Exploring neurodegenerative disorders using advanced magnetic resonance imaging of the glymphatic system.

The glymphatic system, a macroscopic waste clearance system in the brain, is crucial for maintaining neural health. It facilitates the exchange of cerebrospinal and interstitial fluid, aiding the clearance of soluble proteins and metabolites and distributing essential nutrients and signaling molecules. Emerging evidence suggests a link between glymphatic dysfunction and the pathogenesis of neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease.

α-Synuclein Pathology in PRKN-Linked Parkinson's Disease: New Insights from a Blood-Based Seed Amplification Assay.

Pathogenic variants in PRKN cause early-onset Parkinson's disease (PD), while the role of alpha-synuclein in PRKN-PD remains uncertain. One study performed a blood-based alpha-synuclein seed amplification assay (SAA) in PRKN-PD, not detecting seed amplification in 17 PRKN-PD patients. By applying a methodologically different SAA focusing on neuron-derived extracellular vesicles, we demonstrated alpha-synuclein seed amplification in 8 of 13 PRKN-PD patients, challenging the view of PRKN-PD as a non-synucleinopathy.

Neuroenergetic Changes in Patients with X-Linked Dystonia-Parkinsonism and Female Carriers.

Background: X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored.

Objectives: To investigate the bioenergetic state in male patients with XDP and female carriers using phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations.

Levodopa Impairs the Energy Metabolism of the Basal Ganglia In Vivo.

Objective: One proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in-vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown.

Methods: We performed a double-blinded, cross-over, placebo-controlled trial.

Neuroinflammation and Mitochondrial Dysfunction in Parkinson's Disease: Connecting Neuroimaging with Pathophysiology.

There is a pressing need for disease-modifying therapies in patients suffering from neurodegenerative diseases, including Parkinson's disease (PD). However, these disorders face unique challenges in clinical trial designs to assess the neuroprotective properties of potential drug candidates. One of these challenges relates to the often unknown individual disease mechanisms that would, however, be relevant for targeted treatment strategies.

Depressive symptoms in Parkinson's disease are insufficiently but more often treated than in other chronic conditions.

Depressive symptoms in Parkinson's disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit. However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the prevalence and severity of depressive symptoms in PD patients and disease controls (DC).

Iron- and Neuromelanin-Weighted Neuroimaging to Study Mitochondrial Dysfunction in Patients with Parkinson's Disease.

The underlying causes of Parkinson's disease are complex, and besides recent advances in elucidating relevant disease mechanisms, no disease-modifying treatments are currently available. One proposed pathophysiological hallmark is mitochondrial dysfunction, and a plethora of evidence points toward the interconnected nature of mitochondria in neuronal homeostasis. This also extends to iron and neuromelanin metabolism, two biochemical processes highly relevant to individual disease manifestation and progression.

Assessment of Bioenergetic Deficits in Patients With Parkinson Disease and Progressive Supranuclear Palsy Using P-MRSI.

Background And Objective: Bioenergetic disturbance, mainly caused by mitochondrial dysfunction, is an established pathophysiologic phenomenon in neurodegenerative movement disorders. The in vivo assessment of brain energy metabolism by phosphorus magnetic resonance spectroscopy imaging could provide pathophysiologic insights and serve in the differential diagnosis of parkinsonian disorders. In this study, we investigated such aspects of the underlying pathophysiology in patients with idiopathic Parkinson disease (PwPD) and progressive supranuclear palsy (PwPSP).

Bi-Allelic COQ4 Variants Cause Adult-Onset Ataxia-Spasticity Spectrum Disease.

Background: COQ4 codes for a mitochondrial protein required for coenzyme Q (CoQ ) biosynthesis. Autosomal recessive COQ4-associated CoQ deficiency leads to an early-onset mitochondrial multi-organ disorder.

Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4.

Increased Subcortical Sodium Levels in Patients with Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a debilitating neurodegenerative disease characterized by an aggressive disease course. Total and intracellular-weighted sodium imaging (Na-MRI) is a promising method for investigating neurodegeneration in vivo. We enrolled 10 patients with PSP and 20 age- and gender-matched healthy control subjects; all study subjects underwent a neurological examination, whole-brain structural, and (total and intracellular-weighted) Na-MRI.

Neuroimaging Methods to Map In Vivo Changes of OXPHOS and Oxidative Stress in Neurodegenerative Disorders.

Mitochondrial dysfunction is a pathophysiological hallmark of most neurodegenerative diseases. Several clinical trials targeting mitochondrial dysfunction have been performed with conflicting results. Reliable biomarkers of mitochondrial dysfunction in vivo are thus needed to optimize future clinical trial designs.

Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson's disease.

Background: The underlying pathophysiology of Parkinson's disease is complex, involving different molecular pathways, including brain iron deposition and mitochondrial dysfunction. At a molecular level, these disease mechanisms are likely interconnected. Therefore, they offer potential strategies for disease-modifying treatments.

Neuroimaging Correlates of Substantia Nigra Hyperechogenicity in Parkinson's Disease.

Background: Degeneration of dopaminergic neurons within the brainstem substantia nigra (SN) is both a pathological hallmark of Parkinson's disease (PD) and a major contributor to symptom expression. Therefore, non-invasive evaluation of the SN is critical for diagnosis and evaluation of disease progression. Hyperechogenicity (HE+) on midbrain transcranial sonography (TCS) supports the clinically established diagnosis of PD.

The impact of motion artifacts on quantitative optical coherence tomography angiography analysis in Parkinson's disease.

We have previously shown that OCTA imaging in PD patients can be challenging. Our data suggest that retinal perfusion is reduced in both plexuses in PD, which may serve as a noninvasive biomarker in the future. Yet, control of motion artifacts in OCTA measurements is critical in this motor-impaired cohort.

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson's Disease.

Background: Mitochondrial dysfunction has been identified as a pathophysiological hallmark of disease onset and progression in patients with Parkinsonian disorders. Besides the overall emergence of gene therapies in treating these patients, this highly relevant molecular concept has not yet been defined as a target for gene therapeutic approaches.

Methods: This narrative review will discuss the experimental evidence suggesting mitochondrial dysfunction as a viable treatment target in patients with monogenic and idiopathic Parkinson's disease.

Association of Locus Coeruleus and Substantia Nigra Pathology With Cognitive and Motor Functions in Patients With Parkinson Disease.

Objective: To investigate the contribution of substantia nigra (SN) and locus coeruleus (LC) pathology to clinical signs and symptoms in Parkinson disease (PD) by applying neuromelanin-weighted imaging.

Methods: Forty-seven patients with PD and 53 matched controls underwent motor assessment, a neuropsychological test battery, and neuromelanin-weighted MRI. Patients with PD were enrolled after fulfilling the criteria for clinically established PD as defined by the Movement Disorders Society Clinical Diagnostic Criteria.

Clinical MR imaging in Parkinson's disease: How useful is the swallow tail sign?

Background: With conventional MRI, no Parkinson's disease (PD)-specific abnormalities can be detected. However, there is a critical need for accompanying neuroimaging markers to guide the diagnosis. With high-resolution susceptibility-weighted MRI (SWI) sequences, the imaging of nigrosome-1 (N1) is possible.

Task matters - challenging the motor system allows distinguishing unaffected Parkin mutation carriers from mutation-free controls.

Background: Heterozygous carriers of Parkin mutations are suggested to be at risk of developing Parkinson's disease, while biallelic variants are associated with typical autosomal recessive early-onset PD. Investigating unaffected heterozygous mutation carriers holds the potential of a deeper understanding of monogenic PD and has implications for PD in general, in particular regarding the prodromal phase.

Objectives: To discriminate healthy Parkin mutation carriers from healthy non-mutation carriers using a multimodal approach.

Genotype-driven therapeutic developments in Parkinson's disease.

Background: Remarkable advances have been reached in the understanding of the genetic basis of Parkinson's disease (PD), with the identification of monogenic causes (mPD) and a plethora of gene loci leading to an increased risk for idiopathic PD. The expanding knowledge and subsequent identification of genetic contributions fosters the understanding of molecular mechanisms leading to disease development and progression. Distinct pathways involved in mitochondrial dysfunction, oxidative stress, and lysosomal function have been identified and open a unique window of opportunity for individualized treatment approaches.

Applicability of optical coherence tomography angiography (OCTA) imaging in Parkinson's disease.

To evaluate the significance of motion artifacts in optical coherence tomography angiography (OCTA) images of patients with Parkinson's disease (PD) and healthy controls. In this prospective, cross-sectional study subjects with medicated PD (ON) and healthy, age- and gender-matched volunteers were recruited. Participants underwent specific ophthalmological examinations, including OCTA.

The Use of Vitamin K2 in Patients With Parkinson's Disease and Mitochondrial Dysfunction (PD-K2): A Theranostic Pilot Study in a Placebo-Controlled Parallel Group Design.

Despite rapid advances in research on Parkinson's disease (PD), in particular in the elucidation of genetic contributions, no disease-modifying therapy has become available to date. In the proposed project, we aim to investigate the potential effects of vitamin K2 (long-chain menaquinone 7, MK-7) in genetically determined PD with mitochondrial dysfunction. A total of 130 study participants (26 biallelic / mutation carriers, 52 sporadic PD patients, and 52 healthy controls) will receive the trial medication (MK-7 or placebo for 1 week).

Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities.

The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms.