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Objectives: To investigate the extent of synaptic loss, and the contribution of gray matter (GM) inflammation and demyelination to synaptic loss, in multiple sclerosis (MS) brain tissue., Methods: This study was performed on two different post-mortem series of MS and control brains, including deep GM and cortical GM. MS brain samples had been specifically selected for the presence of active demyelinating GM lesions. Over 1,000,000 individual synapses were identified and counted using confocal microscopy, and further characterized as glutamatergic/GABAergic. Synaptic counts were also correlated with neuronal/axonal loss., Results: Important synaptic loss was observed in active demyelinating GM lesions (-58.9%), while in chronic inactive GM lesions, synaptic density was only mildly reduced compared to adjacent non-lesional gray matter (NLGM) (-12.6%). Synaptic loss equally affected glutamatergic and GABAergic synapses. Diffuse synaptic loss was observed in MS NLGM compared to control GM (-21.2% overall)., Conclusion: This study provides evidence, in MS brain tissue, of acute synaptic damage/loss during active GM inflammatory demyelination and of synaptic reorganization in chronically demyelinated GM, affecting equally glutamatergic and GABAergic synapses. Furthermore, this study provides a strong indication of widespread synaptic loss in MS NLGM also independently from focal GM demyelination.

Background: The role of single nucleotide polymorphisms (SNPs) in TP53 in the pathogenesis of glioma is still debated. The aim of our study was to investigate the role of several TP53 SNPs in the risk of glioma and their possible role as prognostic biomarkers of overall and progression-free survival., Methods: We examined 12 SNPs in TP53 from peripheral blood and neoplastic tissue of patients with a diagnosis of glioma who underwent surgery from 2012 to 2015. Direct genomic sequencing of TP53 was performed to detect the presence of polymorphisms. We compared data with a matched cancer-free control group and the NCBI SNPs database. Overall and progression-free survival were analyzed in patients with glioblastoma subjected to gross total resection and concomitant radio-chemotherapy., Results: No association was observed with glioma susceptibility and overall survival. Two new SNPs were detected: c.97-46 G>A (intron 3) and c.783-31 A>G (intron 7). The number of SNPs observed was higher (21.4%) in blood than in tumoral samples. We observed a significant reduction in progression-free survival in patients with at least one exonic SNP., Conclusions: We can hypothesize an involvement of TP53 SNPs in response mechanisms to adjuvant treatment that may affect progression-free survival. Moreover, our blood-tissue combined study revealed a significant difference in SNPs between blood and tumoral samples, probably due to glioma heterogeneity and genomic instability.

The K free light chains index (K-FLC index) has been proposed as an alternative test for intrathecal immunoglobulin synthesis in MS diagnosis. Aim of the study was to assess the accuracy of the K-FLC index in differentiating MS from other immune-mediated CNS disorders and NMOSD. Data were available from a cohort of 371 patients. K-FLC index was significantly higher in MS: MS mean K-FLC index 90.897 ± 134.198; NMOSD 17.992 ± 15.103; other immune-mediated CNS disorders 12.568 ± 24.440. The overall diagnostic accuracy of the K-FLC index was similar to intrathecal oligoclonal bands detection. However, as a quantitative variable, K-FLC index allowed easier discrimination of MS from other immune-mediated CNS disorders: highest K-FLC index values (> 100) were observed almost only in MS and are therefore strongly predictive of MS, in patients with the appropriate clinical presentation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Migraine is one of the most common medical disorder in the world. Metacognition is the ability to monitor one's own cognitive functioning and consequently direct one's behavior. In adult migraine patients, the neuropsychological profile has been poorly investigated, and metacognitive functions have never been assessed. The aim of the present study was therefore to evaluate executive metacognitive abilities in patients with episodic and chronic migraine. Sixty-four migraine patients (male/female = 18/46; mean age = 45.65 ± 11.61 years): 27 patients with episodic migraine without aura (male/female = 9/18; mean age ± SD = 45.11 ± 12.18 years) and 37 patients with chronic migraine and medication-overuse headache (male/female = 9/28; mean age ± SD = 46.05 ± 11.32 years) were selected for the study. Twenty-nine controls (male/female = 12/17; mean age ± SD = 42.86 ± 14.78 years) were also enrolled in the research. Metacognitive and executive skills were assessed using the metacognitive version of Wisconsin Card Sorting Test. Migraine patients exhibited a lower performance in metacognitive tasks in respect to controls in term of worse outcomes in accuracy score (p = 0.012), global monitoring (p = 0.015), monetary gains (p = 0.022), and control sensitivity (p = 0.027). A reduction in accuracy score (p = 0.001), free-choice improvement (p = 0.002), global monitoring (p = 0.003), monetary gains (p = 0.009), and control sensitivity (p < 0.001) was also found in patients with chronic migraine and medication-overuse headache in respect to patients with episodic migraine. Our study supports the hypothesis that migraine patients show metacognitive dysfunctions that become worse with the chronicization of the disease and the increase of medication use., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: The purpose of the study was to determine the prevalence of suicidal ideation and attempts in patients with behavioral variant frontotemporal dementia (bvFTD), evaluating possible risk factors for suicidality., Methods: Risk of suicide was assessed using the Scale for Suicide Ideation (SSI) in 35 patients with bvFTD and 25 controls., Results: According to SSI, 40% of patients with bvFTD had suicidal ideation in comparison to 8% of controls ( P = .009). Four patients with bvFTD have attempted suicide versus none control ( P = .006). Patients with bvFTD with suicide risk showed higher levels of anxiety, depression, stress, and hopelessness than patients without suicide risk ( P < .001). Patients who attempted suicide were younger and had a longer disease duration than those with only suicide ideation. Intriguingly, 40% of patients with parkinsonism presented high level of suicide ideation., Conclusions: Our findings show that patients with bvFTD have a high risk of suicide. Additional studies in larger populations are needed to confirm our results.

Background: Recent studies suggested a potential association between both overt and subclinical hypothyroidism and migraine. Aims of this study were to estimate the comorbidity of migraine in patients with subclinical hypothyroidism and to evaluate associated clinical characteristics., Methods: Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine., Results: The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs. 13%, p < 0.001; OR 5.80; 95% CI = 3.35-10.34). Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls ( p < 0.001 and p = 0.010, respectively). Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine. Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine ( p = 0.005)., Conclusions: Our data suggest that migraine is more frequent in patients with subclinical hypothyroidism in respect to controls. Further studies are needed in order to confirm this association.

Common genetic risk factors are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Intermediate repeat expansions at the Ataxin-2 locus (ATXN2) are a risk factor for ALS and influence the phenotype. We assessed whether ATXN2 is a risk factor for FTD or modify clinical features in a data set of Italian patients. Three hundred sixty-eight unrelated FTD cases and 342 controls were enrolled. The frequency of intermediate CAG repeats in ATXN2 gene was not different comparing patients and controls. CAG repeats were interrupted by CAA in all patients carrying intermediate repeats. Interestingly, patients with an increased number of CAG repeats had an earlier onset of the disease than those without expansions (p = 0.011), and presented more frequently with parkinsonism (p = 0.010), and psychotic symptoms (p = 0.013) at disease onset. Our study does not support a major role of ATXN2 intermediate CAG expansions in predisposing to FTD but suggests that ATXN2 may act as a phenotype modifier., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case.

Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, for example, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas 1 sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10. Muscle biopsy of this patient showed intracellular glycogen accumulation with cytochrome c oxidase negative and ragged red fibers. Our study suggests that the homozygous Pro96Thr mutation in CHCHD10 might be pathogenic but does not support a major role for CHCHD2 in MM pathogenesis., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Purpose: Oxidative stress is a hallmark of Alzheimer's Disease (AD) and promotes tau phosphorylation. Since Thioredoxin Interacting protein (TXNIP), the inhibitor of the anti-oxidant system of Thioredoxin, is up regulated in the hippocampus of AD patients, we investigated whether TXNIP plays a role in promoting tau phosphorylation and whether Verapamil, an inhibitor of TXNIP expression, prevents TXNIP downstream effects., Methods: We analyzed TXNIP expression and tau phosphorylation in the hippocampus of the 5xFAD mice in the absence and presence of a pharmacological treatment with Verapamil. Using SH-SY5Y cells, we verified the causative role of TXNIP in promoting tau phosphorylation at Ser202/Thr205, by inducing TXNIP silencing., Results: The amyloid beta peptide (Aβ 1-42 ) leads to TXNIP over-expression in SH-SY5Y cells, which in turns induces oxidative stress and the activation of p38 MAPK, promoting tau phosphorylation at Ser202/Thr205. Silencing of TXNIP abolishes Aβ 1-42 -induced tau phosphorylation, p38 MAPK phosphorylation and subsequent tau phosphorylation. Verapamil prevents TXNIP expression as well as p38 MAPK and tau phosphorylation at Ser202/Thr205 in the hippocampus of the 5xFAD mice., Conclusions: Our study unveil a novel pathway involved in AD progression that is inhibited by Verapamil, shedding new light on the understanding of the therapeutic potential of Verapamil in AD.

Inflammatory-like changes in the white matter (WM) are commonly observed in conditions of axonal degeneration by different etiologies. This study is a systematic comparison of the principal features of the inflammatory-like changes in the WM in different pathological conditions characterized by axonal damage/degeneration, focusing in particular on Multiple Sclerosis (MS) normal-appearing white matter (NAWM) compared to non immune-mediated disorders. The study was performed on sections of NAWM from 15 MS cases, 11 cases of non immune-mediated disorders with wallerian axonal degeneration (stroke, trauma, amyotrophic lateral sclerosis), 3 cases of viral encephalitis, 6 control cases. Common features of the inflammatory-like changes observed in all of the conditions of WM pathology were diffuse endothelial expression of VCAM-1, microglial activation with expression of M2 markers, increased expression of sphingosine receptors. Inflammation in MS NAWM was characterized, compared to non immune-mediated conditions, by higher VCAM-1 expression, higher density of perivascular lymphocytes, focal perivascular inflammation with microglial expression of M1 markers, ongoing acute axonal damage correlating with VCAM-1 expression but not with microglia activation. Inflammatory changes in MS NAWM share all the main features observed in the WM in non immune-mediated conditions with wallerian axonal degeneration (with differences to a large extent more quantitative than qualitative), but with superimposition of disease-specific perivascular inflammation and ongoing acute axonal damage., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Bipolar disorder is a chronic psychiatric illness characterised by fluctuation in mood state, with a relapsing and remitting course. Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous syndrome, with the most frequent phenotype being behavioural variant frontotemporal dementia (bvFTD). Here, we report the case of an Italian male presenting with late-onset bipolar disorder that developed into bvFTD over time, carrying a mutation in the GRN gene. Interestingly, the patient carried the c.1639 C > T variant in the GRN gene, resulting in a R547C substitution. Our case report further corroborates the notion that, in addition to FTD, progranulin may be involved in the neurobiology of bipolar disorder type 1, and suggests to screen patients with late-onset bipolar disorder for GRN mutations.

Aims: Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes., Methods: TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2)., Results: TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes., Conclusions: In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments., (© 2016 British Neuropathological Society.)

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNF α is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNF α levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNF α toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNF α is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNF α in ALS in the light of its multisystem nature.

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and oxidative stress. The aim of this study was to evaluate the involvement of NADPH oxidases (NOX) in the oxidative damage and progression of ALS neuropathology. We examined the pattern of NOX expression in spinal cords of patients and mouse models of ALS and analyzed the impact of genetic deletion of the NOX1 and 2 isoforms as well as pharmacological NOX inhibition in the SOD1(G93A) ALS mouse model. A substantial (10-60 times) increase of NOX2 expression was detected in three etiologically different ALS mouse models while up-regulation of some other NOX isoforms was model-specific. In human spinal cord samples, high NOX2 expression was detected in microglia. In contrast to previous publications, survival of SOD1(G93A) mice was not modified upon breeding with constitutive NOX1 and NOX2 deficient mice. As genetic deficiency of a single NOX isoform is not necessarily predictive of a pharmacological intervention, we treated SOD1(G93A) mice with broad-spectrum NOX inhibitors perphenazine and thioridazine. Both compounds reached in vivo CNS concentrations compatible with NOX inhibition and thioridazine significantly decreased superoxide levels in the spinal cord of SOD1(G93A) mice in vivo. Yet, neither perphenazine nor thioridazine prolonged survival. Thioridazine, but not perphenazine, dampened the increase of microglia markers in SOD1(G93A) mice. Thioridazine induced an immediate and temporary enhancement of motor performance (rotarod) but its precise mode of action needs further investigation. Additional studies using specific NOX inhibitors will provide further evidence on the relevance of NOX as drug targets for ALS and other neurodegenerative disorders., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of genetic Parkinson disease (PD) known to date. The clinical features of manifesting LRRK2 mutation carriers are generally indistinguishable from those of patients with sporadic PD. However, some PD cases associated with LRRK2 mutations lack Lewy bodies (LBs), a neuropathological hallmark of PD. We investigated whether the presence or absence of LBs correlates with different clinical features in LRRK2-related PD., Observations: We describe genetic, clinical, and neuropathological findings of 37 cases of LRRK2-related PD including 33 published and 4 unpublished cases through October 2013. Among the different mutations, the LRRK2 p.G2019S mutation was most frequently associated with LB pathology. Nonmotor features of cognitive impairment/dementia, anxiety, and orthostatic hypotension were correlated with the presence of LBs. In contrast, a primarily motor phenotype was associated with a lack of LBs., Conclusions and Relevance: To our knowledge, this is the first report of clinicopathological correlations in a series of LRRK2-related PD cases. Findings from this selected group of patients with PD demonstrated that parkinsonian motor features can occur in the absence of LBs. However, LB pathology in LRRK2-related PD may be a marker for a broader parkinsonian symptom complex including cognitive impairment.

Chronic acquired hepatocerebral degeneration (CAHD) is a rare neurological disorder of cirrhotic patients, characterized by parkinsonism and cognitive impairment. A T1 hyperintensity on the globus pallidum due to an accumulation of manganese (Mn) is found in these patients. The aim of the study was to investigate CAHD, Mn and the MRI pallidal signal in a series of cirrhotic patients. The association between pallidal T1 hyperintensity, CAHD, and blood levels of Mn, the effect of orthotopic liver transplantation (OLT) on the MRI signal and neurological findings, and the role of the pallidal signal as a predictor of CAHD were evaluated. Twenty-six out of 90 patients with cirrhosis had pallidal T1 hyperintensity. Seven patients had CAHD. OLT was followed by the disappearance of CAHD and MRI signal in 2/2 patients. The MRI signal disappeared after OLT in 8/13 patients after a median follow-up time of 24 months. In the patients who did not undergo OLT, CAHD did not present after a median follow-up time of 18 months. The cause of cirrhosis, episodes of acute hepatic encephalopathy and signal intensity were not correlated with CAHD. The blood levels of Mn did not reflect either the MRI signal or CAHD. In conclusion, the pallidal T1 hyperintensity is a prerequisite for the clinical manifestations of CAHD but is not sufficient. The blood levels of Mn as routinely monitored are not a useful marker of Mn burden. The MRI pallidal signal is not a predictor of CAHD.

Background: A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration (FTLD). Atypical presentations have been described, particularly psychosis., Methods: We determined the frequency of the hexanucleotide repeat expansions in a population of 651 FTLD patients and compared the clinical characteristics of carriers and noncarriers. In addition, we genotyped 21 patients with corticobasal syndrome, 31 patients with progressive supranuclear palsy, and 222 control subjects., Results: The pathogenic repeat expansion was detected in 39 (6%) patients with FTLD (17 male and 22 female subjects); however, it was not detected in any corticobasal syndrome and progressive supranuclear palsy patients or controls. Twenty-four of 39 carriers had positive family history for dementia and/or amyotrophic lateral sclerosis (61.5%), whereas only 145 of 612 noncarriers had positive family history (23.7%; p<.000001). Clinical phenotypes of carriers included 29 patients with the behavioral variant frontotemporal dementia (bvFTD; 5.2% of all bvFTD cases), 8 with bvFTD/motor neuron disease (32% bvFTD/motor neuron disease cases), 2 with semantic dementia (5.9% of patients with semantic dementia), and none with progressive nonfluent aphasia. The presentation with late-onset psychosis (median age = 63 years) was more frequent in carriers than noncarriers (10/33 vs. 3/37, p = .029), as well as the presence of cognitive impairment at onset (15/33 vs. 5/37; p = .0039)., Conclusions: The repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides., Objectives: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease., Methods: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis)., Results: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing-remitting MS during relapses and in progressive MS patients, compared with relapsing-remitting MS patients during remissions and with non-inflammatory controls., Conclusions: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

TDP-43, encoded by TARDBP, is a ubiquitously expressed, primarily nuclear protein. In recent years, TDP-43 has been identified as the major pathological protein in ALS due to its mislocalisation in the cytoplasm of motor neurons of patients with and without TARDBP mutations and expression in forms that do not match its predicted molecular weight. In this study, the TDP-43 profile was investigated using western immunoblot analysis in whole lysates, nuclei and cytoplasm of circulating lymphomonocytes from 16 ALS patients, 4 with (ALS/TDP+) and 12 without (ALS/TDP-) TARDBP mutations in the protein C-terminal domain, and thirteen age-matched, healthy donors (controls). Three disease-unaffected first-degree relatives of an ALS/TDP+ patient were also included: one carried the parent mutation (Rel/TDP+) whereas the other two did not (Rel/TDP-). In all ALS patients, relatives and controls, TDP-43 retained the predicted molecular weight in whole cell lysates and nuclei, but in the cytoplasm its molecular weight was slightly smaller than expected. In quantitative terms, TDP-43 was expressed at approximately the same levels in whole cell lysates of ALS patients, relatives and controls. In contrast, TDP-43 accumulated in the cytoplasm with concomitant nuclear depletion in all ALS/TDP+ patients, in about 50% of ALS/TDP- patients and in the Rel/TDP+ subject compared to the controls. In the remaining ALS/TDP- patients and in the two Rel/TDP- subjects, TDP-43 matched the control levels in both subcellular compartments. Were these findings further confirmed, circulating lymphomonocytes could be informative of TDP-43 mislocalisation in nervous tissue and used as a biomarker for future disease risk.

Amyotrophic lateral sclerosis (ALS) is generally considered to be a paradigm of pure motor neuron disorder; nevertheless, the possible occurrence of cognitive impairment up to a frank dementia in patients affected by ALS is recognized. The appraisal of the cognitive impairment in ALS patients is crucial not only to the therapeutic trials of this incurable disease, but also to the planning of care, compliance to interventions, the end-of-life decisions. The cognitive/behavioral changes of ALS patients are consistent with frontotemporal dysfunctions; the overlap of neuropathological features of ALS and frontotemporal lobe degeneration (FTLD) supports, in addition, the putative spectrum of ALS and FTD. In the present review, the pertinent clinical, genetic, neuropathological, neuropsychological and neuroimaging data of the literature are comprehensively and critically discussed. The distinct and overlapping features of ALS and FTD are pointed out, as well as the undisclosed questions deserving additional studies.

Linkage analysis identified a region on chromosome 9p associated with Frontotemporal Lobar Degeneration (FTLD). A detailed analysis of candidate genes lying in this region demonstrated an association with Ubiquitin Associated Protein (UBAP)1. The distribution of five Single Nucleotide Polymorphisms (SNPs) located in the chromosome 9 haplotype identified via linkage analysis, including UBAP1 rs7018487, UBAP2 rs1785506 and rs307658, and KIF24 rs17350674 and rs10814083, has been determined in a population of 284 patients diagnosed with FTLD, including 245 with behavioural variant Frontotemporal Dementia (bvFTD), 23 with Progressive Aphasia and 16 with Semantic Dementia, compared with 318 age-matched controls. A statistically significant increased frequency of the KIF24 rs17350674 AA genotype was observed in patients compared with controls (7.4 versus 2.5%; P=0.0068, OR: 3.63, CI: 1.58-8.35). Considering each syndrome separately, similar results where obtained in bvFTD versus controls (7.7 versus 2.5%, P=0.005, OR: 3.26, CI: 1.40-7.57). Stratifying for gender, a statistically significant increased genotypic frequency was observed in female patients as compared with female controls (8.9 versus 2.5%, P=0.008, OR: 3.85, CI: 1.36-10.93). In silico analysis predicted that the substitution from W to L caused by the rs17350674 affects protein function (P<0.05). The KIF24 rs17350674 polymorphism likely acts as a risk factor for sporadic FTLD, but a replication study would be needed to confirm these preliminary findings., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Although a large number of amyotrophic lateral sclerosis (ALS) patients have undergone transplantation procedures with olfactory ensheathing cells (OECs) in the Bejing Hospital, to our knowledge, no post-mortem neuropathologic analyses have been performed. We examined the post-mortem brain of two Italian patients affected by ALS who underwent cellular transplantation in Beijing with their consent. Our aim was to assess the events following the graft procedure to possibly support the rationale of the treatment strategy. The neuropathologic findings were analyzed on the basis of the limited awareness of the experimental conditions and discussed in relation to the safety, efficacy and long-term outcome of the transplanted cells. Islands of quiescent, undifferentiated cells within the delivery track persisting for up to 12 months-24 months were found. Prominent glial and inflammatory reaction around the delivery track strongly supports the encasement of the graft. Evidence of axonal regeneration, neuronal differentiation and myelination was not seen. The surgical procedure of implantation was not compatible with a neurotrophic effect. The OEC transplantation did not modify the neuropathology of ALS in the two patients. In conclusion, the present neuropathologic analysis does not support a beneficial effect of fetal OEC implantation into the frontal lobes of ALS patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder consisting of progressive loss of motor neurons. TDP-43 has been identified as a component of ubiquitin-immunoreactive inclusions of motor neurons in ALS. We focused on the diffuse cytoplasmic TDP-43 immunoreactivity in ALS neurons, and quantitatively assessed it in comparison with skein/round TDP-43 and ubiquitin immunostaining in motor neurons of 30 sporadic ALS cases. The percentage of spinal motor neurons with cytoplasmic TDP-43 immunoreactivity was higher than that of ubiquitin-immunoreactive ones. The percentage of TDP-43-positive motor neurons was independent of neuron counts in anterior horns, while the percentage of ubiquitinated neurons was inversely correlated. Aiming to define the cytosolic localization of TDP-43, the immunoblot analysis of spinal cord and frontal cortex showed that full-length TDP-43, the 45 kDa form and ubiquitinated TDP-43 are found in the soluble inclusion-free fraction. The present data suggest that delocalization, accumulation and ubiquitination of TDP-43 in the cytoplasm of motor neurons are early dysfunctions in the cascade of the events leading to motor neuron degeneration in ALS, preceding the formation of insoluble inclusion bodies. Being cytoplasmic accumulation an ongoing event during the course of the illness, a therapeutic approach to this incurable disease can be envisaged.