Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in Charcot-Marie-Tooth type 2 neuropathies.

HSPB1 [heat shock protein family B (small) member 1] and HSPB8 are essential molecular chaperones for neuronal proteostasis, as they prevent protein aggregation. Mutant HSPB1 and HSPB8 primarily harm peripheral neurons, resulting in axonal Charcot-Marie-Tooth neuropathies (CMT2). Macroautophagy/autophagy is a shared mechanism by which HSPB1 and HSPB8 mutations cause neuronal dysfunction.

Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of Frontotemporal Dementia.

Diagnosis of Frontotemporal dementia (FTD) and the specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD- Tau and FTLD-TDP) is challenging, and thus fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort including patients with FTD (n = 189), Alzheimer's Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 68).

Force-induced dephosphorylation activates the cochaperone BAG3 to coordinate protein homeostasis and membrane traffic.

Proteome maintenance in contracting skeletal and cardiac muscles depends on the chaperone-regulating protein BAG3. Reduced BAG3 activity leads to muscle weakness and heart failure in animal models and patients. BAG3 and its chaperone partners recognize mechanically damaged muscle proteins and initiate their disposal through chaperone-assisted selective autophagy (CASA).

Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disease caused by biallelic variants in the gene encoding for sacsin. More than 200 pathogenic variants have been identified to date, most of which are missense. It is likely that the prevalence of autosomal recessive spastic ataxia of Charlevoix-Saguenay is underestimated due to the lack of an efficient diagnostic tool able to validate variants of uncertain significance.

A genome-wide association meta-analysis of all-cause and vascular dementia.

Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD.

Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD.

Antigen-specific age-related memory CD8 T cells induce and track Alzheimer's-like neurodegeneration.

Cerebral (Aβ) plaque and (pTau) tangle deposition are hallmarks of Alzheimer's disease (AD), yet are insufficient to confer complete AD-like neurodegeneration experimentally. Factors acting upstream of Aβ/pTau in AD remain unknown, but their identification could enable earlier diagnosis and more effective treatments. T cell abnormalities are emerging AD hallmarks, and CD8 T cells were recently found to mediate neurodegeneration downstream of tangle deposition in hereditary neurodegeneration models.

Altered brain expression and cerebrospinal fluid levels of TIMP4 in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies.

Advances and challenges in modeling inherited peripheral neuropathies using iPSCs.

Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes with fundamental roles in the development and function of peripheral nerves. Over the past 10 years, significant advances in identifying molecular disease mechanisms underlying axonal and myelin degeneration, acquired from cellular biology studies and transgenic fly and rodent models, have facilitated the development of promising treatment strategies. However, no clinical treatment has emerged to date.

Decreased microvascular claudin-5 levels in cerebral amyloid angiopathy associated with intracerebral haemorrhage.

Decreased microvascular levels of claudin-5 in the occipital and temporal lobe of patients with cerebral amyloid angiopathy are associated with intracerebral haemorrhage.

Paired plasma lipidomics and proteomics analysis in the conversion from mild cognitive impairment to Alzheimer's disease.

Background: Alzheimer's disease (AD) is a neurodegenerative condition for which there is currently no available medication that can stop its progression. Previous studies suggest that mild cognitive impairment (MCI) is a phase that precedes the disease. Therefore, a better understanding of the molecular mechanisms behind MCI conversion to AD is needed.

A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A.

Background: Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets.

Vitamin D deficiency and osteopenia in spastic paraplegia type 5 indicate impaired bone homeostasis.

Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis.

Dominant mutations causing axonal Charcot-Marie-Tooth disease expand -associated diseases.

Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase () cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy.

Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.

Purpose: We describe 3 families with Charcot-Marie-Tooth neuropathy (CMT), harboring a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant previously linked to fatal Leigh syndrome.

Beyond CSF and Neuroimaging Assessment: Evaluating Plasma miR-145-5p as a Potential Biomarker for Mild Cognitive Impairment and Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. New strategies for the early detection of MCI and sporadic AD are crucial for developing effective treatment options. Current techniques used for diagnosis of AD are invasive and/or expensive, so they are not suitable for population screening.

Overarching pathomechanisms in inherited peripheral neuropathies, spastic paraplegias, and cerebellar ataxias.

International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development.

Contracturing granulomatous myositis in a patient with rheumatoid arthritis: a case report.

Contracturing granulomatous myositis is a rare myopathy in which patients present with flexion contractures of the upper limbs in addition to slowly progressive muscle weakness and pain. Whether it represents a distinct nosological entity remains a point of discussion. We present a patient with isolated granulomatous disease of the muscle that responded very well to intravenous immunoglobulins after treatment failure of corticosteroids and methotrexate.

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients.

Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL).

Diagnostic Performance of Cerebrospinal Fluid Neurofilament Light Chain and Soluble Amyloid-β Protein Precursor β in the Subcortical Small Vessel Type of Dementia.

Background: The subcortical small vessel type of dementia (SSVD) is a common subtype of vascular dementia, but there is a lack of disease-specific cerebrospinal fluid (CSF) biomarkers.

Objective: We investigated whether CSF concentrations of neurofilament light chain (NFL), soluble amyloid-β protein precursor α (sAβPPα), sAβPPβ, and CSF/serum albumin ratio could separate SSVD from healthy controls, Alzheimer's disease (AD), and mixed dementia (combined AD and SSVD).

Methods: This was a mono-center study of patients with SSVD (n = 38), AD (n = 121), mixed dementia (n = 62), and controls (n = 96).

Association between Low Vitamin D Status, Serotonin, and Clinico-Biobehavioral Parameters in Alzheimer's Disease.

Introduction: Studies suggest a role of vitamin D in the progression and symptomatology of Alzheimer's disease (AD), with few in vitro studies pointing to effects on serotonergic and amyloidogenic turnover. However, limited data exist in AD patients on the potential association with cognition and behavioral and psychological signs and symptoms of dementia (BPSD). In this retrospective cross-sectional study, we, therefore, explored potential correlations of serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations, indicative of vitamin D status, with serum serotonin (5-hydroxytryptamine, 5-HT) levels, cognitive/BPSD scorings, and cerebrospinal fluid (CSF) biomarker levels.