Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to ...investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies.
Assessment of neuropathological findings in individuals affected by pathological expansion of CAG HTT.
The association between Parkinson's disease (PD) and mutations in genes involved in lysosomal and mitochondrial function has been previously reported. However, little is known about the involvement ...of other genes or cellular mechanisms. We aim to identify novel genetic associations to better understand the pathogenesis of PD. We performed WES in a cohort of 32 PD patients and 30 age-matched controls. We searched for rare variants in 1667 genes: PD-associated, related to lysosomal function and mitochondrial function and TFEB-regulated. When comparing the PD patient cohort with that of age matched controls, a statistically significant burden of rare variants in the previous group of genes were identified. In addition, the Z-score calculation, using the European population database (GnomAD), showed an over-representation of particular variants in 36 genes. Interestingly, 11 of these genes are implicated in mitochondrial function and 18 are TFEB-regulated genes. Our results suggest, for the first time, an involvement of TFEB-regulated genes in the genetic susceptibility to PD. This is remarkable as TFEB factor has been reported to be sequestered inside Lewy bodies, pointing to a role of TFEB in the pathogenesis of PD. Our data also reinforce the involvement of lysosomal and mitochondrial mechanisms in PD.
Idiopathic Parkinson's disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according ...to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
Improved knowledge of the prediagnostic phase of progressive supranuclear palsy (PSP) might provide information on when and how the disease starts, along with the opportunity to test therapies in ...disease stages with lesser neurodegeneration.
To explore the symptoms in years preceding the PSP diagnosis.
This is a single-center retrospective case-control study based on clinical charts review and a structured interview to PSP patients and their caregivers. Prediagnostic symptoms were defined as those present more than one year before the diagnosis. We explored 35 symptoms in the following domains: visual, dizziness, motor, mood/apathy, cognitive, behavioral, sleep, gastrointestinal/urinary and miscellaneous. Non-parametric statistics were applied, with significance set at <0.05 (FDR-corrected).
We included 150 subjects: 50 PSP patients (38% females, age 75.8) and an age- and sex-matched control group of 50 Parkinson's disease (PD) and 50 subjects (CS) without neurodegenerative disease. The frequencies of visual, motor, cognitive, behaviour and dizziness domains were significantly higher in PSP vs. PD, and so were the motor, mood/apathy, cognitive, behaviour and dizziness ones in PSP vs. CS. Over 50% of prediagnostic falls, apathy and anxiety, depression and memory-attention-executive symptoms, and over 30% of gait disturbances started more than three and up to ten years before the diagnosis. PSP patients had more consultations to ENT and ophthalmologists than PD patients.
PSP patients present a broad variety of motor and non-motor symptoms several years before the diagnosis. The definition of a prediagnostic PSP phase might be helpful to identify patients in early disease stages.
•Motor and non-motor prediagnostic PSP symptoms have not been studied in depth.•We retrospectively assessed prediagnostic symptoms in PSP vs. PD and controls.•Prediagnostic falls but also gait, cognitive and mood disturbances were more frequent in PSP.•These symptoms might help define prediagnostic PSP.•These might assist selection of enriched populations in future PSP research.
Neuroinflammation is a potential player in neurodegenerative conditions, particularly the aggressive ones, such as multiple system atrophy (MSA). Previous reports on cytokine levels in MSA using ...serum or cerebrospinal fluid (CSF) have been inconsistent, including small samples and a limited number of cytokines, often without comparison to Parkinson's disease (PD), a main MSA differential diagnosis.
Cross-sectional study of CSF levels of 38 cytokines using a multiplex assay in 73 participants: 39 MSA patients (19 with parkinsonian type MSAp, 20 with cerebellar type MSAc; 31 probable, 8 possible), 19 PD patients and 15 neurologically unimpaired controls. None of the participants was under non-steroidal anti-inflammatory drugs at the time of the lumbar puncture.
There were not significant differences in sex and age among participants. In global non-parametric comparisons FDR-corrected for multiple comparisons, CSF levels of 5 cytokines (FGF-2, IL-10, MCP-3, IL-12p40, MDC) differed among the three groups. In pair-wise FDR-corrected non-parametric comparisons 12 cytokines (FGF-2, eotaxin, fractalkine, IFN-α2, IL-10, MCP-3, IL-12p40, MDC, IL-17, IL-7, MIP-1β, TNF-α) were significantly higher in MSA vs. non-MSA cases (PD + controls pooled together). Of these, MCP-3 and MDC were the most significant ones, also differed in MSA vs. PD, and were significant MSA-predictors in binary logistic regression models and ROC curves adjusted for age. CSF levels of fractalkine and MIP-1α showed a strong and significant positive correlation with UMSARS-2 scores.
Increased CSF levels of cytokines such as MCP-3, MDC, fractalkine and MIP-1α deserve consideration as potential diagnostic or severity biomarkers of MSA.
•CSF levels of 12 cytokines were higher in MSA (n = 39) vs. PD + controls (n = 19 & 15).•Younger age and increasing CSF levels of MCP-3 and MDC were MSA predictors in adjusted models.•CSF levels of fractalkine and MIP-1α correlated with UMSARS-2 scores.•CSF levels of these cytokines might be diagnostic or severity MSA biomarkers.
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare neurologic disorder included in the group of neurodegeneration with brain iron accumulation diseases (NBIA). Information regarding ...sleep in patients with PKAN is limited.
To describe the clinical and polysomnographic characteristics of sleep in six patients with genetically confirmed PKAN.
The evaluation included a clinical interview, sleep questionnaires -Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS)- and a video-polysomnography (VPSG). In addition to standard sleep measures we manually quantified sleep spindle density in stage N2 and rapid eye movements in REM sleep comparing the results with matched controls. Quantification of EMG activity in REM sleep was performed following standard criteria.
All the patients reported at least one sleep complaint, most commonly sleep fragmentation (4/6) and sleep onset insomnia (3/6). ESS and PSQI were abnormal in 3/6 and 4/6, respectively. VPSG showed in 4/6 decreased ocular movements during REM sleep, an increase in sleep spindles in 3/6 (all of them with deep brain pallidal stimulation), an absence of slow wave sleep in 2 and undifferentiated NREM sleep and delayed sleep phase in one. Three patients had an abnormal sleep apnea/hypopnea index, and 2 periodic limb movements of sleep. REM sleep muscular atonia was preserved in all.
Sleep disorders are common in patients with PKAN. Although our sample is small and heterogeneous, with different symptomatic treatments possibly influencing the results, it suggests that evaluation of sleep should be considered in their management.
•Sleep disorders are common in patients with PKAN.•The most frequent complaints are sleep fragmentation and sleep onset insomnia.•Sleep spindles in N2 sleep are increased in patients treated with DBS in the GPi.•PKAN patients have less rapid eye movements in REM sleep, especially if the ocular motility awake is impaired.•REM sleep behavior disorder does not occur, suggesting that mechanisms of REM sleep atonia are not impaired in PKAN patients.
•Huntington's disease (HD) population exhibits referential anomalies in spontaneous speech.•Changes in the striatum in HD affect the processing of referential dependencies.•HD population manifest a ...loss of sensitivity to locality constraints as enshrined in the Binding Theory principles.•Neuropsychological variables did not improve linguistic performance.
The International Parkinson and Movement Disorder Society-endorsed Progressive Supranuclear Palsy Study Group published clinical diagnostic criteria for progressive supranuclear palsy in 2017, aiming ...to optimize early, sensitive and specific diagnosis.
To assist physicians in the application of these criteria, we developed a video-based tutorial in which all core clinical features and clinical clues are depicted and explained.
Patients provided written informed consent to the publication of their videos. High-quality videos along with essential descriptions were collected by the study group members. Most educational videos were selected in a structured consensus process.
We provide 68 videos of all core clinical features and clinical clues defined by the diagnostic criteria, along with instructive descriptions of the depicted patients, examination techniques and clinical findings.
This comprehensive video-based tutorial will support physicians in the application of the diagnostic criteria of progressive supranuclear palsy.
•Comprehensive video-based tutorial for the correct application of the MDS-PSP criteria.•Displays clinical features associated with PSP pathology.•Promotes an early and accurate clinical diagnosis of PSP.
The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and ...alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of “cocktail” combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such “cocktail” approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers.
•a-synuclein and 4R-tau aggregates often coexist in synucleinopathies and tauopathies.•Anti-Synuclein and anti-tau immunotherapies are being tested in clinical trials.•Increasingly reliable biomarkers foreseeably will allow to assess in vivo co-pathologies.•A cocktail immunotherapy targeting both a-synuclein and 4R-tau is conceivable.
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