Developments in the role of transcranial sonography for the differential diagnosis of parkinsonism

As one of the few people trained to do this examination on PD subjects in the UK I can vouch for the merits of its use in the both the clinical and research setting...

Curr Neurol Neurosci Rep. 2015 Jul;15(7):566. doi: 10.1007/s11910-015-0566-9.

Pilotto A, Yilmaz R, Berg D.

In the last two decades transcranial sonography (TCS) has developed as a valuable, supplementary tool in the diagnosis and differential diagnosis of movement disorders. In this review, we highlight recent evidence supporting TCS as a reliable method in the differential diagnosis of parkinsonism, combining substantia nigra (SN), basal ganglia and ventricular system findings. Moreover, several studies support SN hyperechogenicity as one of most important risk factors for Parkinson's disease (PD). The advantages of TCS include short investigation time, low cost and lack of radiation. Principal limitations are still the dependency on the bone window and operator experience. New automated algorithms may reduce the role of investigator skill in the assessment and interpretation, increasing TCS diagnostic reliability. Based on the convincing evidence available, the EFNS accredited the method of TCS a level A recommendation for supporting the diagnosis of PD and its differential diagnosis from secondary and atypical parkinsonism. An increasing number of training programmes is extending the use of this technique in clinical practice.

Depression and subsequent risk of Parkinson disease: A nationwide cohort study

Interesting stuff indeed...dose dependent effect and significance differences observed up to two decades prior to diagnosis. To my knowledge this is the first study that has suggested depression precedes PD by this length of time but anxiety has been shown to antedate PD by a similar length of time...

Neurology. 2015 May 20. pii: 10.1212/WNL.0000000000001684. [Epub ahead of print]

Gustafsson H, Nordström A, Nordström P.

http://www.neurology.org/content/early/2015/05/20/WNL.0000000000001684.short?rss=1

OBJECTIVE:

To investigate the long-term risk of Parkinson disease (PD) after depression and evaluate potential confounding by shared susceptibility to the 2 diagnoses.

METHODS:

The nationwide study cohort included 140,688 cases of depression, matched 1:3 using a nested case-control design to evaluate temporal aspects of study parameters (total, n = 562,631). Potential familial coaggregation of the 2 diagnoses was investigated in a subcohort of 540,811 sibling pairs. Associations were investigated using multivariable adjusted statistical models.

RESULTS:

During a median follow-up period of 6.8 (range, 0-26.0) years, 3,260 individuals in the cohort were diagnosed with PD. The multivariable adjusted odds ratio (OR) for PD was 3.2 (95% confidence interval [CI], 2.5-4.1) within the first year of depression, decreasing to 1.5 (95% CI, 1.1-2.0) after 15 to 25 years. Among participants with depression, recurrent hospitalization was an independent risk factor for PD (OR, 1.4; 95% CI, 1.1-1.9 for ≥5 vs 1 hospitalization). In family analyses, siblings' depression was not significantly associated with PD risk in index persons (OR, 1.1; 95% CI, 0.9-1.4).

CONCLUSIONS:

The time-dependent effect, dose-response pattern for recurrent depression, and lack of evidence for coaggregation among siblings all indicate a direct association between depression and subsequent PD. Given that the association was significant for a follow-up period of more than 2 decades, depression may be a very early prodromal symptom of PD, or a causal risk factor.

High nigral iron deposition in LRRK2 and Parkin mutation carriers using R2* relaxometry

Interesting work... these kind of radiological markers may help define the pre-diagnostic stage of disease in asymptomatic gene carriers and perhaps more widely...

Mov Disord. 2015 May 22. doi: 10.1002/mds.26218. [Epub ahead of print]

Pyatigorskaya N, Sharman M, Corvol JC, Valabregue R, Yahia-Cherif L, Poupon F, Cormier-Dequaire F, Siebner H, Klebe S, Vidailhet M, Brice A, Lehéricy S.

The goal of this work was to investigate iron deposition in the basal ganglia and thalamus in symptomatic and asymptomatic leucine-rich repeat kinase 2 (LRRK2) and Parkin-associated Parkinson's disease (PD), using R2* relaxometry rate. Twenty subjects with genetic PD (four symptomatic and two asymptomatic Parkin subjects, nine symptomatic and five asymptomatic LRRK2 subjects) were compared with 20 patients with idiopathic PD (IPD) and 20 healthy subjects. Images were obtained at 3 teslas, using multi-echo T2 and T2* sequences. R2 and R2* values were calculated in the substantia nigra (SN), the striatum, the globus pallidus, and the thalamus. The R2* values in the SN were increased in IPD and mutation-carrying patients as compared with controls and in mutation-carrying patients as compared with IPD. Asymptomatic mutation carriers showed higher R2* values than controls and did not differ from IPD patients. No changes were seen in the other structures or in R2 values. These results are consistent with increased iron load in LRRK2- and Parkin-mutation carriers. The increased R2* in asymptomatic PD-mutation carriers suggests that iron deposition occurs early during the preclinical phase of the disease. R2* measurements may be used as markers for investigating nigrostriatal damage in preclinical mutation-carrying patients.

Mullin S, Schapira A. The genetics of Parkinson's disease. Br Med Bull. 2015
May 20. pii: ldv022. [Epub ahead of print] PubMed PMID: 25995343.

http://bmb.oxfordjournals.org/content/early/2015/05/20/bmb.ldv022.short?rss=1

Only 15 years ago in medical school Parkinson’s disease was said to be the very definition of a non genetically inherited disease. It’s taken a giant leap forward in our understanding of genetics to realise that, as is the case in Parkinson’s, genetic inheritance doesn’t have mean one gene giving rise to a disease, but rather many genes, modified possibly by environmental factors or even one another, interacting to cause it. This article describes the genetic causes which account for 30% or so of the inheritance of Parkinson’s disease and speculates on what underlies the 70% of genetic inheritance which is still unclear.    

The genetics of Parkinson's disease

Nice review on this topic by my colleague Stephen Mullin... well worth a read.

Our understanding of the contribution of genetics to PD grows all the time... whilst perhaps not a 'genetic' disorder in the classical sense, it is the very concept of 'genetic disorders' has changed dramatically as a result of Genome Wide Association Studies and will continue to unfold in the current era of Next Generation Sequencing. Things that were considered non-genetic are now increasingly recognised to have a an important and complex genetic contribution...

Br Med Bull. 2015 May 20. pii: ldv022. [Epub ahead of print]

Mullin S, Schapira A.

BACKGROUND:

Parkinson's disease (PD) was previously described as the prototypical sporadic disease; however, rapid advances in population and molecular genetics have revealed the existence of a significant number genetic risk factors, prompting its redefinition as a primarily genetic disorder.

SOURCES OF DATA:

Data for this review have been gathered from the published literature.

AREAS OF AGREEMENT:

Multiple haplotypes conveying variable but quantifiable genetic risk, acting concurrently and possibly interacting with one another, provide the basis for a new model of PD. The beginning of this revolution in our understanding came from the clinical observation of parkinsonism with a Mendelian pattern of inheritance in a number of families. The functional work that followed elucidated multiple disease pathways leading to the degeneration of the substantia nigra that characterizes PD. It is however only in recent years, with the emergence of large cohort genome-wide association studies (GWAS), that the relevance of these pathways to so-called sporadic PD has become apparent.

AREAS OF CONTROVERSY:

A substantial portion of the presumed genetic inheritance of PD remains at present undefined. Although it is likely that so-called intermediate risk genetic risk factors are the principal component of this 'missing heritability', this is yet to be proved.

GROWING POINTS:

Although the picture is by now means complete, the beginnings of rational basis for genetic screening of PD risk have begun to emerge. Equally, this enhanced understanding of the various genetic and in turn biochemical pathways shows promising signs of producing fruitful therapeutic strategies. Technological advances promise to reduce the costs associated with and further increase our capability to understand the complex influence of genetics on the pathogenesis of PD.

AREAS TIMELY FOR DEVELOPING RESEARCH:

The coming years will require the enhancement of current techniques and the development of new ones to define PD's missing heritability. It will also require functional work to define better and in turn potentially reverse the mechanisms that contribute with large effect sizes to the risk of sporadic PD.

External validation of a simple clinical tool used to predict falls in people with Parkinson disease

A different type of prediction for those with PD... one that predicts who might fall. This is really important because falls may be preventable and the sequelae of falls, namely fractures and head injuries can have profound negative effects on those with PD...

Parkinsonism Relat Disord. 2015 May 16. pii: S1353-8020(15)00210-2. doi: 10.1016/j.parkreldis.2015.05.008. [Epub ahead of print]

Duncan RP, Cavanaugh JT, Earhart GM, Ellis TD, Ford MP, Foreman KB, Leddy AL, Paul SS, Canning CG, Thackeray A, Dibble LE.

http://www.sciencedirect.com/science/article/pii/S1353802015002102

BACKGROUND:

Assessment of fall risk in an individual with Parkinson disease (PD) is a critical yet often time consuming component of patient care. Recently a simple clinical prediction tool based only on fall history in the previous year, freezing of gait in the past month, and gait velocity <1.1 m/s was developed and accurately predicted future falls in a sample of individuals with PD.

METHODS:

We sought to externally validate the utility of the tool by administering it to a different cohort of 171 individuals with PD. Falls were monitored prospectively for 6 months following predictor assessment.

RESULTS:

The tool accurately discriminated future fallers from non-fallers (area under the curve [AUC] = 0.83; 95% CI 0.76-0.89), comparable to the developmental study.

CONCLUSION:

The results validated the utility of the tool for allowing clinicians to quickly and accurately identify an individual's risk of an impending fall.

What do patients with scans without evidence of dopaminergic deficit (SWEDD) have? New evidence and continuing controversies

Agree to be honest... likely to represent two broad categories 1) those that are misdiagnosed as having PD and 2) those that are in the early stages and may develop DAT positivity at a later date...

J Neurol Neurosurg Psychiatry. 2015 May 19. pii: jnnp-2014-310256. doi: 10.1136/jnnp-2014-310256. [Epub ahead of print]

Erro R, Schneider SA, Quinn NP, Bhatia KP.

http://jnnp.bmj.com/content/early/2015/05/19/jnnp-2014-310256.abstract

Abstract

The term SWEDD (scans without evidence for dopaminergic deficit) refers to the absence, rather than the presence, of an imaging abnormality in patients clinically presumed to have Parkinson's disease (PD). However, such a term has since been widely used in the medical literature, even as a diagnostic label. While many authors have suggested that different disorders of PD lookalikes may account for a proportion of SWEDD cases, others have claimed that some of them may have a benign subtype of PD. Thus, there has been ensuing controversy and confusion and the use of this term continues without clarity of what it represents. We have systematically reviewed all the studies involving patients with SWEDD with the aim of shedding light on what these patients actually have. It becomes clear from this systematic review that while most 'SWEDD' cases are due to a clinical misdiagnosis of PD, there exists a small proportion of patients with SWEDD who may have PD on the basis of a positive levodopa response, clinical progression, imaging and/or genetic evidence. The latter challenge the seemingly incontrovertible relationship between dopaminergic tracer binding and the diagnosis of nigrostriatal parkinsonism, particularly PD. Patients with SWEDD are unlikely to reflect a single clinical entity and we suggest that the term SWEDD should be abandoned.

Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative

Neurobiol Dis. 2015 May 14. pii: S0969-9961(15)00166-7. doi: 10.1016/j.nbd.2015.05.004. [Epub ahead of print]

Laurens B, Constantinescu R, Freeman R, Gerhard A, Jellinger K, Jeromin A, Krismer F, Mollenhauer B, Schlossmacher MG, Shaw LM, Verbeek MM, Wenning GK, Winge K, Zhang J, Meissner WG.

http://www.sciencedirect.com/science/article/pii/S0969996115001667

Abstract

Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.

Olfactory function combined with morphology distinguishes Parkinson's disease

Interesting to see that this battery can differentiate PD from atypical Parkinson's which can be very tricky. What about PD versus controls does MRI of the bulbs and tracts differentiate these two groups??

Parkinsonism Relat Disord. 2015 May 11. pii: S1353-8020(15)00197-2. doi: 10.1016/j.parkreldis.2015.05.001. [Epub ahead of print]

http://www.prd-journal.com/article/S1353-8020(15)00197-2/abstract

Sengoku R, Matsushima S, Bono K, Sakuta K, Yamazaki M, Miyagawa S, Komatsu T, Mitsumura H, Kono Y, Kamiyama T, Ito K, Mochio S, Iguchi Y.

OBJECTIVE:

This study aimed to examine whether the volume of the olfactory bulbs and tracts (OB & T) on magnetic resonance imaging (MRI) is useful for differentiating Parkinson's disease (PD) from PD-related disorders.

METHODS:

The study group comprised 13 patients with PD, 11 with multiple system atrophy (MSA), five with progressive supranuclear palsy, and five with corticobasal degeneration (PSP/CBD). All patients were evaluated using the odor stick identification test for Japanese (OSIT-J), 123I-meta-iodobenzylguanidine (MIBG) scintigraphy, and brain MRI. OB & T areas on 1-mm-thick coronal images were measured and summed for volumes. We examined relationships between olfactory function and volume, and cardiovascular dysautonomia. We defined the cut-off values for OSIT-J score or MIBG uptake and OB & T volume to discriminate PD from PD-related disorders and calculated the proportional rate of PD in four categorized groups.

RESULTS:

OB & T volume was smaller in PD than in MSA or PSP/CBD (p < 0.05 each). The cut-off for detecting PD patients was OSIT-J score <8, heart/mediastinum ratio <1.6, and OB & T volume <270 mm3. In the group with OSIT-J score <8 and OB & T volume <270 mm3, the proportion of PD patients among all patients with PD-related disorders was 91%. The rate of probable PD gradually increased as OSIT-J score and OB & T volume decreased (p < 0.001).

CONCLUSIONS:

Although preliminary, these data obtained from a combined morphological and functional evaluation of OB or cardiovascular dysautonomia could be useful for further differential of PD and other PD-related disorders.

Neuropathobiology of non-motor symptoms in Parkinson disease

This is important and may underpin efforts to define biomarkers (tissue markers at least) of pre-diagnostic PD... knowing the pathological substrate for these symptoms is essential to characterise and make objective measurement to monitor the pre-diagnosis stage...

J Neural Transm. 2015 May 15. [Epub ahead of print]

Jellinger KA.

http://link.springer.com/article/10.1007%2Fs00702-015-1405-5

Abstract

Parkinson disease (PD) is a multisystem disorder associated with α-synuclein aggregates throughout the central, autonomic, and peripheral nervous system, clinically characterized by motor and non-motor (NM) symptoms. The NMS in PD, many of which antedating motor dysfunction and representing a preclinical phase spanning 20 or more years, are linked to widespread distribution of α-synuclein pathology not restricted to the dopaminergic nigrostriatal system that is responsible for core motor features of PD. The pathologic substrate of NM manifestations such as olfactory, autonomic (gastrointestinal, urogenital, cardia, respiratory), sensory, skin, sleep, visual, neuropsychiatric dysfunctions (cognitive, mood, dementia), and others are critically reviewed. In addition to non-nigral brainstem nuclei, α-synuclein pathology involves sympathetic and parasympathetic, enteric, cardiac and pelvic plexuses, and many other organs indicating a topographical and chronological spread, particularly in the prodromal stages of the disease. Few animal models recapitulate NMS in PD. The relationship between regional α-synuclein/Lewy pathology, neurodegeneration and the corresponding clinical deficits awaits further elucidation. Controlled clinicopathologic studies will refine the correlations between presymptomatic and late-developing NM features of PD and neuropathology, and new premotor biomarkers will facilitate early diagnosis of PD as a basis for more effective preventive and therapeutic options of this devastating disease.

Gastrointestinal dysfunction in Parkinson's disease

Nice Lancet Neurology review of GI dysfunction in PD...

Lancet Neurol. 2015 Jun;14(6):625-639. doi: 10.1016/S1474-4422(15)00007-1.

Fasano A, Visanji NP, Liu LW, Lang AE, Pfeiffer RF.

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(15)00007-1/abstract

Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches.