15-Year Subthalamic Deep Brain Stimulation outcome in a Parkinson's disease patient with Parkin gene mutation: a case report.

INTRODUCTION: Parkinson's Disease (PD) patients with Parkin gene (PRKN) mutations show good response to subthalamic deep brain stimulation (STN-DBS). Currently, the longest follow-up available of these patients is 6 years. We report a very long-term outcome (more than 15 years) of a STN-DBS-treated patient with a compound heterozygous deletion of exons 3 and 11 of the PRKN gene. CASE REPORT: In 1993, a 39-year-old male was diagnosed with PD after the onset of resting tremor. Levodopa was started, and during the following 10 years, he reported good motor symptoms control, with only mild modification of levodopa intake and pramipexole introduction. In 2005, he developed disabling motor fluctuations and dyskinesia. In 2007, he underwent bilateral STN-DBS, with a marked improvement of motor symptoms and fluctuations during the following years. After 6 years, he reported mild motor fluctuations, improved after stimulation and treatment modifications. After 10 years he showed diphasic dyskinesias, feet dystonia, postural instability, and gambling (resolved after pramipexole discontinuation). In 2018, he developed a non-amnestic single-domain mild cognitive impairment (MCI). In 2023, after more than 15 years of STN-DBS, motor symptoms and fluctuations are still well controlled. He reports mild dysphagia, mild depression, and multiple-domain MCI. His quality of life is better than before surgery, and he still reports a subjective significant improvement from STN-DBS. CONCLUSION: Confirming the very long-term efficacy of STN-DBS in PRKN-mutated patients, our case report underlines their peculiar suitability for surgical treatment.

Extracellular Vesicles Released by Tumor Endothelial Cells Spread Immunosuppressive and Transforming Signals Through Various Recipient Cells.

Head and neck squamous cell carcinoma (HNSCC) has a high recurrence and metastatic rate with an unknown mechanism of cancer spread. Tumor inflammation is the most critical processes of cancer onset, growth, and metastasis. We hypothesize that the release of extracellular vesicles (EVs) by tumor endothelial cells (TECs) induce reprogramming of immune cells as well as stromal cells to create an immunosuppressive microenvironment that favor tumor spread. We call this mechanism as non-metastatic contagious carcinogenesis. Extracellular vesicles were collected from primary HNSCC-derived endothelial cells (TEC-EV) and were used for stimulation of peripheral blood mononuclear cells (PBMCs) and primary adipose mesenchymal stem cells (ASCs). Regulation of ASC gene expression was investigated by RNA sequencing and protein array. PBMC, stimulated with TEC-EV, were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting. We validated in vitro the effects of TEC-EV on ASCs or PBMC by measuring invasion, adhesion, and proliferation. We found and confirmed that TEC-EV were able to change ASC inflammatory gene expression signature within 24-48 h. TEC-EV were also able to enhance the secretion of TGF-ß1 and IL-10 by PBMC and to increase T regulatory cell (Treg) expansion. TEC-EV carry specific proteins and RNAs that are responsible for Treg differentiation and immune suppression. ASCs and PBMC, treated with TEC-EV, enhanced proliferation, adhesion of tumor cells, and their invasion. These data indicate that TEC-EV exhibit a mechanism of non-metastatic contagious carcinogenesis that regulates tumor microenvironment and reprograms immune cells to sustain tumor growth and progression.

Parkinsonian traits in amyotrophic lateral sclerosis (ALS): a prospective population-based study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by a spectrum of phenotypes, but only a few studies have addressed the presence of parkinsonian (PK) symptoms. The aim of our study was to investigate the occurrence of PK features in a prospective population-based cohort of ALS patients, determining their demographic, clinical, neuropsychological and genetic characteristics, and identifying their morphological and functional imaging correlates. METHODS: A consecutive series of ALS patients were enrolled and prospectively followed for 2 years. Patients were classified according to the presence (ALS-PK) or absence (ALS) of PK signs, and they underwent neuropsychological testing, genetic analysis for the main ALS and PD genes, brain MRI and 18F-FDG-PET. ALS-PK patients underwent 123I-ioflupane SPECT. RESULTS: Out of 114 eligible patients, 101 (64 men; mean age at onset 65.1 years) were recruited. Thirty-one patients (30.7%) were classified as ALS-PK. Compared to ALS patients, ALS-PK patients were more frequently male, but did not differ for any other clinical, demographic or neuropsychological factors. 123I-ioflupane SPECT was normal in all but two ALS-PK patients. At 18F-FDG-PET, ALS-PK patients showed a relative hypometabolism in left cerebellum and a relatively more preserved metabolism in right insula and frontal regions; MRI fractional anisotropy was reduced in the sagittal stratum and increased in the retrolenticular part of the internal capsule. CONCLUSIONS: In our study, about 30% of ALS patients showed PK signs. Neuroimaging data indicate that PK signs are due to the involvement of brain circuitries other than classical nigrostriatal ones, strengthening the hypothesis of ALS as a complex multisystem disease.

Genetic background and outcome of Deep Brain Stimulation in Parkinson's disease.

Deep Brain Stimulation (DBS) is a well-established therapeutic option for patients with Parkinson's disease (PD). The high variability observed in the outcome demands better prediction criteria to select candidate patients that may obtain the best results from DBS. Recent advances in genetics have provided important tools to investigate variability in clinical features of PD patients, creating the possibility to correlate the patient's individual genotypes with clinical outcome of therapeutic responsiveness. The purpose of this review is to examine current evidence supporting the role of genetic background on the DBS efficacy. Three databases were searched to identify relevant articles reporting the outcomes of DBS in patients with PD and related genetic mutations. Twelve studies that compared the DBS response in different genetic forms of PD and non-mutated cases were found; mutations in PRKN, LRRK2 and GBA were the most common PD-related mutations. All the studies confirmed the effectiveness of DBS to control motor symptoms independently from the genetic status of patients, although some differences in the response to DBS were found. Due to the several limitations of the available data, all the existing evidence is preliminary. Future well-designed studies are needed to draw more consistent conclusions about genotype-related differences on DBS outcome.

Beyond 35 years of Parkinson's disease: a comprehensive clinical and instrumental assessment.

BACKGROUND: We sought to characterize the clinical, neuropsychological, electrophysiological, and neuroimaging features of Parkinson's disease (PD) after over 35 years since the onset of motor symptoms. METHODS: Five consecutively consenting PD patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) were recruited in a cross-sectional study of motor (Unified PD Rating Scale section-III), non-motor (Non-Motor Symptoms Scale), autonomic (Scale for Outcome in PD-Autonomic), and neuropsychological features associated with the very advanced phase of PD. In addition, patients underwent neurophysiological (autonomic tests and nerve conduction studies) and neuroimaging (brain MRI, 123I-FP-CIT SPECT, and 123I-MIBG myocardial scintigraphy) studies, as well as a genetic analysis of 34 genes and single nucleotide polymorphisms associated with PD. RESULTS: There was a sustained motor response to L-dopa (range 14.4-35.6%), STN-DBS (23.3-38.4%), and L-dopa plus STN-DBS (37.8-63.0%). There were mild-to-moderate non-motor symptoms (range 19-83 on a scale of 0 to 360) and autonomic dysfunction (8-28 on a scale of 0-69). Two patients were demented, one had mild cognitive impairment, and two were cognitively preserved. Three patients had a sensory-axonal peripheral neuropathy and two a moderate-to-severe autonomic neuropathy. All cases showed a complete nigro-striatal dopaminergic denervation and a severe cardiovascular noradrenergic denervation. The brain MRI revealed only moderate frontal atrophy. The genetic tests were unremarkable. CONCLUSIONS: Even after more than 35 years of disease, L-dopa  and STN-DBS remain effective on PD cardinal symptoms. Although axial, autonomic, and neuropsychological features may become key determinants of disability, some patients maintain a satisfactory quality of life, without significant motor and non-motor impairment.

Nestin expression and reactive phenomena in the mouse cochlea after kanamycin ototoxicity.

Following injury to the adult mammalian cochlea, hair cells cannot be spontaneously replaced. Nonetheless, the postnatal cochlea contains progenitor cells, distinguished by the expression of nestin, which are able to proliferate and form neurospheres in vitro. Such resident progenitors might be endowed with reparative potential. However, to date little is known about their behaviour in situ following hair cell injury. Using adult mice and ex vivo cochlear cultures, we sought to determine whether: (i) resident cochlear progenitors respond to kanamycin ototoxicity and compensate for it; and (ii) the reparative potential of cochlear progenitors can be stimulated by the addition of growth factors. Morphological changes of cochlear tissue, expression of nestin mRNA and protein and cell proliferation were investigated in these models. Our observations show that ototoxic injury has modest effects on nestin expression and cell proliferation. On the other hand, the addition of growth factors to the injured cochlear explants induced the appearance of nestin-positive cells in the supporting cell area of the organ of Corti. The vast majority of nestin-expressing cells, however, were not proliferating. Growth factors also had a robust stimulatory effect on axonal sprouting and the proliferative response, which was more pronounced in injured cochleae. On the whole, our findings indicate that nestin expression after kanamycin ototoxicity is related to tissue reactivity rather than activation of resident progenitors attempting to replace the lost receptors. In addition, administration of growth factors significantly enhances tissue remodelling, suggesting that cochlear repair may be promoted by the exogenous application of regeneration-promoting substances.

Towards gene therapy for deafness.

Many hearing disorders are associated with the damage or loss of sensory hair cells (HC) which can produce a profound and irreversible deafness. Apoptosis pathway is reported to play an important role leading to rapid expansion of the HC lesion after exposure to intense noise. Furthermore, progress made over the last year in understanding molecular mechanisms involved in the proliferative and regenerative capacity of sensory cells in the mammalian inner ear has raised the possibility that targeted therapies might prevent the loss of these cells and preserve the patient's hearing. A first step towards the successful therapeutic exploitation is a better understanding of the different pathways that control survival and proliferation of sensory cells. In this review, we provide an overview of recent findings concerning the possibility to prevent apoptosis in auditory cells. We also show the current knowledge on the molecular mechanisms involved in the potential regenerative behavior of these cells and the progress of gene therapy to prevent deafness noise-induced.

Perinatal asphyxia affects rat auditory processing: implications for auditory perceptual impairments in neurodevelopmental disorders.

Perinatal asphyxia, a naturally and commonly occurring risk factor in birthing, represents one of the major causes of neonatal encephalopathy with long term consequences for infants. Here, degraded spectral and temporal responses to sounds were recorded from neurons in the primary auditory cortex (A1) of adult rats exposed to asphyxia at birth. Response onset latencies and durations were increased. Response amplitudes were reduced. Tuning curves were broader. Degraded successive-stimulus masking inhibitory mechanisms were associated with a reduced capability of neurons to follow higher-rate repetitive stimuli. The architecture of peripheral inner ear sensory epithelium was preserved, suggesting that recorded abnormalities can be of central origin. Some implications of these findings for the genesis of language perception deficits or for impaired language expression recorded in developmental disorders, such as autism spectrum disorders, contributed to by perinatal asphyxia, are discussed.

Association between hypermethylated tumor and paired surgical margins in head and neck squamous cell carcinomas.

PURPOSE: Surgical margin status is reported to be a relevant prognostic factor in head and neck squamous cell carcinoma (HNSCC), associated with a high risk of local recurrence. This study examines whether gene-promoter hypermethylation could be detected in HNSCC surgical margins with no histologic evidence of malignancy, and if so, whether it reflects epigenetic events of primary tumors. EXPERIMENTAL DESIGN: Promoter methylation status of MGMT, p16, and DAP-K genes was evaluated by methylation-specific PCR in 20 primary HNSCC tumors. Histopathologically negative surgical margins of hypermethylated tumors were collected, and their methylation status compared with the primary tumor status. RESULTS: Promoter hypermethylation in at least one of the three tested genes was detected in 65% (13 of 20) of tumors. MGMT was hypermethylated in 50% (10 of 20), DAP-K in 45% (9 of 20), and p16 in 20% (4 of 20) of tumors. Methylation status was analyzed in 35 margins from 11 of 13 patients showing promoter hypermethylation in the tumor tissue. Identical methylation events were seen for at least one gene in primary tumor and surgical margins in 9 of 11 cases (82%). Association was found for gene-specific hypermethylation status in tumors and paired surgical margins, and gene-specific concordance was 63% for MGMT (kappa = 0.24), 90% for DAP-K (kappa = 0.74), and 90% for p16 (kappa = 0.79). CONCLUSIONS: Our results support the hypothesis that detection of gene promoter hypermethylation in HNSCC tumor cells-free surgical margins may be a helpful biomarker to identify molecularly altered fields in areas adjacent to the tumor.

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas.

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.

Prognostic relevance of CD105+ microvessel density in HNSCC patient outcome.

Angiogenesis is essential for the development and progression of malignant tumours, and there is increasing evidence that microvessel density (MVD) can be considered an indirect marker of neo-angiogenesis. However, there is still disagreement concerning the clinical relevance and prognostic significance of MVD in head and neck squamous cell carcinomas (HNSCCs). MVD was evaluated in 127 HNSCC patients by means of immunohistochemistry using monoclonal antibodies (mAbs) against CD34 and CD105 (endoglin), which has recently been described as a potent marker of neo-vascularisation in various malignancies. MVD was expressed as the mean number of vessels/mm2. The mean CD34+ and CD105+ MVD values were significantly higher in T3-T4 tumours and those in an advanced clinical stage; furthermore, CD105+ MVD was significantly higher in N+ tumours. The patients with a high CD105+ MVD had a significantly shorter disease-free and overall survival; CD34+ MVD was not associated with survival. Similarly, in the subset of lymph-node negative patients, higher CD105+ MVD values were significantly associated with either OS and DFS. Multivariate analysis showed that a high CD105+ MVD was the only independent marker of tumour recurrence or death. Our data suggest that CD105+ MVD may represent an additional prognostic factor in HNSCC patients providing more accurate data for the determination of prognosis and management in the subset of lymph node negative patients.

Constitutive expression of interleukin-18 in head and neck squamous carcinoma cells.

BACKGROUND: Interleukin (IL)-18 is a potent immunomodulatory cytokine promoting TH-1 and cytotoxic immune responses through interferon (IFN)-gamma induction. The aim of this study was to investigate the production of IL-18 by squamous cell carcinoma of the head and neck (HNSCC). METHODS: The expression of IL-18 was analyzed by reverse transcriptase-polymerase chain reaction, Western blot, and ELISA in untreated and 5-fluorouracil (5-FU)-treated HNSCC cell lines. Immunohistochemical analysis was performed on tumor specimens from 16 patients with primary invasive HNSCC. RESULTS: We have demonstrated that HNSCC cell lines express IL-18 at the mRNA, as well as the protein, level. However, the IL-18 protein was expressed intracellularly and predominantly released as an unprocessed inactive 24-kDa form. After exposure to 5-FU, the processed form of IL-18 was detected in the supernatants of both HNSCC cell lines. CONCLUSIONS: These results indicate that HNSCC cells are a potential source of IL-18 cytokine. The finding that the exposure to 5-FU can elicit its processing suggests a novel target for immunomodulatory intervention in patients with HNSCC.