Cognitive impairment in Parkinson's disease and dementia with Lewy bodies

Cognitive impairment is a common outcome in PD and mild cognitive impairment may be seen in some patients at the point of diagnosis. Better biomarkers and neuroprotective strategies to prevent descent into dementia are essential...

Parkinsonism Relat Disord. 2015 Sep 21. pii: S1353-8020(15)00425-3. doi: 10.1016/j.parkreldis.2015.09.034. [Epub ahead of print]

Aarsland D.

http://www.sciencedirect.com/science/article/pii/S1353802015004253

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share clinical and pathological similarities. The defining features are motor parkinsonism and cognitive impairment, often accompanied by visual hallucinations, fluctuating consciousness, autonomic and sleep disturbances, and a number of other non-motor symptoms. Mild cognitive impairment (MCI) can be identified in 15% of PD patients at time of diagnosis, and may even precede motor symptoms. MCI usually progresses further, and dementia is a common endpoint. Cognitive impairment is usually the initial symptom of DLB, and the disease course is severe. A variety of biomarkers can assist in the diagnosis and prognosis of PD and DLB, including structural and functional imaging, cerebrospinal fluid, and EEG. Compared to the many treatments available for motor symptoms, relatively few systematic studies exist to guide the treatment of cognitive impairment in PD, and even less in DLB. However, there is good evidence for cholinesterase inhibitors in both DLB and PD with dementia, and some indications that memantine is helpful. Emerging evidence suggest that physical exercise and cognitive training are also effective, as are some reports of various brain stimulation techniques. Disease-modifying agents that delay the rate of cognitive decline in PD and DLB are urgently needed.

The relevance of pre-motor symptoms in Parkinson's disease

New review on early non-motor features of PD...

Expert Rev Neurother. 2015 Oct;15(10):1205-17. doi: 10.1586/14737175.2015.1083423. Epub 2015 Sep 1.

Visanji N, Marras C.

Abstract

Parkinson's disease (PD) has a wide range of non-motor symptoms including; constipation, sleep disturbance, deficits in vision and olfaction, mood disorders and cardiac autonomic dysfunction. Several of these non-motor symptoms can manifest prior to the onset of motor symptoms. Recognizing these pre-motor symptoms may enable early diagnosis of PD. Currently, no single pre-motor symptom is able to predict the development of PD with 100% sensitivity or specificity. Ongoing studies in several independent at-risk cohorts should reveal the potential of combinations of pre-motor symptoms and multi-stage screening strategies to identify individuals at increased risk of PD. PD progression may be governed by a prion-like spread of a-syn throughout the nervous system. Identifying individuals at the earliest stage will likely be critical to preventing the pathological progression of PD, highlighting the relevance of pre-motor symptoms in the future treatment of the disease.

A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease

de novo mutations identified through unbiased exome sequencing approach...

Hum Mol Genet. 2015 Sep 11. pii: ddv376. [Epub ahead of print]

Kun-Rodrigues C, Ganos C, Guerreiro R, Schneider SA, Schulte C, Lesage S, Darwent L, Holmans P, Singleton A; International Parkinson's Disease Genomics Consortium (IPDGC), Bhatia K, Bras J.

http://hmg.oxfordjournals.org/content/early/2015/09/11/hmg.ddv376.long

Abstract

Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical Parkinson's disease to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1,200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.

REM sleep behavior disorder, as assessed by questionnaire, in G2019S LRRK2 mutation PD and carriers

RBD may be less common in LRRK2 manifesting and non-manifesting carriers which could explain some of the differences here... but more apparent is the very high rate of RBD in healthy controls. This is similar to the rate observed in PREDICT-PD and PPMI healthy controls and suggests that over-diagnosis is significant with the RBDSQ...The validity of the RBDSQ is context specific as recently reported by the original author of the RBDSQ earlier this year...

Mov Disord. 2015 Sep 14. doi: 10.1002/mds.26413. [Epub ahead of print]

Saunders-Pullman R, Alcalay RN, Mirelman A, Wang C, Luciano MS, Ortega RA, Glickman A, Raymond D, Mejia-Santana H, Doan N, Johannes B, Yasinovsky K, Ozelius L, Clark L, Orr-Utreger A, Marder K, Giladi N, Bressman SB; AJ LRRK2 Consortium.

http://onlinelibrary.wiley.com/doi/10.1002/mds.26413/abstract;jsessionid=6D5178912E439FF9007326DE72844CB8.f03t01

BACKGROUND:

Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established.

METHODS:

One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire.

RESULTS:

Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P < 0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P < 0.05).

CONCLUSIONS:

A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD.

New clinical trials for nonmotor manifestations of Parkinson's disease

Review on trials in the underserved topic of non-motor features of PD. Better treatments certainly needed...

Mov Disord. 2015 Sep 15;30(11):1490-1504. doi: 10.1002/mds.26415.

Schrag A, Sauerbier A, Chaudhuri KR.

Non-motor manifestations in Parkinson's disease (PD) encompass a range of clinical features, including neuropsychiatric problems, autonomic dysfunction, sleep disorders, fatigue, and pain. Despite their importance for patients' quality of life, the evidence base for their treatment is relatively sparse. Nevertheless, the last few years have seen a number of new trials starting that specifically address nonmotor features as an outcome measure in clinical trials. Large randomized, controlled trials in the last 3 years reported improvement of psychosis with the new selective serotonin 5-HT2A inverse agonist pimavanserin and of postural hypotension with the oral norepinephrine precursor droxidopa. Smaller new randomized, controlled trials support the effectiveness of Deep Brain Stimulation and opiates for pain, of rivastigmine for apathy and piribedil for apathy post-DBS, group cognitive behavioral therapy for depression and/or anxiety, continuous positive airway pressure for sleep apnea in PD and doxepin for insomnia, and of solifenacin succinate and transcutaneous tibial nerve stimulation for urinary symptoms. A number of new smaller or open trials as well as post-hoc analyses of randomized, controlled trials have suggested usefulness of other treatments, and new randomized, controlled trials are currently ongoing.

Structure of the toxic core of α-synuclein from invisible crystals

Getting to the core of it...

Nature. 2015 Sep 9. doi: 10.1038/nature15368. [Epub ahead of print]

Rodriguez JA, Ivanova MI, Sawaya MR, Cascio D, Reyes FE, Shi D, Sangwan S, Guenther EL, Johnson LM, Zhang M, Jiang L, Arbing MA, Nannenga BL, Hattne J, Whitelegge J, Brewster AS, Messerschmidt M, Boutet S, Sauter NK, Gonen T, Eisenberg DS.

Abstract

The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 Å resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.

Autosomal dominant Parkinson's disease caused by SNCA duplications

The effect that mutations (and duplication and triplication) in SNCA have strongly implicated alpha-synuclein in the pathogenesis of PD... the disease is an aggressive one with autonomic dysfunction and cognitive impairment. Cases are rare but important for understanding both genetic and sporadic PD...

Parkinsonism Relat Disord. 2015 Sep 3. pii: S1353-8020(15)00382-X. doi: 10.1016/j.parkreldis.2015.09.007. [Epub ahead of print]

Konno T, Ross OA, Puschmann A, Dickson DW, Wszolek ZK.

http://www.prd-journal.com/article/S1353-8020(15)00382-X/abstract

Abstract

The discovery in 1997 that mutations in the SNCA gene cause Parkinson's disease (PD) greatly advanced our understanding of this illness. There are pathogenic missense mutations and multiplication mutations in SNCA. Thus, not only a mutant protein, but also an increased dose of wild-type protein can produce autosomal dominant parkinsonism. We review the literature on SNCA duplications and focus on pathologically-confirmed cases. We also report a newly-identified American family with SNCA duplication whose proband was autopsied. We found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations (usually visual) and cognitive deficits leading to dementia. Only a few cases have presented with typical features of PD. Our case presented with depression and RBD that preceded parkinsonism, and dysautonomia that led to an initial diagnosis of multiple system atrophy. Dementia and visual hallucinations followed. Our patient and the other reported cases with SNCA duplications had widespread cortical Lewy pathology. Neuronal loss in the hippocampal cornu ammonis 2/3 regions were seen in about half of the autopsied SNCA duplication cases. Similar pathology was also observed in SNCA missense mutation and triplication carriers.

Gastrointestinal complications in newly diagnosed Parkinson's disease: A case-control study

Not prodromal PD but still speaks to the significant GI problems that affect patients with PD...

Trop Gastroenterol. 2014 Oct-Dec;35(4):227-31.

Owolabi LF, Samaila AA, Sunmonu T.

BACKGROUND AND AIM:

In spite of the overwhelming emphasis on motor symptoms in Parkinson's disease(PD), a number of studies have revealed that the non-motor symptoms including gastrointestinal, psychiatric and sleep symptoms have a greater influence on the quality of life of many patients. This study aimed to determine the frequencies of gastrointestinal symptoms in PD patients in comparison to healthy controls and to evaluate the relationship between these GI symptoms and severity of PD.

METHODS:

This cross-sectional study was conducted over a 2-year period. Consecutive new patients of Parkinson's disease were recruited at the neurology clinics of Aminu Kano Teaching Hospital (AKTH) and Murtala Muhammad specialist hospital (MMSH). Healthy age and sex matched volunteers constituted the control group. A structured, pre-tested, close-ended questionnaire inquiring about common gastrointestinal symptoms as well as demographic, and PD characteristics was administered to all cases and controls. PD severity was assessed using the Hoehn and Yahr scale (H and Y).

RESULTS:

A total of 80 patients and 80 controls were recruited during the study period. Their age ranged between 39 and 80 years. The mean age of the patients and controls were 61.1 ± 8.5 and 61.0 ± 8.4 years, respectively. The male to female ratio was 5:2. The most common gastrointestinal symptoms were constipation (48.8%), sialorrhea (18%), dysphagia (16.2%), difficulty in mastication (12.5%), and choking/aspiration (12.5%).When compared with age and sex-matched controls the differences in the occurrence of these symptoms were statistically significant.Constipation, dysphagia, difficult mastication, sialorrhea, and aspiration/choking were found to be more severe on the H and Y scale.

CONCLUSION:

Significant features of gastrointestinal dysfunction in PD include constipation, sialorrhea, dysphagia, difficult mastication and choking. These symptoms were significantly associated with increasing severity of Parkinson's disease.

Constipation preceding Parkinson's disease: a systematic review and meta-analysis

Very pleased about this one... its my first senior author publication. Well done to Kerala for all her hard work. It's known that constipation is a risk factor for PD. Here we pool data from 9 studies which demonstrate the nature of this association very nicely. In fact almost all of them found a similar magnitude of effect (there was little heterogeneity between estimates). Most interestingly, the effect is seen more than 10 years prior to PD diagnosis. Is constipation one of the earliest non-motor features??? 

J Neurol Neurosurg Psychiatry. 2015 Sep 7. pii: jnnp-2015-311680. doi: 10.1136/jnnp-2015-311680. [Epub ahead of print]

Adams-Carr KL, Bestwick JP, Shribman S, Lees A, Schrag A, Noyce AJ.

http://jnnp.bmj.com/content/early/2015/09/07/jnnp-2015-311680.abstract

OBJECTIVE:

To systematically review published literature to estimate the magnitude of association between premorbid constipation and later diagnosis of Parkinson's disease.

BACKGROUND:

Constipation is a recognised non-motor feature of Parkinson's and has been reported to predate diagnosis in a number of observational studies.

METHODS:

A systematic review and meta-analysis was carried out following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) criteria. A literature search was undertaken in December 2014 using PubMed and the search terms 'Parkinson's disease' and 'constipation'. Articles were screened for suitability and reviewed against inclusion and exclusion criteria. Studies were included if they assessed constipation by means of a structured questionnaire or if constipation/drugs used to treat constipation were coded in patient medical records. Data were extracted using a standardised template and effect size estimates combined using a fixed-effects model. Heterogeneity was explored with the I2 statistic.

RESULTS:

9 studies were included in the meta-analysis, with a combined sample size of 741 593 participants. Those with constipation had a pooled OR of 2.27 (95% CI 2.09 to 2.46) for developing subsequent Parkinson's disease compared with those without constipation. Weak evidence for heterogeneity was found (I2=18.9%, p=0.282). Restricting analysis to studies assessing constipation more than 10 years prior to Parkinson's disease gave a pooled OR of 2.13 (95% CI 1.78 to 2.56; I2=0.0%).

CONCLUSIONS:

This systematic review and meta-analysis demonstrates that people with constipation are at a higher risk of developing Parkinson's disease compared with those without and that constipation can predate Parkinson's diagnosis by over a decade.

The utility of α-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature

...On the use of alpha-synuclein as a biomarker of neurodegeneration...

http://www.futuremedicine.com/doi/abs/10.2217/BMM.14.105?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

Biomark Med. 2015 Aug 28. [Epub ahead of print]

Simonsen AH, Kuiperij B, Ali El-Agnaf OM Engelborghs S, Herukka SK, Parnetti L, Rektorova I, Vanmechelen E, Kapaki E, Verbeek M, Mollenhauer B.

Abstract

The discovery of α-synuclein (α-syn) as a major component of Lewy bodies, neuropathological hallmark of Parkinson's disease (PD), dementia with Lewy bodies and of glial inclusions in multiple system atrophy initiated the investigation of α-syn as a biomarker in cerebrospinal fluid (CSF). Due to the involvement of the periphery in PD the quantification of α-syn in peripheral fluids such as serum, plasma and saliva has been investigated as well. We review how the development of multiple assays for the quantification of α-syn has yielded novel insights into the variety of α-syn species present in the different fluids; the optimal preanalytical conditions required for robust quantification and the potential clinical value of α-syn as biomarker. We also suggest future approaches to use of CSF α-syn in neurodegenerative diseases.