The progression of many neurodegenerative diseases is thought to be driven by the template-directed misfolding, seeded aggregation and cell-cell transmission of characteristic disease-related ...proteins, leading to the sequential dissemination of pathological protein aggregates. Recent evidence strongly suggests that the anatomical connections made by neurons - in addition to the intrinsic characteristics of neurons, such as morphology and gene expression profile - determine whether they are vulnerable to degeneration in these disorders. Notably, this common pathogenic principle opens up opportunities for pursuing novel targets for therapeutic interventions for these neurodegenerative disorders. We review recent evidence that supports the notion of neuron-neuron protein propagation, with a focus on neuropathological and positron emission tomography imaging studies in humans.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little ...is known so far about the clinical impact of AQP4-Ab seropositivity.
To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.
Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).
Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.
This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
The pathological process underlying amyotrophic lateral sclerosis (ALS) is associated with the formation of cytoplasmic inclusions consisting mainly of phosphorylated 43-kDa transactive response ...DNA-binding protein (pTDP-43), which plays an essential part in the pathogenesis of ALS. Preliminary evidence indicates that neuronal involvement progresses at different rates, but in a similar sequence, in different patients with ALS. This observation supports the emerging concept of prion-like propagation of abnormal proteins in noninfectious neurodegenerative diseases. Although the distance between involved regions is often considerable, the affected neurons are connected by axonal projections, indicating that physical contacts between nerve cells along axons are important for dissemination of ALS pathology. This article posits that the trajectory of the spreading pattern is consistent with the induction and dissemination of pTDP-43 pathology chiefly from cortical neuronal projections, via axonal transport, through synaptic contacts to the spinal cord and other regions of the brain.
Objective
To see whether the distribution patterns of phosphorylated 43kDa TAR DNA‐binding protein (pTDP‐43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of ...neuropathological stages.
Methods
pTDP‐43 immunohistochemistry was performed on 70μm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background.
Results
ALS cases with the lowest burden of pTDP‐43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X–XII, and spinal cord α‐motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP‐43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP‐43 lesions showed pTDP‐43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP‐43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP‐43 pathology.
Interpretation
pTDP‐43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP‐43 pathology is propagated along axonal pathways. Moreover, the finding that pTDP‐43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS. Ann Neurol 2013;74:20–38
Biomarkers for the diagnosis of motoneuron diseases (MND) are urgently needed to improve the diagnostic pathway, patient stratification and monitoring. The aim of this study was to validate candidate ...markers for MND in cerebrospinal fluid (CSF) and specify cut-offs based on large patient cohorts by especially considering patients who were seen under the initial differential diagnosis (MND mimics).
In a prospective study, we investigated CSF of 455 patients for neurofilament light chain (NfL), phosphorylated heavy chain (pNfH), tau protein (Tau) and phospho-tau protein (pTau). Analysed cohorts included patients with apparently sporadic and familial amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) (MND, n=253), MND mimics (n=85) and neurological control groups. Cut-off values were specified, and diagnostic performance and correlation with progression were analysed.
Nfs were significantly higher in the MND group compared to the control groups, whereas Tau and pTau did not differ. At a cut-off level of 2200 pg/mL for NfL, a 77% diagnostic sensitivity (CI 71% to 82%), 85% specificity (CI 79% to 90%) and 87% positive predictive value (PPV) (CI 81% to 91%) were achieved. For pNfH, we calculated 83% sensitivity (CI 78% to 88%), 77% specificity (CI 71% to 83%) and 82% PPV (CI 77% to 86%) at 560 pg/mL. There were no significant differences between sporadic and genetic ALS or PLS. Nf levels were elevated at early disease stage, and correlated moderately with MND progression and duration.
Neurofilaments in CSF have a high relevance for the differential diagnosis of MNDs and should be included in the diagnostic work-up of patients. Their value as prognostic markers should be investigated further.
Objective
To characterize sequential patterns of regional neuropathology and clinical symptoms in a well‐characterized cohort of 21 patients with autopsy‐confirmed Pick disease.
Methods
Detailed ...neuropathological examination using 70μm and traditional 6μm sections was performed using thioflavin‐S staining and immunohistochemistry for phosphorylated tau, 3R and 4R tau isoforms, ubiquitin, and C‐terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n = 5), converging evidence was obtained using antemortem neuroimaging measures of gray and white matter integrity.
Results
Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus, and raphe nuclei (phase II), followed by primary motor cortex and precerebellar nuclei (phase III) and finally visual cortex in the most severe (phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18 of 21), but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease duration and inversely correlated with brain weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau–positive and 4R tau–negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions.
Interpretation
Pick disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau‐mediated neurodegeneration. Ann Neurol 2016;79:272–287
Background
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent ...symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS. This is an update of a review first published in 2008.
Objectives
To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life.
Search methods
On 2 July 2012, we searched the following databases: the Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), CINAHL (January 1982 to June 2012), AMED (January 1985 to June 2012) and LILACS (January 1982 to June 2012). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials.
Selection criteria
We searched for randomised or quasi‐randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis.
Data collection and analysis
We collected data using a specially designed form and analysed them using the Cochrane Review Manager software.
Main results
We found no randomised or quasi‐randomised controlled trials on drug therapy for pain in ALS or MND.
Authors' conclusions
There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS.
We examined regional distribution patterns of phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in frontotemporal lobar degeneration (FTLD). Immunohistochemistry was ...performed on 70 μm sections from FTLD-TDP autopsy cases (
n
= 39) presenting with behavioral variant frontotemporal dementia. Two main types of cortical pTDP-43 pathology emerged, characterized by either predominantly perikaryal pTDP-43 inclusions (cytoplasmic type, cFTLD) or long aggregates in dendrites (neuritic type, nFTLD). Cortical involvement in nFTLD was extensive and frequently reached occipital areas, whereas cases with cFTLD often involved bulbar somatomotor neurons and the spinal cord. We observed four patterns indicative of potentially sequential dissemination of pTDP-43: cases with the lowest burden of pathology (pattern I) were characterized by widespread pTDP-43 lesions in the orbital gyri, gyrus rectus, and amygdala. With increasing burden of pathology (pattern II) pTDP-43 lesions emerged in the middle frontal and anterior cingulate gyrus as well as in anteromedial temporal lobe areas, the superior and medial temporal gyri, striatum, red nucleus, thalamus, and precerebellar nuclei. More advanced cases showed a third pattern (III) with involvement of the motor cortex, bulbar somatomotor neurons, and the spinal cord anterior horn, whereas cases with the highest burden of pathology (pattern IV) were characterized by pTDP-43 lesions in the visual cortex. We interpret the four neuropathological patterns in bvFTD to be consistent with the hypothesis that pTDP-43 pathology can spread sequentially and may propagate along axonal pathways.
We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with ...alterations in microglial inflammatory activity.
Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion.
Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease.
This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 ...patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9–11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf’s nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke’s column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.
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