Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.

Background: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease.

Objective: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype.

Methods: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families.

NfL and pNfH are increased in Friedreich's ataxia.

Objective: To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia.

Methods: Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length.

TREM2 rare variant p.R47H is not associated with Parkinson's disease.

Variant p.R47H of triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with Parkinson's disease (PD). We screened this TREM2-variant in 821 PD patients including 261 demented PD patients (PDD) and in healthy controls (n = 919).

Clinical and brain imaging characteristics in leucine-rich repeat kinase 2-associated PD and asymptomatic mutation carriers.

The objective of this research was to evaluate a possible endophenotype in leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Ten symptomatic LRRK2 patients, 24 sporadic Parkinson's disease patients as well as 10 asymptomatic LRRK2 mutation carriers and 29 matched healthy controls underwent comprehensive clinical assessments with respect to motor and non-motor symptoms. Transcranial sonography and magnetic resonance imaging (voxel-based morphometry [VBM]) were assessed to evaluate morphological imaging characteristics.

The modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect.

Full expansions of the polyglutamine domain (polyQ≥34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27≤polyQ≤33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation.

Enlarged substantia nigra hyperechogenicity and risk for Parkinson disease: a 37-month 3-center study of 1847 older persons.

Objective: To evaluate whether enlarged substantia nigra hyperechogenicity (SN+) is associated with an increased risk for Parkinson disease (PD) in a healthy elderly population.

Design: Longitudinal 3-center observational study with 37 months of prospective follow-up.

Setting: Individuals 50 years or older without evidence of PD or any other neurodegenerative disease.

Reduced but not oxidized cerebrospinal fluid glutathione levels are lowered in Lewy body diseases.

Reduced (GSH(R)) but not oxidized glutathione (GSSG) has been shown to be dramatically altered in the substantia nigra (SN) of Lewy body disease (LBD) patients post mortem; but up to now, there is no convincing evidence that these changes can be monitored in vivo. We investigated GSH(R) and GSSG in rapidly processed cerebrospinal fluid (CSF) and plasma samples of 80 LBD and 35 control subjects and detected reduced CSF GSH(R) levels in LBD subjects. The reduction was negatively associated with age but not with disease-associated parameters.

Enlarged hyperechogenic substantia nigra is related to motor performance and olfaction in the elderly.

Enlarged substantia nigra hyperechogenicity (SN+) assessed by transcranial sonography (TCS) may be associated with Parkinson's disease (PD) risk markers such as impaired motor performance and hyposmia. The aim of this multicenter cross-sectional study was to define the association between SN+ and these risk markers in a large population older than 50 years without the diagnosis of PD. In three centers (Tuebingen, Homburg, and Innsbruck), 1,839 individuals were examined.

Progression of Parkinson's disease in the clinical phase: potential markers.

Neuromodulatory or even neuroprotective therapy could soon be available for Parkinson's disease (PD), raising the question of how we should define and measure disease progression. Reported evidence suggests that several symptoms worsen with disease duration. Bradykinesia, rigidity, and activities of daily living deteriorate faster at the beginning of the disease, and this deterioration is paralleled by a decline in functional presynaptic dopaminergic activity, as shown by imaging techniques.

Pre-motor signs of PD are related to SN hyperechogenicity assessed by TCS in an elderly population.

Much effort has been put in the identification of risk factors and pre-motor markers for Parkinson's disease (PD). In contrast to many of the pre-motor markers, SN hyperechogenicity (SN+) assessed by transcranial sonography (TCS) has been found to be conclusive for vulnerability for PD. In two centers in Germany 1204 individuals ≥50 years without the diagnosis of PD were recruited and the prevalence and relation of SN+ to a range of pre-motor markers was evaluated.

Cortical hypometabolism assessed by a metabolic ratio in Parkinson's disease primarily reflects cognitive deterioration-[18F]FDG-PET.

In Parkinson's disease patients with cognitive deterioration, regional cortical hypometabolism has been observed with [(18)F]fluorodeoxyglucose-positron emission tomography (FDG-PET). Our aim was to develop a robust method to subsume the overall degree of metabolic deterioration in Parkinson's disease by means of a single index and to investigate which of the clinical features correlates best with hypometabolism. Twenty-two Parkinson's patients (10 demented) and seven controls underwent FDG-PET.

Effect of genetic variation in Kv1.3 on olfactory function.

Background: Olfactory function is reduced in aged humans and diabetes mellitus patients. However, little is known about the pathogenic mechanisms leading to olfactory dysfunction. Recently, it has been shown that the voltage-gated potassium channel Kv1.

Cortical PIB binding in Lewy body disease is associated with Alzheimer-like characteristics.

About one fourth of Lewy body disease (LBD) patients show cortical beta-amyloid load, basically a hallmark of Alzheimer disease (AD). Using [11C]PIB-PET, we tested whether LBD patients with beta-amyloid burden differ from those without with respect to demographic, clinical, biochemical and genetic parameters. Thirty-five LBD subjects (9 patients with Lewy body dementia, DLB; 12 demented Parkinson patients, PDD; 14 non-demented PD, PDND) underwent [11C]PIB-PET, and were classified as either PIB(+) or PIB(-) according to cortical PIB uptake.

The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study.

Background: Increased echogenicity of the substantia nigra (SN), as determined by transcranial sonography (TCS), is characteristic of idiopathic Parkinson's disease (iPD). The results of initial retrospective studies indicate that this ultrasound sign is specific for iPD and can help to differentiate it from atypical parkinsonian syndromes (aPS); however, these early studies were done in patients with later disease stages and known clinical diagnosis. We aimed to determine the diagnostic value of TCS in the early stages of parkinsonian syndromes, when the clinical symptoms often do not enable a definite diagnosis to be made.

Substantia nigra hyperechogenicity assessed by transcranial sonography is related to neuropsychological impairment in the elderly population.

Transcranial sonography (TCS) is a valuable tool in the diagnosis of Parkinson's disease (PD). However, substantia nigra hyperechogenicity (SN+) in TCS has been shown to be also evident in about 8-10% of healthy persons. Neuroimaging studies and slight motor deficits in subjects with SN+ indicate functional impairment of the nigrostriatal system associated with the ultrasound sign.

[11C]PIB binding in Parkinson's disease dementia.

[(11)C]PIB ((11)C-6-OH benzothiazole) reflects the regional distribution of amyloid (beta-sheeted proteins) in patients with Alzheimer's disease (AD). Proteinaceous inclusions in Parkinson's disease with dementia (PDD), so-called Lewy bodies, also consist of fibrillar, misfolded proteins, chiefly alpha-synuclein. To test whether PDD subjects show specific amyloid binding in vivo and whether this could reflect fibrillar alpha-synuclein accumulation, we investigated 10 PDD subjects with [(11)C]PIB-PET.

Sonographic abnormalities of brainstem structures in restless legs syndrome.

Background And Purpose: Using transcranial B-mode sonography (TCS), the first morphological marker for restless legs syndrome (RLS), hypoechogenicity of the substantia nigra (SN) has been found. The aim of this study was to validate SN hypoechogenicity as a morphological marker for RLS in a large patient cohort and to investigate further RLS-associated brain abnormalities using TCS.

Methods: One hundred forty-three RLS patients (37 with symptomatic RLS) and 45 controls, matched for age and gender, underwent TCS by an experienced and independent rater who was blinded to clinical data.

Treatment of dementia in parkinsonian syndromes with cholinesterase inhibitors.

In Parkinsonian syndromes behavioural symptoms and dementia can be even more debilitating than motor symptoms and are an important predictor for nursing home placement and mortality. Neuropathologically, dementia seems to be primarily related to cortical changes rather than to subcortical alterations. Concerning neurotransmitter systems, the cholinergic system has been proposed to play a key role in cognitive disturbances.

Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome.

Pathological studies demonstrate a decreased iron content in the substantia nigra (SN) contributing to the pathophysiology of restless legs syndrome (RLS). SN echogenicity as measured by transcranial sonography (TCS) correlates with the SN iron content. The objective of this study was to determine a critical value to define SN hypoechogenicity as a potential marker for RLS.