as background for phenotypic variability.

To investigate the nature of the apraxia in corticobasal degeneration (CBD) five patients with CBD and five matched controls were compared on tests of: i) meaningless and symbolic gesture production, ii) a battery of semantic tasks based on 20 everyday items (involving naming and picture-picture matching according to semantic attributes, matching gestures-to-objects, object usage from name and with the real object) and iii) a novel tool test of mechanical problem solving. All five patients showed severe impairment in the production of meaningless and symbolic gestures from command, and by imitation, and were also impaired when using real objects. Deficits were not, however, restricted to action production: four were unable to match gestures to objects and all five showed impairment in the selection and usage of novel tools in the mechanical problem solving task. Surprising was the finding of an additional semantic knowledge breakdown in three cases, two of whom were markedly anomic. The apraxia in CBD is, therefore, multifactorial. There is profound breakdown in the organisation and co-ordination of motor programming. In addition, patients show central deficits in action knowledge and mechanical problem solving, which has been linked to parietal lobe pathology. General semantic memory may also be affected in CBD in some cases and this may then contribute to impaired object usage. This combination of more than one deficit relevant for object use may explain why CBD patients are far more disabled by their dyspraxia in everyday life than any other patient group.

We investigated the efficacy of botulinum toxin A (BtxA) therapy in patients with atypical parkinsonian disorders (APD) exhibiting different types of disabling focal dystonia unresponsive to oral drug therapy. Eight patients with functionally disabling focal dystonia out of a series of 60 consecutive patients with APDs regularly treated at our outpatient movement disorders clinic were included. Patients were diagnosed according to established criteria and had disabling limb dystonia (n=4) or craniocervical dystonia (n=4) unresponsive to oral pharmacological treatment. Localization and dose of BtxA injections was determined individually based on clinical examination as well as EMG in patients with limb dystonia. BtxA reduced dystonic symptoms in all patients; only one developed a transient local side-effect. BtxA was particularly effective in the long-term treatment (up to 50 months) of blepharospasm associated with progressive supranuclear palsy (PSP). BtxA also alleviated PSP-associated retrocollis and orofacial dystonia with lower lip retraction associated with PSP and multiple system atrophy. BtxA treatment of limb dystonia in corticobasal degeneration (CBD) temporarily improved hand and arm function in early-disease stages while treatment in advanced stages reduced pain, facilitated hygiene and prevented secondary contractures. Limb dystonia was also alleviated by BtxA therapy in one patient with neuronal multisystem degeneration of undetermined cause. The results suggest that BtxA therapy may represent an effective means of alleviating disabling focal dystonia in different APDs. Particularly in early stage APD with disabling limb dystonia local BtxA injections may result in functional improvement.

The ‘applause sign’ refers to a tendency to initiate an automatic series of hand-claps despite instruction to clap three times only [1]. It is not specific for any one condition, but has been associated with progressive supranuclear palsy (PSP) in particular [2] and has also been described in corticobasal degeneration, multiple system atrophy and idiopathic Parkinson’s disease [3]. Localisation of the pathology that gives rise to the applause sign is uncertain. A combination of frontal cortical and basal ganglia dysfunction has been suggested. There has been one previous report of the applause sign in a patient without a known neurodegenerative disease. This occurred in a patient with diffuse B-cell lymphoma involving the putamen on one side; however, there was also extensive subcortical white matter disease bilaterally [4]. A 70-year-old man presented with sudden onset left hemiparesis. He was a diabetic with hypertension and hyperlipidemia. His family reported that he was an active and highly motivated individual who continued to successfully manage a number of businesses. On admission he was found to have atrial fibrillation. There was a mild left facial weakness. Power of shoulder abduction, elbow flexion and finger extension in the left upper limb was 4/5 (MRC scale). Hip flexion was 4/5 in the left lower limb with normal power otherwise. There was mild right more than left upper limb bradykinesia with decrement and mild bilateral rigidity at the wrist with co-activation. No micrographia, rest, postural or action tremor were evident. The left plantar response was extensor. Marked hypomimia and hypophonia were evident. Myerson’s sign was present and there was a strong grasp reflex present bilaterally. When asked to copy the examiner by clapping three times only the response was consistently greater than twenty claps. He would not attempt to walk but with encouragement could mobilise with maximal assistance of two people, tending to fall towards his weaker left side. MRI of brain revealed T2 hyperintensities involving the lentiform nucleus bilaterally, predominantly in the region of the putamen with probable capsular involvement on the right. These lesions were bright on diffusion-weighted imaging (DWI) sequences, consistent with acute infarction (see Fig. 1). A T2 hyperintensity was noted in the head of the caudate on the left without corresponding restriction of diffusion on the DWI sequences. No other acute changes were seen. There was mild generalised cortical atrophy with associated dilatation of the lateral ventricles, including involvement of the frontal lobes on T1 weighted sequences. These changes were felt to be age appropriate. Over the following 3 months rehabilitation was limited by profound apathy, passivity and low mood. Despite only mild weakness, progress was poor with reluctance to mobilise. Resistance to participation in cognitive testing and poor attention made formal assessment impossible. Slow improvement in spontaneous speech, motivation and mood was observed after treatment with sertraline titrated Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-5904-5) contains supplementary material, which is available to authorized users.

Over the last 20 years the nomenclature, the different clinical and neuropathological subtypes and thus the classification of corticobasal syndrome have changed considerably. The clinical diagnosis of corticobasal syndrome and its different subtypes is still difficult with low predictive values when the pathological diagnosis as the gold standard is applied. This is the major handicap in the field of corticobasal syndrome for all clinical MRI, functional MRI and PET studies as well as treatment trials (all the latter had been negative). Further, there is no general agreement on the nomenclature and the subtypes of corticobasal syndrome. Clinically, it is characterised by a slow onset and progressive asymmetric cortical and extrapyramidal dysfunction. The different subtypes of corticobasal syndrome (CBS) can be classified based on different pathologies as follows: corticobasal degeneration (CBS–CBD), progressive supranuclear palsy (CBS–PSP), Alzheimer’s disease (CBS–AD) and frontotemporal lobe degeneration (FTLD) with ubiquitin-only immunoreactive inclusions mainly showing immunoreactivity to the TAR DNA-binding protein of 43 kDa (CBS–TDP) (for references see Whitwell et al. 2010). This month’s Journal Club will focus on three recently published articles on corticobasal syndrome. In the first, a very carefully performed clinicopathological re-evaluation, all the archival cases in the Queen Square Brain Bank over a 20-year period with either the clinical diagnosis of corticobasal syndrome or the pathological diagnosis of corticobasal degeneration were re-evaluated. It is important to note that the sensitivity and the predictive positive value were remarkably low even in this highly qualified centre. This is something one should always bear in mind in any study on non-pathologically proven cases of corticobasal degeneration. In the second study, the patterns of atrophy on imaging were correlated with the histopathological diagnosis and different subtypes of corticobasal syndrome. It is important to note that all cases were proven histopathologically. Therefore, this study is of diagnostic value for the discrimination of the different subtypes of corticobasal syndrome. In the third study, the cholinergic deficits in different areas of the brain were examined in a PET study in patients with corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia. These cases, however, were not autopsy-proven and thus the results must be interpreted with caution.