Risk factor studies of age-at-onset in a sample ascertained for Parkinson disease affected sibling pairs: a cautionary tale

An association between exposure to a risk factor and age-at-onset of disease may reflect an effect on the rate of disease occurrence or an acceleration of the disease process. The difference in age-at-onset arising from case-only studies, however, may also reflect secular trends in the prevalence of exposure to the risk factor. Comparisons of age-at-onset associated with risk factors are commonly performed in case series enrolled for genetic linkage analysis of late onset diseases. We describe how the results of age-at-onset studies of environmental risk factors reflect the underlying structure of the source population, rather than an association with age-at-onset, by contrasting the effects of coffee drinking and cigarette smoking on Parkinson disease age-at-onset with the effects on age-at-enrollment in a population based study sample. Despite earlier evidence to suggest a protective association of coffee drinking and cigarette smoking with Parkinson disease risk, the age-at-onset results are comparable to the patterns observed in the population sample, and thus a causal inference from the age-at-onset effect may not be justified. Protective effects of multivitamin use on PD age-at-onset are also shown to be subject to a bias from the relationship between age and multivitamin initiation. Case-only studies of age-at-onset must be performed with an appreciation for the association between risk factors and age and ageing in the source population

The ongoing pursuit of neuroprotective therapies in Parkinson disease

Many agents developed for neuroprotective treatment of Parkinson disease (PD) have shown great promise in the laboratory, but none have translated to positive results in patients with PD. Potential neuroprotective drugs, such as ubiquinone, creatine and PYM50028, have failed to show any clinical benefits in recent high-profile clinical trials. This 'failure to translate' is likely to be related primarily to our incomplete understanding of the pathogenic mechanisms underlying PD, and excessive reliance on data from toxin-based animal models to judge which agents should be selected for clinical trials. Restricted resources inevitably mean that difficult compromises must be made in terms of trial design, and reliable estimation of efficacy is further hampered by the absence of validated biomarkers of disease progression. Drug development in PD dementia has been mostly unsuccessful; however, emerging biochemical, genetic and pathological evidence suggests a link between tau and amyloid-β deposition and cognitive decline in PD, potentially opening up new possibilities for therapeutic intervention. This Review discusses the most important 'druggable' disease mechanisms in PD, as well as the most-promising drugs that are being evaluated for their potential efficiency in treatment of motor and cognitive impairments in PD

Three Dimensional Functional Cartography Of The Human Basal Ganglia By Registration Of Optical And Histological Serial Sections

In functional neurosurgery, there is a need for accurate locatisation of the functional targets. One example is given by Parkinson's disease. The surgical intervention is based on the introduction of electrodes in the subthalamic nucleus. This nucleus is targeted on pre-operative stereotactic MR acquisitions. But MR imaging of the basal ganglia is intrinsically limited, first by image resolution, and second by the relationship between the measured MR signal and the real anatomy, not clearly understood. On the other hand, detailed and accurate cartography of the basal ganglia can be performed on post mortem histological serial sections. Indeed, histology overcomes the limitations of MR imaging. Moreover, staining of histological sections allows to recover functional information. But histology is by nature two-dimensional. An histological data set consists in a series of disorganized serial sections, as three dimensional shape information was lost during sectioning. Therefore, the first step toward the integration of histological and MR information is to perform a reliable three dimensional reconstruction of the histological volume. Acquisition of photographs during sectioning, showing the histological sections before sectioning, as well as fiducial landmarks, allows to reconstruct a volume with three dimensional integrity, and is further used to register each histological section with its corresponding optical section

Fusion of Histological Sections and MR Images: Towards the Construction of an Atlas of the Human Basal Ganglia

In neurosurgery, loca lisa tion of deepbra in structures isa crucia issue, which c a beaqB71 ed bya 3-dimensiona bra: a tlafiTk Our goa is to build such a ala by fusing histologica d aa witha 3D MR ima ge of the sa me subject. This requires two steps: firsta 2D rea lignment of the histologica l sections in order to obta ina three-dimensiona l block, thena 3D registra tion between this reconstructed blocka nd the MR imaHT Both stepsaq baqk on the sa e robust registr a iona lgorithm.

Co-registration of histological, optical and MR data of the human brain

In order to allow accurate pre-operative localisation of functional taxgets in functional neurosurgery, we aim at constructing a three dimensional registrable caxtography of the basal ganglia, based on histology. For doing this, a post mortera MR study was conducted on a cadaver's head, and the brain was then extracted and processed for histology. The post mortera MR image will allow to report the caxtography on the patient's anatomy, by its registration with the patient's MR image. In this paper, we focus on the problem of co-registering the histological and post mortera MR data of the same subject. First, realignment of the histological sections into a reliable three dimensional volume is performed. Then the reconstructed volume is registered with the post mortera MR image. To insure three dimensional integrity of the histological reconstructed volume, a reference volume is first constructed from photographs of the unstained surface of the frozen brain. This reference is then used as an intermediate volume for, on the one hand, independant alignment of each histological section with its corresponding optical section and on the other hand, three dimensional registration with the post mortera MR image