De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).

Objective: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years.

Methods: In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies.

Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus.

Purpose: To characterize changes in the magnetic resonance (MR) relaxation properties of progressive supranuclear palsy (PSP) and tissue from neurologically normal brains by using high-resolution (21.1-T, 900-MHz) MR microscopy of postmortem human midbrain and basal ganglia.

Materials And Methods: This HIPAA-compliant study was approved by the institutional review board at the Mayo Clinic and informed consent was obtained.

A quantitative postmortem MRI design sensitive to white matter hyperintensity differences and their relationship with underlying pathology.

White matter hyperintensities (WMHs) associate with both cognitive slowing and motor dysfunction in the neurologically normal elderly. A full understanding of the pathology underlying this clinicoradiologic finding is currently lacking in autopsy-confirmed normal brains. To determine the histopathologic basis of WMH seen on magnetic resonance imaging, we studied the relationship between postmortem fluid-attenuated inversion recovery (FLAIR) intensity and neuropathologic markers of WM lesions (WMLs) that correspond to WMH in cognitively normal aging brains.

[Magnetic resonance imaging with 21.1 T and pathological correlations--diffuse Lewy body disease].

We investigated fixed basal ganglia specimens, including globus pallidus and putamen, with 21.1-Tesla MRI allowing us to achieve a microscopic level resolution from a patient with pathologically confirmed dementia with Lewy bodies (DLB) and a neurologically normal control case. We acquired T2 and T2 * weighted images that demonstrated diffuse and patchy lower intensities in the basal ganglia compared to control.

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.

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.

Iron and reactive oxygen species activity in parkinsonian substantia nigra.

Objectives: We sought to determine concentrations of total and labile iron in substantia nigra from patients with Parkinson disease and from controls to assess if oxidative stress is triggered by an increased concentration of iron.

Methods: Total iron concentration in the whole substantia nigra was evaluated in 17 parkinsonian and 29 control samples. Concentrations of labile iron and copper were assessed in 6 parkinsonian and 8 control samples.

Baroreflex sensitivity and power spectral analysis during autonomic testing in different extrapyramidal syndromes.

Autonomic dysfunction has been frequently demonstrated in patients with extrapyramidal diseases by cardiovascular autonomic testing. In addition to classical testing, we applied the more detailed baroreflex and spectral analysis on three traditional cardiovascular tests in this study to get additional information on autonomic outflow. We recorded continuously blood pressure, electrocardiogram, and respiration in 35 patients with multiple system atrophy, 32 patients with progressive supranuclear palsy, 46 patients with idiopathic Parkinson's disease and in 27 corresponding healthy subjects during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt).

Loss of nocturnal blood pressure fall in various extrapyramidal syndromes.

Cardiovascular autonomic dysfunction has frequently been reported in some patients with extrapyramidal syndromes, especially multiple system atrophy (MSA) but also Parkinson's disease (PD). However, there are only few reports on the prevalence of cardiovascular autonomic dysfunction progressive in supranuclear palsy (PSP). Moreover, the relation of detailed cardiovascular testing and easy to assess 24-hour ambulatory blood pressure (BP) is not known.

Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes.

Autonomic dysfunction in patients with progressive supranuclear palsy.

The most important features that characterize and differentiate progressive supranuclear palsy (PSP) from other parkinsonian syndromes are postural instability, supranuclear gaze palsy, pseudobulbar palsy, and cognitive disturbances. Although it has been reported that significant autonomic dysfunction is an exclusionary feature for PSP diagnosis, we could demonstrate in this study using semiquantitative clinical interview and cardiovascular testing that both PSP and idiopathic Parkinson's disease (PD) patients can present with significant autonomic dysfunction. The parasympathetic cardiovascular system seems to be involved to a similar extent in PD and PSP patients, whereas sympathetic cardiovascular dysfunction is more frequent and severe in PD patients, but can also be found in PSP patients.

Autonomic dysfunction in different subtypes of multiple system atrophy.

Multiple system atrophy (MSA) can clinically be divided into the cerebellar (MSA-C) and the parkinsonian (MSA-P) variant. However, till now, it is unknown whether autonomic dysfunction in these two entities differs regarding severity and profile. We compared the pattern of autonomic dysfunction in 12 patients with MSA-C and 26 with MSA-P in comparison with 27 age- and sex-matched healthy controls using a standard battery of autonomic function tests and a structured anamnesis of the autonomic nervous system.

Multiregional brain iron deficiency in restless legs syndrome.

Evidence for tissue iron deficiency in restless legs syndrome (RLS) is limited to the substantia nigra (SN). Using MRI, we assessed T2 values of various brain regions in 6 RLS patients and 19 controls and correlated them with sonographically assessed SN echogenicity. Both neuroimaging features are supposed to correlate with tissue iron content.

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.

Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation.

Homozygous mutations in the PINK1 gene have been shown to cause early-onset parkinsonism. Here, we describe a novel homozygous mutation (Q126P), identified in two affected German sisters with a clinical phenotype typical for PINK1-associated parkinsonism. We analysed lactate, pyruvate, carnitine and acylcarnitine blood levels, lactate levels under exercise and in the cerebrospinal fluid, activity of respiratory chain complexes I-IV in muscle biopsies and proteasomal activity in immortalized lymphoblasts, but found no evidence for mitochondrial or proteasomal dysfunction.

Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain.

Genetic variability in the promoter and 3' region of the SNCA gene coding alpha-synuclein modulates the risk to develop sporadic Parkinson's disease (PD). Whether this is mediated by regulating alpha-synuclein expression levels remains unknown. Therefore, we analyzed levels of alpha-synuclein in blood and human post mortem brain tissue including the substantia nigra using quantitative real-time reverse transcriptase-polymerase chain reaction and enzyme linked immunosorbent assay in vivo.

[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.

Pupil diameter in darkness differentiates progressive supranuclear palsy (PSP) from other extrapyramidal syndromes.

The most important features that characterize and differentiate progressive supranuclear palsy from other Parkinsonian syndromes are postural instability, supranuclear gaze palsy, pseudobulbar palsy, parkinsonism, and cognitive disturbances. In this article, we demonstrate that progressive supranuclear palsy patients exhibit pathologically decreased pupil diameters after dark adaptation recorded by TV pupillography. A cut off value of 3.

Transcranial ultrasound in different monogenetic subtypes of Parkinson's disease.

Hyperechogenicity of the substantia nigra (SN) has been found to be a typical sign in idiopathic Parkinson's disease (PD), prevalent in more than 90% of affected individuals. To see whether SN hyperechogenicity is also characteristic for monogenetically caused PD, we investigated PD patients with alpha-synuclein, LRRK2, parkin, PINK1 and DJ-1 mutations by transcranial sonography (TCS). In all these patients the area of SN echogenicity was significantly larger than in healthy controls, but smaller, than in idiopathic PD.