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The emergence of new artistic activities or shifts in artistic style in patients with frontotemporal dementia (FTD) syndromes is well documented at or after disease onset. However, a closer look in the literature reveals emerging artistic creativity also before FTD onset, although the significance and underlying pathology of such creative endeavors remain elusive. Here, we systematically review relevant studies and report an additional FTD case to elaborate on artistic activities that developed years before disease manifestation by paying particular attention to the sequence of events in individual patients' biography and clinical history. We further discuss the FTD patient's creative activities in the context of their life events, other initial or "premorbid" dementia symptoms or risk factors described in the literature such as mental illness and mild behavioral impairment (MBI), as well as changes in neuronal systems (i.e., neuroimaging and neuropathology). In addition to our FTD patient, we identified five published cases with an FTD syndrome, including three with FTD, one with primary progressive aphasia (PPA), and one with the behavioral variant of PPA (bvPPA). Premorbid novel creativity emerged across different domains (visual, musical, writing), with the FTD diagnosis ensuing artistic productivity by a median of 8 years. Data on late-life and pre-dementia life events were available in four cases. The late creative phase in our case was accompanied by personality changes, accentuation of personality traits, and cessation of painting activities occurred with the onset of memory complaints. Thus, premorbid personality changes in FTD patients can be associated with de novo creative activity. Stressful life events may also contribute to the burgeoning of creativity. Moreover, primary neocortical areas that are largely spared by pathology at early FTD stages may facilitate the engagement in artistic activities, offering a window of opportunity for art therapy and other therapeutic interventions during the MBI stage or even earlier.

Numerous papers report on connections between creative work and dementing illness, particularly in frontotemporal dementia (FTD), which may combine with motor neuron disease (FTD-MND). However, the emergence of FTD(-MND) patients’ de novo artistic activities is rarely reported and underappreciated. Therefore, the present review summarizes relevant case studies’ outcomes, capturing creativity’s multifaceted nature. Here, we systematically searched for case reports by paying particular attention to the chronological development of individual patients’ clinical symptoms, signs, and life events. We synoptically compared the various art domains to the pattern of brain atrophy, the clinical and pathological FTD subtypes. 22 FTD(-MND) patients were identified with creativity occurring either at the same time (41%) or starting after the disease onset (59%); the median lag between the first manifestation of disease and the beginning of creativity was two years. In another five patients, novel artistic activity was developed by a median of 8 years before the start of dementia symptoms. Artistic activity usually evolved over time with a peak in performance, followed by a decline that was further hampered by physical impairment during disease progression. Early on, the themes and objects depicted were often concrete and realistic, but they could become more abstract or symbolic at later stages. Emergent artistic processes may occur early on in the disease process. They appear to be a communication of inner life and may also reflect an attempt of compensation or “self-healing”. The relative preservation of primary neocortical areas such as the visual, auditory, or motor cortex may enable the development of artistic activity in the face of degeneration of association cortical areas and subcortical, deeper central nervous system structures. It is crucial to understand the differential loss of function and an individual's creative abilities to implement caregiver-guided, personalized therapeutic strategies such as art therapy.

Here, we review the morphological taxonomy of neurons proposed by Enrique Ramón-Moliner in the vertebrate central nervous system based on "dendroarchitectonics" and compare these findings with Santiago Ramón y Cajal's work. Ramón-Moliner distinguished three main groups of nerve cells situated on a spectrum of dendritic configuration in the mammalian central nervous system with decreasing degree of morphological specialization, i.e., idiodendritic, allodendritic, and isodendritic neurons. Leptodendritic neurons would be an even more primitive type, and lophodendritic nerve cells would develop into pyramidal neurons. Using two developmental lines (i.e., telencephalic and rhombencephalic trends), Ramón-Moliner reconstructed the probable course of events in the phylogenetic history that led to the dendroarchitectonic families. While an increasing morphological specialization is associated with the projected phylogenetic development as an abstract "whole," phylogenetically "primitive neurons" such as the reticular formation may be present in later phylogenetic stages, and vice versa, phylogenetical "new arrivals," such as the cortical pyramidal cell, may be found early in phylogeny. Thus, Ramón-Moliner adopted the notion of an in-parallel neuronal development during phylogeny and ontogeny. In contrast, Cajal argued earlier in favor of the idea that ontogeny recapitulates phylogeny, focusing on the pyramidal neuron. In ontogeny, the early developmental features show a higher degree of similarity than the comparison of their adult forms. These results corroborate the rejection of the interpretative framework of ontogeny as a simple, speedy repetition of the phylogeny. Understanding morphological findings with the change in their interpretation and the historic underpinnings provide a framework for refined scientific hypotheses.

The emergence of new artistic activities or shifts in artistic style in patients with frontotemporal dementia (FTD) syndromes is well documented at or after disease onset. However, a closer look in the literature reveals emerging artistic creativity also before FTD onset, although the significance and underlying pathology of such creative endeavors remain elusive. Here, we systematically review relevant studies and report an additional FTD case to elaborate on artistic activities that developed years before disease manifestation by paying particular attention to the sequence of events in individual patients' biography and clinical history. We further discuss the FTD patient's creative activities in the context of their life events, other initial or "premorbid" dementia symptoms or risk factors described in the literature such as mental illness and mild behavioral impairment (MBI), as well as changes in neuronal systems (i.e., neuroimaging and neuropathology). In addition to our FTD patient, we identified five published cases with an FTD syndrome, including three with FTD, one with primary progressive aphasia (PPA), and one with the behavioral variant of PPA (bvPPA). Premorbid novel creativity emerged across different domains (visual, musical, writing), with the FTD diagnosis ensuing artistic productivity by a median of 8 years. Data on late-life and pre-dementia life events were available in four cases. The late creative phase in our case was accompanied by personality changes, accentuation of personality traits, and cessation of painting activities occurred with the onset of memory complaints. Thus, premorbid personality changes in FTD patients can be associated with de novo creative activity. Stressful life events may also contribute to the burgeoning of creativity. Moreover, primary neocortical areas that are largely spared by pathology at early FTD stages may facilitate the engagement in artistic activities, offering a window of opportunity for art therapy and other therapeutic interventions during the MBI stage or even earlier.

ZusammenfassungDie Tätigkeiten im Notarzt- und Rettungsdienst sind häufig mit persönlichen Gefährdungen verbunden. Im Vordergrund steht jedoch immer die Problematik der Gefährdungssituationen, die durch den Notarzt wahrgenommen werden. In der vorliegenden Arbeit wird vor allem vor dem Hintergrund der Erforderlichkeit und Zumutbarkeit die Frage diskutiert, ob und inwieweit ein Notarzt zum Handeln verpflichtet ist. Im Ergebnis ist objektiv typisierend auf den Facharztstandard beziehungsweise den Indikationskatalog für den Notarzteinsatz in Kombination mit arzt-/berufsrechtlichen Gesichtspunkten (zum Beispiel Freiberuflichkeit) hinzuweisen. Es handelt sich jedoch immer um eine Einzelfallbetrachtung und um eine individuelle, fallbezogene Entscheidung. Bei seltenen, sehr unwahrscheinlichen Situationen mit relativer Ermangelung von objektiv typisierbaren Gesichtspunkten werden die Anforderungen, aber auch die Chancen an die „höchstpersönliche“ Berufsausübung und an die Persönlichkeit des Arztes (vor allem in der Entscheidungsfindung) umso größer.

Numerous papers report on connections between creative work and dementing illness, particularly in frontotemporal dementia (FTD), which may combine with motor neuron disease (FTD-MND). However, the emergence of FTD(-MND) patients' de novo artistic activities is rarely reported and underappreciated. Therefore, the present review summarizes relevant case studies' outcomes, capturing creativity's multifaceted nature. Here, we systematically searched for case reports by paying particular attention to the chronological development of individual patients' clinical symptoms, signs, and life events. We synoptically compared the various art domains to the pattern of brain atrophy, the clinical and pathological FTD subtypes. 22 FTD(-MND) patients were identified with creativity occurring either at the same time (41%) or starting after the disease onset (59%); the median lag between the first manifestation of disease and the beginning of creativity was two years. In another five patients, novel artistic activity was developed by a median of 8 years before the start of dementia symptoms. Artistic activity usually evolved over time with a peak in performance, followed by a decline that was further hampered by physical impairment during disease progression. Early on, the themes and objects depicted were often concrete and realistic, but they could become more abstract or symbolic at later stages. Emergent artistic processes may occur early on in the disease process. They appear to be a communication of inner life and may also reflect an attempt of compensation or "self-healing". The relative preservation of primary neocortical areas such as the visual, auditory, or motor cortex may enable the development of artistic activity in the face of degeneration of association cortical areas and subcortical, deeper central nervous system structures. It is crucial to understand the differential loss of function and an individual's creative abilities to implement caregiver-guided, personalized therapeutic strategies such as art therapy.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease associated with neurodegeneration and intracellular pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) positive inclusions. The various clinical symptoms, such as motor disorders and cognitive impairment, reflect the degeneration of certain areas of the nervous system. Since the discovery of the significance of pathological TDP-43 for human disease including ALS, there has been an increasing number of studies reporting on the distribution and severity of neurodegeneration. These have rekindled the old debate about whether the first or second motor neuron is the primary site of degeneration in ALS. To shed light on this question, the following is a review of the relevant neuropathological studies.

F. Geser, J. A. Malunda, H. I. Hurtig, J. E. Duda, G. K. Wenning, S. Gilman, P. A. Low, V. M.-Y. Lee and J. Q. Trojanowski (2011) Neuropathology and Applied Neurobiology37, 358–365 TDP-43 pathology occurs infrequently in multiple system atrophy Aims and Methods: The α-synucleinopathy multiple system atrophy (MSA) and diseases defined by pathological 43-kDa transactive response DNA-binding protein (TDP-43) or fused in sarcoma (FUS) aggregates such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration show overlapping clinico-pathological features. Consequently, we examined MSA for evidence of TDP-43 or FUS pathology utilizing immunohistochemical studies in autopsy material from 29 MSA patients. Results: TDP-43 pathology was generally rare, and there were no FUS lesions. The TDP-43 lesions were located predominantly in medio-temporal lobe and subcortical brain areas and were comprised mainly of dystrophic processes and perivascular (and subpial) lesions. Conclusions: The multisystem clinical symptoms and signs of MSA, and in particular the neurobehavioural/cognitive and pyramidal features, appear not to result from concomitant TDP-43 or FUS pathology, but rather from widespread white matter α-synuclein positive glial cytoplasmic inclusions and neurodegeneration in keeping with a primary α-synuclein-mediated oligodendrogliopathy. The gliodegenerative disease MSA evidently results from different pathogenetic mechanisms than neurodegenerative diseases linked to pathological TDP-43.

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. (C) 2010 Movement Disorder Society

Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a well-recognized entity. However, the molecular underpinnings of this devastating disease are poorly understood. Here, we present genetic and neuropathological characterizations in two young women with fatal rapidly progressive ALS with basophilic inclusions. In one case, a germline mutation (P525L) was detected in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene, whereas no mutation was identified in the other case. Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum. In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei. In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein. These results underscore the importance of FUS mutations and pathology in rapidly progressive juvenile ALS. Furthermore, our study represents the first detailed characterizations of neuropathological findings in rapidly progressive juvenile ALS patients with a mutation in the FUS/TLS gene.

The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

It is the intention of this article on De Trinitate by St. Augustine to show that his doctrine is built upon applied epistemology aimed at the acquisition ofintellectus fidei. The main part of this paper explores the Augustinian search for vestigia trinitatis which reveals striking “psychological analogues” of thedivine trinity present in the human mind (Books 8-15). A mystical union with the holy trinity, however, appears impossible due to the impar imago of thehuman mind.

The aim of the study was to investigate the efficacy of the antibiotic minocycline as a drug treatment in patients with Multiple-System-Atrophy Parkinson-type (MSA-P). Sixty-three patients were randomized to minocycline 200 mg/d (n = 32) or a matching placebo (n = 31). The primary outcome variable was the change in the value of the motor score of the Unified Multiple-System-Atrophy Rating-Scale (UMSARSII) from baseline to 48 weeks. Secondary outcome variables included subscores and individual Parkinsonian symptoms as determined by the UMSARS and the Unified-Parkinson's-Disease Rating-Scale (UPDRS). Health-related quality of life (HrQoL) was assessed using the EQ-5D and SF-12. "Progression rate" was assumed to be reflected in the change in motor function over 48 weeks. At 24 weeks and 48 weeks of follow-up, there was a significant deterioration in motor scores in both groups, but neither the change in UMSARSII nor in UPDRSIII differed significantly between treatment groups, i.e. "progression rate" was considered to be similar in both treatment arms. HrQoL did not differ among the two treatment arms. In a small subgroup of patients (n = 8; minocycline = 3, placebo = 5)[(11)C](R)-PK11195-PET was performed. The three patients in the minocycline group had an attenuated mean increase in microglial activation as compared to the placebo group (P = 0.07) and in two of them individually showed decreased [11C](R)-PK11195 binding actually decreased. These preliminary PET-data suggest that minocycline may interfere with microglial activation. The relevance of this observation requires further investigation. This prospective, 48 week, randomized, double-blind, multinational study failed to show a clinical effect of minocycline on symptom severity as assessed by clinical motor function.

Frontotemporal lobar degeneration with TDP- 43 inclusions (FTLD-TDP) is characterized by progressive decline in behavior, executive function, and language. Progranulin (GRN) gene mutations are pathogenic for FTLD-TDP, and GRN transcript haploinsufficiency is the proposed disease mechanism. However, the evidence for this hypothesis comes mainly from blood-derived cells; we measured progranulin expression in brain. We characterized mRNA and protein levels of progranulin from four brain regions (frontal cortex, temporal cortex, occipital cortex, and cerebellum) in FTLD-TDP patients with and without GRN mutations, as well as neurologically normal individuals. Moreover, we performed immunohistochemistry to evaluate the degree of TDP-43 pathology and microglial infiltration present in these groups. In most brain regions, patients with GRN mutations showed mRNA levels comparable to normal controls and to FTLD-TDP without GRN mutations. However, GRN transcript levels in a brain region severely affected by disease (frontal cortex) were increased in mutation-bearing patients. When compared with normal individuals, GRN mutation-bearing cases had a significant reduction in the amount of progranulin protein in the cerebellum and occipital cortex, but not in the frontal and temporal cortices. In GRN mutant cases, GRN mRNA originated from the normal allele, and moderate microglial infiltration was observed. In conclusion, GRN mutation carriers have increased levels of mRNA transcript from the normal allele in brain, and proliferation of microglia likely increases progranulin levels in affected regions of the FTLD-TDP brain, and whether or not these findings underlie the accumulation of TDP-43 pathology in FTLD-TDP linked to GRN mutations remains to be determined.

Frontotemporal lobar degeneration is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function and sometimes language. Disease mechanisms remain poorly understood. Recently, however, the DNA- and RNA-binding protein TDP-43 has been identified as the major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology. Using the Affymetrix U133A microarray platform, we profiled global gene expression in both histopathologically affected and unaffected areas of human FTLD-U brains. We then characterized differential gene expression with biological pathway analyses, cluster and principal component analyses, and subgroup analyses based on brain region and progranulin (GRN) gene status. Comparing 17 FTLD-U brains to 11 controls, we identified 414 upregulated and 210 downregulated genes in frontal cortex (P-value < 0.001). Moreover, cluster and principal component analyses revealed that samples with mutations or possibly pathogenic variations in the GRN gene (GRN+, 7/17) had an expression signature that was distinct from both normal controls and FTLD-U samples lacking GRN gene variations (GRN-, 10/17). Within the subgroup of GRN+ FTLD-U, we found >1300 dysregulated genes in frontal cortex (P-value < 0.001), many participating in pathways uniquely dysregulated in the GRN+ cases. Our findings demonstrate a distinct molecular phenotype for GRN+ FTLD-U, not readily apparent on clinical or histopathological examination, suggesting distinct pathophysiological mechanisms for GRN+ and GRN- subtypes of FTLD-U. In addition, these data from a large number of human brains provide a valuable resource for future testing of disease hypotheses.

Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD–MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD–MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD–MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD–MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining (“pre-inclusion”) was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD–MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.

Objective Amyotrophic lateral sclerosis (ALS) is a common, fatal motor neuron disorder with no effective treatment. Approximately 10% of cases are familial ALS (FALS), and the most common genetic abnormality is superoxide dismutase-1 (SOD1) mutations. Most ALS research in the past decade has focused on the neurotoxicity of mutant SOD1, and this knowledge has directed therapeutic strategies. We recently identified TDP-43 as the major pathological protein in sporadic ALS. In this study, we investigated TDP-43 in a larger series of ALS cases (n = 111), including familial cases with and without SOD1 mutations. Methods Ubiquitin and TDP-43 immunohistochemistry was performed on postmortem tissue from sporadic ALS (n = 59), ALS with SOD1 mutations (n = 15), SOD-1–negative FALS (n = 11), and ALS with dementia (n = 26). Biochemical analysis was performed on representative cases from each group. Results All cases of sporadic ALS, ALS with dementia, and SOD1-negative FALS had neuronal and glial inclusions that were immunoreactive for both ubiquitin and TDP-43. Cases with SOD1 mutations had ubiquitin-positive neuronal inclusions; however, no cases were immunoreactive for TDP-43. Biochemical analysis of postmortem tissue from sporadic ALS and SOD1-negative FALS demonstrated pathological forms of TDP-43 that were absent in cases with SOD1 mutations. Interpretation These findings implicate pathological TDP-43 in the pathogenesis of sporadic ALS. In contrast, the absence of pathological TDP-43 in cases with SOD1 mutations implies that motor neuron degeneration in these cases may result from a different mechanism, and that cases with SOD1 mutations may not be the familial counterpart of sporadic ALS. Ann Neurol 2007;61:427–434

The diagnosis of multiple system atrophy (MSA) in life rests on clinical history and neurological examination. An accurate pre-mortem diagnosis of MSA is important because of prognostic and therapeutic implications. Consensus diagnostic criteria have been developed, but their use does not always improve recognition of MSA, particularly in early disease stages. A range of warning signs (red flags) may point towards MSA. However, their predictive value has never been determined prospectively. Additional investigations such as autonomic function tests, sphincter electromyography, or neuroimaging may be used to support the diagnosis or to exclude other diseases.

By using diffusion-weighted imaging (DWI), we have recently shown abnormal diffusivity in the putamen of patients with the Parkinson variant of multiple system atrophy (MSA-P) which also correlated with disease severity, indicating the capability of putaminal diffusivity to serve as a marker for disease progression. We therefore performed a serial DWI study in 10 patients with MSA-P compared to 10 patients with Parkinson's disease (PD) to evaluate the dynamic evolution of diffusion properties in the basal ganglia including putamen, caudate nucleus and globus pallidum by means of the trace of the diffusion tensor (Trace(D)). For comparison, we have also analyzed the frequency and semiquantitative grading of MSA-P-related structural changes on conventional MRI including putaminal atrophy, lateral hyperintense margination of the putamen and putaminal signal hypointensity relative to the globus pallidum on T2 MR images. None of the Trace(D) values in the basal ganglia regions in the PD group changed significantly at follow-up compared to baseline. In MSA-P, a significant increase of the Trace(D) was found in the putamen, which correlated with motor progression as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). No significant change of any of the abnormal putaminal findings on routine MRI was obtained. We suggest that abnormal diffusivity in the putamen is sensitive to change over time in MSA-P and correlates with motor progression indicating that DWI may serve to monitor disease progression in MSA-P in an objective and quantitative manner.

Background: The formation of alpha-synuclein aggregates may be a critical event in the pathogenesis of multiple system atrophy (MSA). However, the role of this gene in the aetiology of MSA is unknown and untested.Method: The linkage disequilibrium (LD) structure of the alpha-synuclein gene was established and LD patterns were used to identify a set of tagging single nucleotide polymorphisms (SNPs) that represent 95% of the haplotype diversity across the entire gene. The effect of polymorphisms on the pathological expression of MSA in pathologically confirmed cases was also evaluated.Results and conclusion: In 253 Gilman probable or definite MSA patients, 457 possible, probable, and definite MSA cases and 1472 controls, a frequency difference for the individual tagging SNPs or tag-defined haplotypes was not detected. No effect was observed of polymorphisms on the pathological expression of MSA in pathologically confirmed cases.

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people that has only been recognized in the past decade and that remains widely underdiagnosed. At postmortem examination, affected patients show numerous alpha-synuclein-positive Lewy bodies (LB) in many parts of the cerebral cortex, particularly neocortical and limbic areas in addition to the nigral LB degeneration characteristic of Parkinson's disease (PD). Clinical presentation, unlike PD, is with progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function accompanied by usually only mildly to moderately severe parkinsonism, which is often akineto-rigid without the classical parkinsonian rest-tremor. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance. The two main differential diagnoses are Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). To improve the differential diagnosis of DLB, consensus criteria have been developed that establish possible and probable levels of clinical diagnostic accuracy. Generally, their sensitivity is variable and low but their specificity is high. Current consensus is to restrict a diagnosis of DLB only to patients with parkinsonism who develop dementia within 12 months of the onset of motor symptoms. Using operationalized criteria, DLB can be diagnosed clinically with an accuracy similar to that achieved for AD or PD. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. We review the present state of the best practice in the clinical diagnosis of DLB. Future modifications of diagnostic criteria would ideally include the full range of clinical presentations that can be associated with LB disease.

This review provides an update on therapeutic principles and their implications for practical management in multiple system atrophy (MSA), a sporadic neurodegenerative disorder characterized clinically by various combinations of dysautonomia, Parkinsonism, or cerebellar ataxia, often associated with other warning features (red flags), and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in selected multiple regions of the brain and spinal cord. Because of the small number of randomized controlled trials, the management of MSA is largely based on empirical or open-label evidence. Parkinsonism often shows a poor or unsustained response to chronic levodopa therapy, although more patients than previously recognized may experience an initial moderate-to-good dopaminergic response. There is no effective drug treatment for cerebellar ataxia. However, features of dysautonomia such as orthostatic hypotension, urinary retention or incontinence, constipation, and impotence, may often be relieved if recognized by the treating physician. Because no drug treatment consistently benefits patients with this disease in the long-term, palliative therapies are all the more important. Novel symptomatic and neuroprotective therapies are urgently required.

Summary Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterised clinically by any combination of parkinsonian, autonomic, cerebellar, or pyramidal signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several CNS structures. Owing to the recent advances in its molecular pathogenesis, MSA has been firmly established as an α-synucleinopathy along with other neurodegenerative diseases. In parallel, the clinical recognition of MSA has improved and the recent consensus diagnostic criteria have been widely established in the research community as well as movement disorders clinics. Although the diagnosis of this disorder is largely based on clinical expertise, several investigations have been proposed in the past decade to assist in early differential diagnosis. Symptomatic therapeutic strategies are still limited; however, several candidate neuroprotective agents have entered phase II and phase III clinical trials.

Background: The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. In the present study, the intrarater agreement of the motor examination part of the UMSARS was determined. Methods: All patients were first examined face to face, while being video-recorded, by two senior and two junior investigators. The patients' videotaped examinations were reevaluated after 3 months. Intrarater reliability for each item was analyzed by kappa statistics. Results: Overall weighted kappa (κ) values were at least substantial or excellent for all UMSARS motor examination items, except for ocular motor dysfunction, which showed only moderate intrarater agreement. Intrarater reliability was comparable between senior and junior raters, with all κ differences being ≤ 0.22. Conclusions: The motor examination part of the UMSARS was found to have satisfactory intrarater reliability in the present cohort. © 2012 Movement Disorder Society

Pathological 43-kDa transactive responsive DNA-binding protein (TDP-43) has been identified as the major, i.e. disease defining, pathological protein in the majority of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) or frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (FTLD-U) with or without motor neuron disease (MND), which is known now as FTLD-TDP (1,2). ALS has been linked to FTLD through TDP-43 pathology that may be widespread in the central nervous system (CNS), thereby creating a new concept of TDP-43 proteinopathy as a disease continuum that encompasses ALS and FTLD as well as rarer conditions such as progressive muscular atrophy or primary lateral sclerosis (3, for review see (4)). TDP-43 pathology in addition, or ‘secondary’, to disease defining inclusion pathologies may occur in other neurodegenerative diseases such as tauopathies or α-synulceinopathies (4). A subgroup of ALS and FTLD cases with neuronal inclusions composed of an ubiquitinated protein, negative for pathological TDP-43, tau, or α-synuclein, was shown to be characterized by the pathological aggregation of a protein called fused in sarcoma (FUS), which shows functional homology to TDP-43 (5–7). Previous to the identification of these two disease defining proteins, there have been reports of single cases of sporadic or familiar ALS or FTLD cases showing pathological tau aggregations (or neurofibrillary tangles) as their pathological hallmark feature with (8) or without (9–14) the presence of additional ubiquitinated inclusions, published by research groups in continental Europe and Asia. The tau pathology in these cases is in part reminiscent of the Parkinsonism-dementia complex and ALS (ALS/PDC) occurring in geographic isolates such as the Kii Peninsula of Japan (15) or Guam in the Mariana Islands (16–18). These are tauopathies that differ from Alzheimer’s disease (AD) in terms of their topographical distribution of tau pathology and the lower level of amyloid-β depositions (19). We here report a patient with sporadic ALS and eye closure apraxia from the continental United States showing multisystem tau pathology atypical for AD by morphology in the brain and spinal cord. There also were robust cortical amyloid-β deposits, but no pathognomonic TDP-43, FUS or α-synuclein pathology. We conclude that tau pathology alone is sufficient to cause ALS and FLTD-MND-like neurodegeneration in the continental United States suggesting that, in part, similar pathogenetic mechanisms might be involved in the patient described in this report, as in ALS occurring in the Kii Peninsula and Guam.

Summary Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials. Funding Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.

Aggregation of TDP-43 proteins to form intracellular inclusions is the primary pathology in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (FTLD-TDP). Histologically, in the cerebral cortex and limbic regions of affected ALS and FTLD-TDP patients, these pathologies occur as a variety of cytoplasmic, neuritic and intranuclear TDP-43 inclusions. In the spinal cord and lower brainstem of ALS patients, the lesions form cytoplasmic dashes or complex filamentous and spherical profiles in addition to skein-like inclusions (SLI). Ultrastructurally, the morphology of TDP-43 inclusions is heterogeneous but mainly composed of loose bundles of 10- to 20-nm-diameter straight filaments associated with electron-dense granular material. All of these TDP-43 inclusions are generally described as disordered amorphous aggregations unlike the amyloid fibrils that characterize protein accumulations in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. We here report that Thioflavin-S positive SLI are present in a subset of ALS cases, while TDP-43 inclusions outside the spinal cord lack the chemical properties of amyloid. Further, we examine the differential enrichment of fibrillar profiles in SLI of ALS cases by TDP-43 immuno-electron microscopy (immuno-EM). The demonstration that pathological TDP-43 can be amyloidogenic in situ suggests the following conclusions: (1) the conformational changes associated with TDP-43 aggregation are more complex than previously thought; (2) Thioflavin-S positive SLI may be composed primarily of filamentous ultrastructures.

Apolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia.The study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody.Both APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer's Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes.Lower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers' decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.

The Unified Multiple System Atrophy Rating Scale (UMSARS) was developed to provide a surrogate measure of disease progression in multiple system atrophy. In the present study, the intrarater agreement of the motor examination part of the UMSARS was determined.All patients were first examined face to face, while being video-recorded, by two senior and two junior investigators. The patients' videotaped examinations were reevaluated after 3 months. Intrarater reliability for each item was analyzed by kappa statistics.Overall weighted kappa (κ) values were at least substantial or excellent for all UMSARS motor examination items, except for ocular motor dysfunction, which showed only moderate intrarater agreement. Intrarater reliability was comparable between senior and junior raters, with all κ differences being ≤ 0.22.The motor examination part of the UMSARS was found to have satisfactory intrarater reliability in the present cohort.

While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer's disease (AD) pathology. Tau and Aβ pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Aβ pathology in limbic and most cortical regions. Tau and Aβ pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE.

The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n=66) and without dementia (n=42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-β pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-β plaques, more abundant neocortical amyloid-β deposition and hippocampal sclerosis with its attendant TDP-43 pathology. © The Author (2011).

Background: We sought to describe the antemortem clinical and neuroimaging features among patients with frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP). Methods: Subjects were recruited from a consecutive series of patients with a primary neuropathologic diagnosis of FTLD-TDP and antemortem MRI. Twenty-eight patients met entry criteria: 9 with type 1, 5 with type 2, and 10 with type 3 FTLD-TDP. Four patients had too sparse FTLD-TDP pathology to be subtyped. Clinical, neuropsychological, and neuroimaging features of these cases were reviewed. Voxel-based morphometry was used to assess regional gray matter atrophy in relation to a group of 50 cognitively normal control subjects. Results: Clinical diagnosis varied between the groups: semantic dementia was only associated with type 1 pathology, whereas progressive nonfluent aphasia and corticobasal syndrome were only associated with type 3. Behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease were seen in type 2 or type 3 pathology. The neuroimaging analysis revealed distinct patterns of atrophy between the pathologic subtypes: type 1 was associated with asymmetric anterior temporal lobe atrophy (either left- or right-predominant) with involvement also of the orbitofrontal lobes and insulae; type 2 with relatively symmetric atrophy of the medial temporal, medial prefrontal, and orbitofrontal-insular cortices; and type 3 with asymmetric atrophy (either left- or right-predominant) involving more dorsal areas including frontal, temporal, and inferior parietal cortices as well as striatum and thalamus. No significant atrophy was seen among patients with too sparse pathology to be subtyped. Conclusions: FTLD-TDP subtypes have distinct clinical and neuroimaging features, highlighting the relevance of FTLD-TDP subtyping to clinicopathologic correlation.

Motor neuron disease (MND) may present as an isolated lower motor neuron (LMN) disorder. Although the significance of pathological 43 kDa transactive responsive sequence DNA binding protein (TDP-43) for amyotrophic lateral sclerosis (ALS) was appreciated only recently, the topographical distribution of TDP-43 pathology in MND clinically isolated to the LMN versus normal controls (COs) is only incompletely described. Therefore, we performed longitudinal clinical evaluation and retrospective chart review of autopsied patients diagnosed with isolated LMN disease. Cases with a disease duration over 4 years were designated as progressive muscular atrophy (PMA), and those with a more rapid course as MND/LMN. Immunohistochemistry was employed to identify neuronal and glial TDP-43 pathology in the central nervous system (CNS) in patients and COs. We examined 19 subjects including six patients (i.e., four with MND/LMN and two with PMA) and 13 COs. All patients showed significant TDP-43 linked degeneration of LMNs, and five cases showed a lesser degree of motor cortex degeneration. Additional brain areas were affected in varying degrees, ranging from predominantly brainstem pathology to significant involvement of the whole CNS including neocortical and limbic areas. Pathological TDP-43 was present only rarely in the CO group. We conclude that MND limited to the LMN and PMA is part of a disease continuum that includes ALS and FTLD-TDP, all of which are characterized by widespread TDP-43 pathology. Hence, we suggest that the next revision of the El Escorial criteria for the diagnosis of ALS include MND patients with disease clinically limited to the LMN and PMA as variants of ALS, which like classical ALS, are TDP-43 proteinopathies.

Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like α-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas.

Background Major psychiatric diseases such as schizophrenia and mood disorders have not been linked to a specific pathology, but their clinical features overlap with some aspects of the behavioral variant of frontotemporal lobar degeneration. Although the significance of pathological 43-kDa (transactivation response) DNA-binding protein (TDP-43) for frontotemporal lobar degeneration was appreciated only recently, the prevalence of TDP-43 pathology in patients with severe mental illness vs controls has not been systematically addressed. Objective To examine patients with chronic psychiatric diseases, mainly schizophrenia, for evidence of neurodegenerative TDP-43 pathology in comparison with controls. Design Prospective longitudinal clinical evaluation and retrospective medical record review, immunohistochemical identification of pathological TDP-43 in the central nervous system, and genotyping for gene alterations known to cause TDP-43 proteinopathies including the TDP-43 ( TARDBP ) and progranulin ( GRN ) genes. Setting University health system. Participants One hundred fifty-one subjects including 91 patients with severe mental illness (mainly schizophrenia) and 60 controls. Main Outcome Measures Clinical medical record review, neuronal and glial TDP-43 pathology, and TARDP and GRN genotyping status. Results Significant TDP-43 pathology in the amygdala/periamygdaloid region or the hippocampus/transentorhinal cortex was absent in both groups in subjects younger than 65 years but present in elderly subjects (29% [25 of 86] of the psychiatric patients and 29% [10 of 34] of control subjects). Twenty-three percent (8 of 35) of the positive cases showed significant TDP-43 pathology in extended brain scans. There were no evident differences between the 2 groups in the frequency, degree, or morphological pattern of TDP-43 pathology. The latter included (1) subpial and subependymal, (2) focal, or (3) diffuse lesions in deep brain parenchyma and (4) perivascular pathology. A new GRN variant of unknown significance (c.620T>C, p.Met207Thr) was found in 1 patient with schizophrenia with TDP-43 pathology. No known TARDBP mutations or other variants were found in any of the subjects studied herein. Conclusions The similar findings of TDP-43 pathology in elderly patients with severe mental illness and controls suggest common age-dependent TDP-43 changes in limbic brain areas that may signify that these regions are affected early in the course of a cerebral TDP-43 multisystem proteinopathy. Finally, our data provide an age-related baseline for the development of whole-brain pathological TDP-43 evolution schemata.

TMEM106B has recently been identified as a genetic risk factor for frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). Amyotrophic lateral sclerosis (ALS), like FTLD-TDP, is characterized by pathological TDP-43 inclusions. We therefore investigated whether FTLD-TDP-associated risk genotypes at TMEM106B (1) contribute to risk of developing ALS or (2) modify the clinical presentation in ALS. Detailed clinical and pathological information from 61 postmortem ALS patients was collected by database query, retrospective chart review, and histopathological slide review. DNA from these patients, as well as 24 additional ALS patients, was genotyped for three TMEM106B single nucleotide polymorphisms known to confer increased risk of FTLD-TDP. Associations between TMEM106B genotype and ALS were investigated by comparing TMEM106B genotypes in ALS patients (n = 85) and normal controls (n = 553), and associations between TMEM106B genotype and clinical and pathologic features were explored using linear regression. Multivariate linear models were used to evaluate the contributions of TMEM106B genotype and TDP-43 pathology to cognitive performance in ALS as measured by a phonemic verbal fluency test. We found that TMEM106B genotypes did not differ between ALS patients and normal controls. However, protective alleles at TMEM106B were significantly associated with preserved cognition in ALS patients, with the strongest association seen under a major-allele-dominant genetic model. While lower TDP-43 pathology scores and protective alleles at TMEM106B both correlated with better cognitive scores, these factors were not correlated with each other and demonstrated independent effects. These findings implicate the FTLD-TDP risk gene TMEM106B in the development of cognitive impairment in ALS.

It is now established that pathological transactive response DNA-binding protein with a Mr of 43 kD (TDP-43) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis is the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin-positive inclusions (now known as FTLD-TDP). In fact, the discovery of pathological TDP-43 solidified the idea that these disorders are multi-system diseases and this led to the concept of a TDP-43 proteinopathy as a spectrum of disorders comprised of different clinical and pathological entities extending from ALS to ALS with cognitive impairment/dementia and FTLD-TDP without or with motor neuron disease (FTLD-MND). These align along a broad disease continuum sharing similar pathogenetic mechanisms linked to pathological TDP-43. We here review salient findings in the development of a concept of TDP-43 proteinopathy as a novel group of neurodegenerative diseases similar in concept to alpha-synucleinopathies and tauopathies.

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.

Publisher Summary This chapter reviews the available evidence on the etiopathogenesis and pathology of multiple system atrophy (MSA). MSA is a neurodegenerative disease of unknown etiology that manifests clinically with autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in various combinations. The finding of polymorphisms in various proinflammatory pathways is a promising step in elucidating the pathogenesis of MSA. There is significant overlap in the clinical features between the fragile X–associated tremor/ataxia syndrome (FXTAS) and atypical parkinsonism—in particular, MSA associated with cerebellar ataxia (MSA-C). Polymorphisms associated with an elevated risk for MSA include interleukin (IL)-1A, IL-1β, IL-8, intercellular adhesion molecule-1, tumor necrosis factor-1031C,38, and α1-antichymotrypsin. Diffuse neuronal cytoplasmic α-synuclein immunoreactivity is often referred to as “preinclusions” and may reflect incipient inclusion or Lewy body-like formation enhanced in sympathetic ganglia in MSA patients. Although MSA is now widely accepted as a single multisystem disease, there is evidence of clinicopathological heterogeneity. Autonomic failure in MSA is caused by dysfunction of (1) central and preganglionic efferent autonomic activity, (2) neuronal networks in the brainstem that control cardiovascular and respiratory function, and (3) the neuroendocrine component of the autonomic regulation via the hypothalamopituitary axis. The correlation of subregional glial cytoplasmic inclusion (GCI) density and neuronal loss suggests that α-synuclein aggregation is tightly linked to selective neurodegeneration in MSA.

Ever since the significance of pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) for human disease has been recognized in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), a number of publications have emerged reporting on this pathology in a variety of neurodegenerative diseases. Given the heterogeneous and, in part, conflicting nature of the recent findings, we here review pathological TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. To this end, we propose a classification scheme in which pathological TDP-43 is the major disease defining pathology in one group, or is present in addition to other neurodegenerative hallmark pathologies in a second category. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders akin to alpha-synucleinopathies and tauopathies, with the concept of ALS and FTLD-U to be widened to a broad clinico-pathological multisystem disease, i.e., TDP-43 proteinopathy.

To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.Performance of immunohistochemical whole-central nervous system scans for evidence of pathological TDP-43 and retrospective clinical medical record review.An academic medical center.We included 64 patients with clinically and pathologically confirmed frontotemporal lobar degeneration with ubiquitinated inclusions with or without motor neuron disease and amyotrophic lateral sclerosis with or without cognitive impairment.Neuronal and glial TDP-43 pathology.We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.These findings strongly suggest that amyotrophic lateral sclerosis, frontotemporal lobar degeneration with amyotrophic lateral sclerosis or motor neuron disease, and frontotemporal lobar degeneration with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

Background Pathological 43-kDa transactivating responsive sequence DNA-binding protein (TDP-43) has been identified recently as the major disease protein in amyotrophic lateral sclerosis (ALS), and in frontotemporal lobar degeneration with ubiquitinated inclusions, with or without motor neuron disease, but the distribution of TDP-43 pathology in ALS may be more widespread than previously described. Objective To determine the extent of TDP-43 pathology in the central nervous systems of patients with clinically confirmed and autopsy confirmed diagnoses of ALS. Design Performance of an immunohistochemical whole–central nervous system scan for evidence of pathological TDP-43 in ALS patients. Setting An academic medical center. Participants We included 31 patients with clinically and pathologically confirmed ALS and 8 control participants. Main Outcome Measures Immunohistochemistry and double-labeling immunofluorescence to assess the frequency and severity of TDP-43 pathology. Results In addition to the stereotypical involvement of upper and lower motor neurons, neuronal and glial TDP-43 pathology was present in multiple areas of the central nervous systems of ALS patients, including in the nigro-striatal system, the neocortical and allocortical areas, and the cerebellum, but not in those of the controls. Conclusions These findings suggest that ALS does not selectively affect only the pyramidal motor system, but rather is a multisystem neurodegenerative TDP-43 proteinopathy.

The clinical diagnosis Of Multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/- 7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P. (C) 2008 Movement Disorder Society.

To assess severity and progression of self-perceived dysautonomia and their impact on health-related quality of life (Hr-QoL) in multiple system atrophy (MSA), twenty-seven patients were recruited by the European MSA Study Group (EMSA-SG). At baseline, all patients completed the Composite Autonomic Symptom Scale (COMPASS) and the 36 item Short Form Health Survey (SF-36), and they were assessed using the 3-point global disease severity scale (SS-3) and the Unified MSA Rating Scale (UMSARS). After 6 months follow-up, the self completed COMPASS Change Scale (CCS), the SF-36, SS-3, and UMSARS were obtained. MSA patients showed marked self-perceived dysautonomia at baseline visit and pronounced worsening of dysautonomia severity on the CCS at follow-up. Severity and progression of dysautonomia did not correlate with age, disease duration, motor impairment and overall disease severity at baseline. There were no significant differences between genders and motor subtypes. Baseline COMPASS scores were, however, inversely correlated with SF-36 scores. Progression of self-perceived dysautonomia did not correlate with global disease progression. Hr-QoL scores were stable during follow-up. This is the first study to investigate self-perceived dysautonomia severity in MSA and its evolution over time. Our data suggest that dysautonomia should be recognized as a key target for therapeutic intervention in MSA.