Tuesday, 31 March 2015

Detecting and monitoring the symptoms of Parkinson's disease using smartphones: A pilot study

Good to see some data on this finally... there's been a lot of media on the subject in the last few years. Feels like a step in the right direction and interested in the remote UPDRS assessments too...

Parkinsonism Relat Disord. 2015 Mar 7. pii: S1353-8020(15)00081-4. doi: 10.1016/j.parkreldis.2015.02.026. [Epub ahead of print]
Arora S, Venkataraman V, Hang A, Donohue S, Biglan KM, Dorsey ER, Little MA.

BACKGROUND:
Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking.

METHODS:
Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS.

RESULTS:
Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11-34) was 1.26 UPDRS points (SD 0.16).

CONCLUSION:

Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool.

The diagnostic value of minor salivary gland biopsy in clinically diagnosed patients with Parkinson's disease: comparison with DAT PET scans

Previously not thought to be useful in comparison to deep salivary gland biopsy, here's some indication that further exploration of minor salivary glands could be worthwhile...

Neurol Sci. 2015 Mar 28. [Epub ahead of print]
Gao L, Chen H, Li X, Li F, Ou-Yang Q, Feng T.


Abstract

To investigate the predictive value of minor salivary gland biopsy in clinically diagnosed early stage Parkinson's disease (PD) patients, and to provide more evidence of minor salivary gland biopsy as a pathological diagnostic biomarker of PD. Thirteen patients with early stage PD and 13 age-matched controls were recruited. Hoehn and Yahr stage and Unified Parkinson's disease Rating Scale Part III were employed to evaluate their severity of the disease. All the subjects underwent minor salivary gland biopsy and 11C-methyl-N-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) DAT-PET scan. Immunohistochemical staining for Lewy-type alpha-synucleinopathy using antibody against alpha-synuclein (α-Syn) was performed in the tissues obtained from minor salivary gland. Abnormal accumulation of α-Syn was found around the gland cells in 9 of the 13 patients with PD, but in none of the control subjects. The α-Syn immunoreactive structures were located in the periacinar space. Twelve clinically diagnosed PD patients showed asymmetrical and relatively severe reduction of 11C-CFT uptake in the posterior putamen compared with the control. The sensitivity, specificity, positive predictive value and negative predictive value of minor salivary gland biopsy were 75, 100, 100 and 25%, respectively, when compared with the DAT-PET imaging. Our results suggest that minor salivary gland biopsy does not hold high diagnostic accuracy as DAT-PET, but still has the potential to be a useful pathologic biomarker for PD, which is worth more investigations.

Monday, 30 March 2015

Nonmotor symptoms in healthy Ashkenazi Jewish carriers of the G2019S mutation in the LRRK2 gene

Mov Disord. 2015 Mar 21. doi: 10.1002/mds.26213. [Epub ahead of print]

Mirelman A, Alcalay RN, Saunders-Pullman R, Yasinovsky K, Thaler A, Gurevich T, Mejia-Santana H, Raymond D, Gana-Weisz M, Bar-Shira A, Ozelius L, Clark L, Orr-Urtreger A, Bressman S, Marder K, Giladi N; LRRK2 AJ consortium.


BACKGROUND:
The asymptomatic carriers of the Leucine rich repeat kinase 2 (LRRK2) G2019S mutation represent a population at risk for developing PD. The aim of this study was to assess differences in nonmotor symptoms between nonmanifesting carriers and noncarriers of the G2019S mutation.

METHODS:
Two hundred fifty-three subjects participated in this observational cross-sectional multicenter study. Standard questionnaires assessing anxiety, depression, cognition, smell, nonmotor symptoms, and rapid eye movement (REM) sleep behavior were administered. Analyses were adjusted for age, sex, family relations, education, and site.

RESULTS:
One hundred thirty-four carriers were identified. Carriers had higher nonmotor symptoms score on the Nonmotor symptoms (NMS) questionnaire (P = 0.02). These findings were amplified in carriers older than age 50 y, with higher nonmotor symptoms scores and trait anxiety scores (P < 0.03).

CONCLUSIONS:

In this cross-section study, carriers of the G2019S LRRK2 mutation endorsed subtle nonmotor symptoms. Whether these are early features of PD will require a longitudinal study.

Sunday, 29 March 2015

Obstructive sleep apnea and risk of Parkinson's disease: a population-based cohort study

Haven't yet seen the full paper, but important to adjust for BMI and medication, and perhaps to exclude those with other sleep disorders....

J Sleep Res. 2015 Mar 22. doi: 10.1111/jsr.12289. [Epub ahead of print]
Chen JC, Tsai TY, Li CY, Hwang JH.

Abstract

Sleep disorders could be associated with neurodegenerative diseases. This study aimed to determine the risk of Parkinson's disease in patients with obstructive sleep apnea. The incident cases of newly diagnosed obstructive sleep apnea were identified between 2000 and 2009 from the medical claims database of National Health Institute of Taiwan. The risk of Parkinson's disease onset at least 1 year after the diagnosis of obstructive sleep apnea was measured during and up to 11 years of period, compared to that of age- and gender-matched controls estimated in the same period. A total of 5864 patients with newly diagnosed obstructive sleep apnea and 23 269 subjects without obstructive sleep apnea were identified for data analysis. The study reported that the incidence of Parkinson's disease in the obstructive sleep apnea cohort was approximately two times higher than that in the control cohort (2.57 versus 1.32 per 1000 person-years), with an adjusted hazard ratio of 1.84. Furthermore, the risk of Parkinson's disease was particularly greater for the obstructive sleep apnea with insomnia subgroup (adjusted hazard ratio = 1.97, 95% confidence interval = 1.44-2.69) than for the control cohort. The sex-age-specific analysis further discovered that the most elevated risk of Parkinson's disease onset was noted in female obstructive sleep apnea patients aged 50-69 years (adjusted hazard ratio = 2.82). This population-based study indicated that patients with obstructive sleep apnea, especially those who suffered from insomnia, are at an increased risk of Parkinson's disease onset.

Friday, 27 March 2015

Prevalence and correlates of sleep disorders in Parkinson's disease: a polysomnographic study

RBD in 37.5% on PSG... more than I expected...

Arq Neuropsiquiatr. 2015 Mar;73(3):241-5. doi: 10.1590/0004-282X20140228.
Alatriste-Booth V, Rodríguez-Violante M, Camacho-Ordoñez A, Cervantes-Arriaga A.

Abstract

Objective Sleep disorders in Parkinson's disease are very common. Polysomnography (PSG) is considered the gold standard for diagnosis. The aim of the present study is to assess the prevalence of nocturnal sleep disorders diagnosed by polysomnography and to determine the associated clinical factors. Method A total of 120 patients with Parkinson's disease were included. All patients underwent a standardized overnight, single night polysomnography. Results Ninety-four (78.3%) patients had an abnormal PSG. Half of the patients fulfilled criteria for sleep apnea-hypopnea syndrome (SAHS); rapid eye movement behavior disorder (RBD) was present in 37.5%. Characteristics associated with SAHS were age (p = 0.049) and body mass index (p = 0.016). Regarding RBD, age (p < 0.001), left motor onset (p = 0.047) and levodopa equivalent dose (p = 0.002) were the main predictors. Conclusion SAHS and RBD were the most frequent sleep disorders. Higher levodopa equivalent dose and body mass index appear to be risk factors for RBD and SAHS, respectively.

Thursday, 26 March 2015

Parkinsonism following neuroleptic exposure: A double-hit hypothesis?

Even with a large effect size, association is not the same as causation, but the observation is interesting... my suspicion is a shared biological component...we co-author a paper on shared genetic risk for PD and schizophrenia last year. I for one would like to see more on the relationship between the two diseases.

Mov Disord. 2015 Mar 18. doi: 10.1002/mds.26209. [Epub ahead of print]
Erro R, Bhatia KP, Tinazzi M.


Abstract

Drug-induced parkinsonism is caused by an offending drug and should resolve after the causative agent has been withdrawn. However, in a number of patients, symptoms persist or may even worsen over time, suggesting the development of concomitant Parkinson's disease. The prevalence estimates of Parkinson's disease after neuroleptic exposure are unexpectedly high, suggesting a causal relationship. We critically review available literature in this regard, and some pathophysiological hypotheses that might explain such a relationship are suggested. Some patients may have an undetermined genetic susceptibility to parkinsonism. We speculate that the possible neurotoxic effect of neuroleptics exerted on a susceptible dopaminergic system would lead over the long-term to a self-fostering, progressive process. Knowledge gaps and future perspectives are discussed.

Wednesday, 25 March 2015

Identification of novel biomarkers for Parkinson's disease by metabolomic technologies

Good stuff... maybe the finding of lower caffeine metabolites and higher levodopa metabolites in PD patients is not particularly newsworthy BUT they do add credence to the other observations... definitely a field that will grow in the next few years and hopefully lead to robust biomarkers...


J Neurol Neurosurg Psychiatry. 2015 Mar 20. pii: jnnp-2014-309676. doi: 10.1136/jnnp-2014-309676. [Epub ahead of print]
Hatano T, Saiki S, Okuzumi A, Mohney RP, Hattori N.

OBJECTIVE:
The pathogenesis of Parkinson's disease (PD) involves complex interactions between environmental and genetic factors. Metabolomics can shed light on alterations in metabolic pathways in many diseases, including neurodegenerative diseases. In the present study, we attempted to elucidate the candidate metabolic pathway(s) associated with PD.

METHODS:
Serum samples were collected from 35 individuals with idiopathic PD without dementia and 15 healthy age-matched control participants without PD. This analysis used a combination of three independent platforms: ultrahigh-performance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) optimised for basic species, UPLC/MS/MS optimised for acidic species and gas chromatography/MS (GC/MS).

RESULTS:
The metabolomic profiles of PD were clearly different from normal controls. PD profiles had significantly lower levels of tryptophan, caffeine and its metabolites, bilirubin and ergothioneine, and significantly higher levels of levodopa metabolites and biliverdin than those of normal controls. Alterations in the bilirubin/biliverdin ratio and ergothioneine can indicate oxidative stress intensity and may suggest elevated oxidative stress and/or insufficient ability for scavenging free radicals, which could contribute to PD pathogenesis. Decreased serum tryptophan level is associated with psychiatric problems in PD. A decrease in serum caffeine levels is consistent with an inverse association of caffeine consumption with development of PD based on past epidemiological studies.

CONCLUSIONS:

Metabolomic analysis detected biomarkers associated with PD pathogenesis and disease progression. Since critical metabolic biomarkers need to be identified in PD, future studies should include assay validation and replication in independent cohorts.

Tuesday, 24 March 2015

Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: A multicenter study

Ann Neurol. 2015 Mar 13. doi: 10.1002/ana.24385. [Epub ahead of print]
Postuma RB, Iranzo A, Hogl B, Arnulf I, Ferini-Strambi L, Manni R, Miyamoto T, Oertel W, Dauvilliers Y, Ju YE, Puligheddu M, Sonka K, Pelletier A, Santamaria J, Frauscher B, Leu-Semenescu S, Zucconi M, Terzaghi M, Miyamoto M, Unger MM, Carlander B, Fantini ML, Montplaisir JY

OBJECTIVE:
To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD).

METHODS:
Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan-Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression.

RESULTS:
Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio [OR] = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6).

INTERPRETATION:

Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences.

Monday, 23 March 2015

Dorsolateral nigral hyperintensity on 3.0T susceptibility-weighted imaging in neurodegenerative Parkinsonism

An alternative to DaTSCAN??... will be interesting to learn when this appears in disease course

Mov Disord. 2015 Mar 15. doi: 10.1002/mds.26171. [Epub ahead of print]

Reiter E, Mueller C, Pinter B, Krismer F, Scherfler C, Esterhammer R, Kremser C, Schocke M, Wenning GK, Poewe W, Seppi K.


Absence of a hyperintense, ovoid area within the dorsolateral border of the otherwise hypointense pars compacta of the substantia nigra (referred to as dorsolateral nigral hyperintensity) on iron-sensitive high-field magnetic resonance imaging sequences seems to be a typical finding for patients with Parkinson's disease (PD). This study was undertaken to evaluate the diagnostic value of the dorsolateral nigral hyperintensity in a cohort of patients with neurodegenerative parkinsonism including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) as well as healthy controls using high-field susceptibility-weighted imaging (SWI) at 3.0 Tesla (T). Absence of dorsolateral nigral hyperintensity was assessed on visual inspection of anonymized 3.0T SWI scans in a case-control study including 148 patients with neurodegenerative parkinsonism (PD: n = 104; MSA: n = 22; PSP: n = 22) and 42 healthy controls. Dorsolateral nigral hyperintensity was absent unilaterally in all patients with MSA or PSP, in 83 of 90 patients with PD, but only in one of the healthy controls resulting in an overall correct classification of 95.2% in discriminating neurodegenerative parkinsonism from controls in the per-protocol analysis. Overall correct classification was 93.2% in the intent-to-diagnose analysis, including also SWI scans with poor quality (12.1% of all scans) for nigral evaluation. Visual assessment of dorsolateral nigral hyperintensity on high-field SWI scans may serve as a new simple diagnostic imaging marker for neurodegenerative parkinsonian disorders.

Sunday, 22 March 2015

Skin biopsy and I-123 MIBG scintigraphy findings in idiopathic Parkinson's disease and parkinsonism: A comparative study

Mov Disord. 2015 Mar 17. doi: 10.1002/mds.26189. [Epub ahead of print]
Giannoccaro MP, Donadio V, Incensi A, Pizza F, Cason E, Di Stasi V, Martinelli P, Scaglione C, Capellari S, Treglia G, Liguori R.

BACKGROUND:
123 I-meta-iodobenzylguanidine (123 I-MIBG) myocardial scintigraphy is considered reliable in differentiating idiopathic Parkinson's disease (IPD) from other parkinsonisms, but it is biased by pharmacological treatments. Skin biopsy is not influenced by therapy and has disclosed skin denervation in IPD. Our aims were to compare 123 I-MIBG scintigraphy and skin biopsy findings in IPD and parkinsonisms to (1) verify whether myocardial and skin denervations are linked; (2) explore the simultaneous extent of the autonomic dysfunction.

METHODS:
We studied 22 IPD and 11 parkinsonism patients by means of 123 I-MIBG scintigraphy and skin biopsies.

RESULTS:
In the IPD group, both 123 I-MIBG scintigraphy and skin biopsy results were abnormal in 91% of patients, showing concordance in 82% of cases. In parkinsonisms, results of both tests were normal in all patients.

CONCLUSION:

(1) Skin biopsy and 123 I-MIBG scintigraphy provide comparable results; (2) in IPD, autonomic dysfunctions are often simultaneously widespread at cardiac and skin branches.

Friday, 20 March 2015

Polygenic risk of Parkinson disease is correlated with disease age at onset

Nice work... realigning our thinking about the genetic component of PD... who would have believed this 10 years ago?

Ann Neurol. 2015 Mar 13. doi: 10.1002/ana.24335. [Epub ahead of print]
Escott-Price V; International Parkinson's Disease Genomics Consortium, Nalls MA, Morris HR, Lubbe S, Brice A, Gasser T, Heutink P, Wood NW, Hardy J, Singleton AB, Williams NM; IPDGC consortium members.

OBJECTIVE:
We have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset.

METHODS:
This study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset.

RESULTS:
Our polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome-wide association cohorts (minimum p = 3.76 × 10-6). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p = 0.00014).

INTERPRETATION:

This provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes.

Saturday, 14 March 2015

Re-emergent Tongue Tremor as the Presenting Symptom of Parkinson's Disease

Balkan Med J. 2015 Jan;32(1):127-8. doi: 10.5152/balkanmedj.2015.15008. Epub 2015 Jan 1.
Delil Ş, Bölükbaşı F, Yeni N, Kızıltan G.

BACKGROUND:
The most common symptom of Parkinson's disease is the unilateral, typically resting tremor in body parts, most commonly in the upper extremities. However, this finding can spread to the other parts of the body like lips, chin, jaw and tongue during the course of the disease. Nevertheless, we have not come across any Parkinson's disease case presenting with tongue tremor in the literature.

CASE REPORT:
Here, we present a 58 year-old man with Parkinson's disease presenting with tongue tremor, his striking response to the levodopa test and his follow-up data.

CONCLUSION:

The topography of motor symptoms at onset in Parkinson's disease is presumably determined by the severity of the Lewy body neuronal degeneration in distinct parts of the substantia nigra. Therefore, patterns of somatic symptom progression in Parkinson's disease indicate that involvement of the cranial structures always follows the development of symptoms in the extremities. However, in our case, cranial structures seem to precede the involvement of extremity-related areas.

Post-traumatic neurodegeneration and chronic traumatic encephalopathy

Mol Cell Neurosci. 2015 Mar 7. pii: S1044-7431(15)00036-6. doi: 10.1016/j.mcn.2015.03.007. [Epub ahead of print]
Daneshvar DH, Goldstein LE, Kiernan PT, Stein TD, McKee AC.


Traumatic brain injury (TBI) is a leading cause of mortality and morbidity around the world. Concussive and subconcussive forms of closed-head injury due to impact or blast neurotrauma represent the most common types of TBI in civilian and military settings. It is becoming increasingly evident that TBI can lead to persistent, long-term debilitating effects, and in some cases, progressive neurodegeneration and chronic traumatic encephalopathy (CTE). The epidemiological literature suggests that a single moderate-to-severe TBI may be associated with accelerated neurodegeneration and increased risk of Alzheimer's disease, Parkinson's disease, or motor neuron disease. However, the pathologic phenotype of these post-traumatic neurodegenerations is largely unknown and there may be pathobiological differences between post-traumatic disease and the corresponding sporadic disorder. By contrast, the pathology of CTE is increasingly well known and is characterized by a distinctive pattern of progressive brain atrophy and accumulation of hyperphosphorylated tau neurofibrillary and glial tangles, dystrophic neurites, 43 kDa TAR DNA-binding protein (TDP-43) neuronal and glial aggregates, microvasculopathy, myelinated axonopathy, neuroinflammation, and white matter degeneration. Clinically, CTE is associated with behavioral changes, executive dysfunction, memory deficits, and cognitive impairments that begin insidiously and most often progress slowly over decades. Although research on the long-term effects of TBI is advancing quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. Critical knowledge gaps include elucidation of pathogenic mechanisms, identification of genetic risk factors, and clarification of relevant variables-including age at exposure to trauma, history of prior and subsequent head trauma, substance use, gender, stress, and comorbidities-all of which may contribute to risk profiles and the development of post-traumatic neurodegeneration and CTE.

Thursday, 12 March 2015

Epidemiology of mild traumatic brain injury and neurodegenerative disease

Mol Cell Neurosci. 2015 Mar 4. pii: S1044-7431(15)00030-5. doi: 10.1016/j.mcn.2015.03.001. [Epub ahead of print]
Gardner RC, Yaffe K.

Abstract

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repetitive MTBI and repetitive sub-concussive head trauma has been linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE). CTE is a unique neurodegenerative tauopathy first described in boxers but more recently described in a variety of contact sport athletes, military veterans, and civilians exposed to repetitive MTBI. Studies of repetitive MTBI and CTE have been limited by referral bias, lack of consensus clinical criteria for CTE, challenges of quantifying MTBI exposure, and potential for confounding. The prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear. This review will summarize the current literature regarding the epidemiology of MTBI, post-TBI dementia and Parkinson's disease, and CTE while highlighting methodological challenges and critical future directions of research in this field.

Wednesday, 11 March 2015

Transcranial magnetic stimulation follow-up study in early Parkinson's disease: A decline in compensation with disease progression?

Mov Disord. 2015 Mar 5. doi: 10.1002/mds.26167. [Epub ahead of print]
Kojovic M, Kassavetis P, Bologna M, Pareés I, Rubio-Agusti I, Beraredelli A, Edwards MJ, Rothwell JC, Bhatia KP.

Abstract

A number of neurophysiological abnormalities have been described in patients with Parkinson's disease, but very few longitudinal studies of how these change with disease progression have been reported. We describe measures of motor cortex inhibition and plasticity at 6 and 12 mo in 12 patients that we previously reported at initial diagnosis. Given the well-known interindividual variation in these measures, we were particularly concerned with the within-subject changes over time. Patients were assessed clinically, and transcranial magnetic stimulation (TMS) was used to measure motor cortical excitability, inhibition (short interval intracortical inhibition, cortical silent period), and plasticity (response to excitatory paired associative stimulation protocol) in both hemispheres. All measurements were performed 6 mo and 12 mo after the baseline experiments. Asymmetry in clinical motor symptoms was reflected in asymmetry of plasticity and inhibition. In the group as a whole, little change was seen in any of the parameters over 12 mo. However, analysis of within-individual data showed clear correlations between changes in clinical asymmetry and asymmetry of response to paired associative stimulation protocol and cortical silent period. Longitudinal changes in cortical silent period and response to paired associative stimulation protocol in Parkinson's disease reflect dynamic effects on motor cortex that are related to progression of motor signs. They are useful objective markers of early disease progression that could be used to detect effects of disease-modifying therapies. The decline in heightened plasticity that was present at disease onset may reflect failure of compensatory mechanisms that maintained function in the preclinical state.

Tuesday, 10 March 2015

Cognitive performance and neuropsychiatric symptoms in early, untreated Parkinson's disease

From PPMI...

Mov Disord. 2015 Mar 4. doi: 10.1002/mds.26170. [Epub ahead of print]
Weintraub D, Simuni T, Caspell-Garcia C, Coffey C, Lasch S, Siderowf A, Aarsland D, Barone P, Burn D, Chahine LM, Eberling J, Espay AJ, Foster ED, Leverenz JB, Litvan I, Richard I, Troyer MD, Hawkins KA; and the Parkinson's Progression Markers Initiative.

Abstract

This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson's disease (PD). Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS. Parkinson's Progression Markers Initiative (PPMI) is a multi-site study of early, untreated PD patients and healthy controls (HCs), the latter with normal cognition. At baseline, participants were assessed with a neuropsychological battery and for symptoms of depression, anxiety, impulse control disorders (ICDs), psychosis, and apathy. Baseline data of 423 PD patients and 196 HCs yielded no between-group differences in demographic characteristics. Twenty-two percent of PD patients met the PD-recommended screening cutoff for CI on the Montral Cognitive Assessment (MoCA), but only 9% met detailed neuropsychological testing criteria for mild cognitive impairment (MCI)-level impairment. The PD patients were more depressed than HCs (P < 0.001), with twice as many (14% vs. 7%) meeting criteria for clinically significant depressive symptoms. The PD patients also experienced more anxiety (P < 0.001) and apathy (P < 0.001) than HCs. Psychosis was uncommon in PD (3%), and no between-group difference was seen in ICD symptoms (P = 0.51). Approximately 10% of PD patients in the early, untreated disease state met traditional criteria of CI, which is a lower frequency compared with previous studies. Multiple dopaminergic-dependent NPS are also more common in these patients compared with the general population, but others associated with dopamine replacement therapy are not or are rare. Future analyses of this cohort will examine biological predictors and the course of CI and NPS.

Quality of sleep in young onset Parkinson's disease: Any difference from older onset Parkinson's disease

Parkinsonism Relat Disord. 2015 Feb 18. pii: S1353-8020(15)00062-0. doi: 10.1016/j.parkreldis.2015.02.007. [Epub ahead of print]
Mahale R, Yadav R, Pal PK.

BACKGROUND:
Sleep disorders occur commonly in Parkinson's disease and are often under-recognized and under treated in clinical practice.

OBJECTIVES:
To determine the quality of sleep in patients with Young onset Parkinson's disease (YOPD) and to note whether there is any difference in quality of sleep from those patients with older onset Parkinson's disease (OOPD).

METHODS:
One hundred and fifty six patients with Parkinson's disease (YOPD-51, OOPD-105) were clinically examined and quality of sleep was determined using Pittsburgh sleep quality index (PSQI), Parkinson's disease Sleep Scale (PDSS) and Epworth Sleep Scale (ESS). Other scales included Unified Parkinson's Disease Rating Scale -part III (UPDRS-III), Hoehn & Yahr Stage, Mini Mental Status Examination, Hamilton anxiety rating scale and Hamilton depression rating scale.

RESULTS:
The frequency of insomnia was higher in OOPD (55.2%) as compared to YOPD (27.5%) group (p = 0.001). The frequency of nightmares was lower in YOPD (7.8%) when compared to OOPD (24.8%) group (p = 0.012). The mean hours of actual sleep per night were higher in YOPD patients. Global PSQI score was better in YOPD indicating good overall sleep quality in YOPD patients. The total ESS score was significantly lower in YOPD (p = 0.019). The total PDSS score was significantly better in YOPD patients (p = 0.018).

CONCLUSIONS:

Patients with YOPD had an overall better quality of sleep with lesser incidence of insomnia, nightmares, daytime sleepiness and restlessness during sleep.

Monday, 9 March 2015

Increased bilirubin levels in de novo Parkinson's disease

Eur J Neurol. 2015 Mar 5. doi: 10.1111/ene.12688. [Epub ahead of print]
Moccia M, Picillo M, Erro R, Longo K, Amboni M, Santangelo G, Palladino R, Allocca R, Caporale O, Triassi M, Pellecchia MT, Barone P, Vitale C.

BACKGROUND AND PURPOSE:
Oxidative stress is a central pathogenic mechanism of Parkinson's disease (PD), and the heme oxygenase (HO) bilirubin pathway is one of the main mammalian antioxidative defences. Indeed, there is growing evidence of HO-bilirubin upregulation from early phases of PD. Our aim was to investigate bilirubin as a possible biomarker of PD diagnosis and progression.

METHODS:
A cross-sectional case-control study was performed to evaluate differences in bilirubin levels between newly diagnosed, drug-naïve PD subjects and controls. Afterwards, PD subjects were included in a 2-year longitudinal study to evaluate disease progression in relation to baseline bilirubin levels.

RESULTS:
Seventy-five de novo PD subjects were selected and matched with 75 controls by propensity score. Analysis of variance showed higher bilirubin levels in PD patients compared with controls (P < 0.001). Linear regression analysis failed to show a relationship between bilirubin and Unified Parkinson's Disease Rating Scale (UPDRS) part III (P = 0.283) at baseline evaluation. At 2-year follow-up, indirect relationships between bilirubin levels and UPDRS part III (P = 0.028) and between bilirubin levels and levodopa-equivalent daily dosage (P = 0.012) were found.

CONCLUSIONS:

Parkinson's disease subjects showed higher levels of bilirubin compared with controls. Bilirubin increase might be due to HO overexpression as a compensatory response to oxidative stress occurring from early stages of PD.

Measuring the burden and mortality of hospitalisation in Parkinson's disease: A cross-sectional analysis of the English Hospital Episodes Statistics database 2009-2013

Confirms what one suspects and the scenarios are all too familiar... interventions are essential!!

Parkinsonism Relat Disord. 2015 Feb 17. pii: S1353-8020(15)00052-8. doi: 10.1016/j.parkreldis.2015.01.017. [Epub ahead of print]
Low V, Ben-Shlomo Y, Coward E, Fletcher S, Walker R, Clarke CE.

BACKGROUND:
Patients with Parkinson's disease have higher hospital admission rates than the general population. We examined the reasons for admission, length of stay, costs, and in-hospital mortality in a national sample of Parkinson's disease patients.

METHODS:
We used hospital admission data from the English Hospital Episodes Statistics database (2009-2013). Patients with Parkinson's disease or Parkinson's disease dementia and aged over 35 years were compared to all other admissions, excluding the above, with the same age criteria. We examined reasons for admissions (ICD-10), length of stay and in-hospital mortality. We used indirect standardisation and Poisson modelling to derive proportional ratios adjusting for age group and sex.

RESULTS:
There were 324,055 Parkinson's disease admissions in 182,859 patients over 4 years which included 232,905 non-elective admissions (72%). This resulted in expenditure of £907 million (£777 million for non-elective admissions). The main reasons for admission were pneumonia (13.5%), motor decline (9.4%), urinary tract infection (9.2%), and hip fractures (4.3%). These conditions occurred 1.5 to 2.6 times more frequently in patients than controls. Patients with Parkinson's disease were almost twice as likely to stay in hospital for more than 3 months (ratio 1.90, 95% CI 1.83, 1.97) and even more likely die in hospital (ratio 2.46, 95% CI 2.42, 2.49).

CONCLUSIONS:

Parkinson's disease patients in England have higher rates of emergency admissions with longer hospital stays, higher costs and in-hospital mortality. Urgent attention should be given to developing cost-effective interventions to reduce the burden of hospitalisation for patients, carers and healthcare systems.

Sunday, 8 March 2015

Head trauma in sport and neurodegenerative disease: an issue whose time has come?

Timely given the post 3 days ago....

Neurobiol Aging. 2015 Mar;36(3):1383-1389. doi: 10.1016/j.neurobiolaging.2014.12.024. Epub 2014 Dec 29.
Pearce N, Gallo V, McElvenny D.


A number of small studies and anecdotal reports have been suggested that sports involving repeated head trauma may have long-term risks of neurodegenerative disease. There are now plausible mechanisms for these effects, and a recognition that these problems do not just occur in former boxers, but in a variety of sports involving repeated concussions, and possibly also in sports in which low-level head trauma is common. These neurodegenerative effects potentially include increased risks of impaired cognitive function and dementia, Parkinson's disease, and amyotrophic lateral sclerosis. Many would argue for taking a precautionary approach and immediately banning or restricting sports such as boxing. However, there are important public health issues in terms of how wide the net should be cast in terms of other sports, and what remedial measures could be taken? This in turn requires a major research effort involving both clinical and basic research to understand the underlying mechanisms, leading from head trauma to neurodegenerative disease and epidemiologic studies to assess the long-term consequences.



Saturday, 7 March 2015

Characterization of gastrointestinal disorders in patients with parkinsonian syndromes

Parkinsonism Relat Disord. 2015 Feb 14. pii: S1353-8020(15)00058-9. doi: 10.1016/j.parkreldis.2015.02.005. [Epub ahead of print]
Park H, Lee JY, Shin CM, Kim JM, Kim TJ, Kim JW.

OBJECTIVES:
This study was aimed to investigate gastrointestinal (GI) dysfunction in patients with Parkinson's disease (PD) compared with those in patients with other parkinsonian disorders, and to characterize parkinsonian motor and non-motor correlates for GI dysfunction.

METHODS:
Consecutive patients with PD, atypical parkinsonism (P-plus) and vascular parkinsonism (VP) were enrolled in this multicenter systematic survey. Data for weight loss, appetite loss, sialorrhea, dysphagia, gastroesophageal reflux disease (GERD) and constipation were simultaneously collected using symptom-specific, structured questionnaires. For the PD group, information for onset age, PD duration, anti-parkinsonian drug dosages, unified PD rating scale, and Hoehn & Yahr stage were collected at the time of the interview.

RESULTS:
Enrolled in the study were 329 PD, 82 P-plus, and 62 VP patients. GI symptom frequencies were similar in PD and other parkinsonian groups. Among the PD patients, constipation was the most common symptom, followed by appetite loss, weight loss, dysphagia, sialorrhea, and GERD (64.9%, 45.4%, 35.7%, 19.4%, 15.0%, and 9.6%, respectively). Dysphagia, sialorrhea, and constipation became more frequent with more advanced PD stages. Cognition, sleep and mood disturbances were significantly associated with weight loss, appetite loss, and dysphagia, whereas bradykinesia, axial and postural instability with gait disturbance were associated with dysphagia.

CONCLUSIONS:

GI disturbance is common in patients with non-PD parkinsonism as well as in those with PD. GI symptoms correlated with distinct parkinsonian motor and nonmotor features in PD. Further studies are warranted to reveal the pathophysiological mechanisms and prognostic features of GI disturbances in parkinsonian disorders.

Friday, 6 March 2015

Traumatic brain injury in later life increases risk for Parkinson's disease

Thorough work... and the magnitude of the effect feels correct. That there is a dose effect provides even stronger evidence...

Ann Neurol. 2015 Feb 27. doi: 10.1002/ana.24396. [Epub ahead of print]
Gardner RC, Burke JF, Nettiksimmons J, Goldman S, Tanner CM, Yaffe K.

Abstract

Objective: Traumatic brain injury (TBI) is thought to be a risk factor for Parkinson's disease (PD) but results are conflicting. Many studies do not account for confounding or reverse-causation. We sought to address these concerns by quantifying risk of PD after TBI compared to non-TBI trauma (NTT, defined as fractures). Methods: Using inpatient/emergency department (ED) ICD-9 code data for California hospitals from 2005-2006, we identified patients age ≥55 with TBI (n=52,393) or NTT (n=113,406) and without baseline PD or dementia who survived hospitalization. Using Kaplan-Meier estimates and Cox proportional hazards models (adjusted for age, sex, race/ethnicity, income, comorbidities, healthcare use, trauma severity), we estimated risk of PD after TBI during follow-up ending in 2011. We also assessed interaction with mechanism of injury (fall vs. non-fall) and effect of TBI-severity (mild vs. moderate/severe) and TBI-frequency (1 TBI vs. >1 TBI). Results: TBI patients were significantly more likely to be diagnosed with PD compared to NTT patients (1.7% versus 1.1%, p<0.001, adjusted hazard ratio (HR) 1.44, 95% CI 1.31-1.58). Risk of PD was similar for TBI sustained via falls versus non-falls (interaction p=0.6). Assessment by TBI-severity (mild TBI HR 1.24, 95% CI 1.04-1.48; moderate/severe TBI HR 1.50, 95% CI 1.35-1.66) and TBI-frequency (1 TBI HR 1.45, 95% CI 1.30-1.60; >1 TBI HR 1.87, 95% CI 1.58-2.21) revealed a dose-response. Interpretation: Among patients age ≥55 presenting to inpatient/ED settings with trauma, TBI is associated with a 44% increased risk of developing PD over 5-7 years that is unlikely due to confounding or reverse-causation.

Thursday, 5 March 2015

Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain

It's hard not to be excited by this... great stuff and feels like a step in the right direction


Brain. 2015 Mar 1. pii: awv040. [Epub ahead of print]
Roberts RF, Wade-Martins R, Alegre-Abarrategui J.

Abstract

Oligomeric forms of alpha-synuclein are emerging as key mediators of pathogenesis in Parkinson's disease. Our understanding of the exact contribution of alpha-synuclein oligomers to disease is limited by the lack of a technique for their specific detection. We describe a novel method, the alpha-synuclein proximity ligation assay, which specifically recognizes alpha-synuclein oligomers. In a blinded study with post-mortem brain tissue from patients with Parkinson's disease (n = 8, age range 73-92 years, four males and four females) and age- and sex-matched controls (n = 8), we show that the alpha-synuclein proximity ligation assay reveals previously unrecognized pathology in the form of extensive diffuse deposition of alpha-synuclein oligomers. These oligomers are often localized, in the absence of Lewy bodies, to neuroanatomical regions mildly affected in Parkinson's disease. Diffuse alpha-synuclein proximity ligation assay signal is significantly more abundant in patients compared to controls in regions including the cingulate cortex (1.6-fold increase) and the reticular formation of the medulla (6.5-fold increase). In addition, the alpha-synuclein proximity ligation assay labels very early perikaryal aggregates in morphologically intact neurons that may precede the development of classical Parkinson's disease lesions, such as pale bodies or Lewy bodies. Furthermore, the alpha-synuclein proximity ligation assay preferentially detects early-stage, loosely compacted lesions such as pale bodies in patient tissue, whereas Lewy bodies, considered heavily compacted late lesions are only very exceptionally stained. The alpha-synuclein proximity ligation assay preferentially labels alpha-synuclein oligomers produced in vitro compared to monomers and fibrils, while stained oligomers in human brain display a distinct intermediate proteinase K resistance, suggesting the detection of a conformer that is different from both physiological, presynaptic alpha-synuclein (proteinase K-sensitive) and highly aggregated alpha-synuclein within Lewy bodies (proteinase K-resistant). These disease-associated conformers represent previously undetected Parkinson's disease pathology uncovered by the alpha-synuclein proximity ligation assay.

Sunday, 1 March 2015

Neurodegenerative diseases and therapeutic strategies using iron chelators

J Trace Elem Med Biol. 2015 Jan 22. pii: S0946-672X(15)00006-1. doi: 10.1016/j.jtemb.2014.12.012. [Epub ahead of print]
Ward RJ, Dexter DT, Crichton RR.

Abstract

This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.

The BRAIN test: a keyboard-tapping test to assess disability and clinical features of multiple sclerosis

Okay. Not strictly Parkinson's research but the BRAIN tap test comes from the PREDICT-PD team. Here we show that the BRAIN test can be u...