Brain health: Pathway to primary prevention of neurodegenerative disorders of environmental origin.

While rising global rates of neurodegenerative disease encourage early diagnosis and therapeutic intervention to block clinical expression (secondary prevention), a more powerful approach is to identify and remove environmental factors that trigger long-latencybrain disease (primary prevention) by acting on a susceptible genotype or acting alone. The latter is illustrated by the post-World War II decline and disappearance of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC), a prototypical often-familial neurodegenerative disease formerly present in very high incidence on the island of Guam. Lessons learned from 75 years of investigation on the etiology of ALS/PDC include: the importance of focusing field research on the disease epicenter and patients with early-onset disease; soliciting exposure history from patients, family, and community to guide multidisciplinary biomedical investigation; recognition that disease phenotype may vary with exposure history, and that familial brain disease may have a primarily environmental origin.

SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia.

Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %).

Age-specific progression of nigrostriatal dysfunction in Parkinson's disease.

Objective: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD).

Methods: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [¹¹C](±)dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [¹¹C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[¹⁸F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase.

Results: The study comprised 438 PD scans and 241 control scans (679 scans in total).

Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study.

Parkinson's disease is a heterogeneous disorder with multiple factors contributing to disease initiation and progression. Using serial, multi-tracer positron emission tomography imaging, we studied a cohort of 78 subjects with sporadic Parkinson's disease to understand the disease course better. Subjects were scanned with radiotracers of presynaptic dopaminergic integrity at baseline and again after 4 and 8 years of follow-up.

DCTN1 mutations in Perry syndrome.

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.

Genetic factors influencing age at onset in LRRK2-linked Parkinson disease.

Patients with Leucine-rich repeat kinase 2 (LRRK2) linked Parkinson's disease (PD) clinically present with typical idiopathic PD. However, LRRK2-linked PD displays a pleomorphic neuropathology and high variability in age at disease onset (AAO) which suggests that environmental and/or genetic factors other than the mutation itself influence the course of the disease. We investigated the modulation of AAO by genetic factors including the mutation-containing domain and PD associated polymorphisms in the gene coding alpha-synuclein (SNCA) and tau (MAPT) in 44 patients from 19 affected families.

Pallidonigral TDP-43 pathology in Perry syndrome.

Objective: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis.

Identification of a novel risk locus for progressive supranuclear palsy by a pooled genomewide scan of 500,288 single-nucleotide polymorphisms.

To date, only the H1 MAPT haplotype has been consistently associated with risk of developing the neurodegenerative disease progressive supranuclear palsy (PSP). We hypothesized that additional genetic loci may be involved in conferring risk of PSP that could be identified through a pooling-based genomewide association study of >500,000 SNPs. Candidate SNPs with large differences in allelic frequency were identified by ranking all SNPs by their probe-intensity difference between cohorts.

PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation.

Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology.

A reassessment of the Lewy body.

Lewy body has been linked to Parkinson's disease for almost a century, but its significance in neurodegenerative diseases is not known. Whether it is toxic, protective, or just a bystander has been a subject of debate. Recent advances in molecular and genetic works suggest Lewy bodies are not essential for the diagnosis and pathogenesis of Parkinson's disease.

Severe vascular disturbance in a case of familial brain calcinosis.

Here we present the first neuropathological study of a case of autosomal dominant brain calcinosis in a family followed through five generations. The 71-year-old female who came to autopsy had unusually severe and extensive bilateral brain calcifications. The process appeared to start with deposition of minute calcium-positive spheroids of less than 1 mum in diameter in capillaries that otherwise appeared normal.

Lack of regional selectivity during the progression of Parkinson disease: implications for pathogenesis.

Background: Dopamine terminal loss in the putamen of patients with Parkinson disease (PD) shows a regional heterogeneity, reflecting selective vulnerability of degenerating neurons to mechanisms of cell death.

Hypothesis: If the same pathogenic mechanisms are responsible for the onset and progression of PD, the regional selectivity of dopamine cell loss will be the same throughout the course of the disorder.

Objective: To investigate the regional selectivity of dopamine terminal loss during the progression of PD.

Is the neuropathological 'gold standard' diagnosis dead? Implications of clinicopathological findings in an autosomal dominant neurodegenerative disorder.

Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neuropathological criteria for diagnosis. Implications regarding an autosomal dominant neurodegenerative disorder (PARK 8) in which four different neuropathological diagnoses were found at autopsy are discussed. We suggest that just as there is currently no clinical 'gold standard' for Parkinson's disease, there is no pathological 'gold standard.

Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8).

Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias.

Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.

Clustering of Parkinson disease: shared cause or coincidence?

Background: The spatial and temporal pattern of excessive disease occurrence, termed clustering, may provide clues about the underlying etiology.

Objective: To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada.

Design And Patients: We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments.

Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2).

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor.

The neuromythology of Parkinson's Disease.

Over the last century three central points have become the orthodox dogma accepted and taught by those who study Parkinson's Disease. These are: Parkinson's Disease is one disease. Lewy bodies in the substantia nigra are an acceptable hallmark of Parkinson's Disease.

Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model.

Levodopa-treated Parkinson's disease is often complicated by the occurrence of motor fluctuations, which can be predictable ('wearing-off') or unpredictable ('on-off'). In contrast, untreated dopa-responsive dystonia (DRD) is usually characterized by predictable diurnal fluctuation. The pathogenesis of motor fluctuations in treated Parkinson's disease and diurnal fluctuation in untreated DRD is poorly understood.

The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval.

Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region.

Protective effects of intracerebral adenoviral-mediated GDNF gene transfer in a rat model of Parkinson's disease.

This study focuses on the potential protective effects of intracerebral adeno-viral mediated glial cell line derived neurotrophic factor (GDNF) gene transfer in a rat model of Parkinson's disease (PD). Thirty-five SD rats were divided into three groups to receive perinigral injections of recombinant adenovirus encoding GDNF (Ad-GDNF), LacZ (Ad-LacZ) or PBS, respectively. One week later, an intrastriatal injection of 6-hydroxydopamine (6-OHDA) was administered to induce the progressive degeneration of dopaminergic neurons.

Determination of an occupational exposure guideline for manganese using the benchmark method.

An occupational risk assessment for manganese (Mn) was performed based on benchmark dose analysis of data from two epidemiological studies providing dose-response information regarding the potential neurological effects of exposure to airborne Mn below the current Occupational Safety and Health Administration (OSHA) Permissible Exposure Level (PEL) of 5 mg Mn/m3. Based on a review of the scientific evidence regarding the toxicity of Mn, it was determined that the most appropriate measure of exposure to airborne Mn for the subclinical effects measured in these studies is recent (rather than historical or cumulative) concentration of Mn in respirable (rather than total) particulate. For each of the studies analyzed, the individual exposure and response data from the original study had been made available by the investigators.

VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET.

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study.

Age and severity of nigrostriatal damage at onset of Parkinson's disease.

The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect.