Tuesday, 30 September 2014

Parkinson's disease and age: The obvious but largely unexplored link

Are age-related changes in the way proteins are handled the key to everything??

Exp Gerontol. 2014 Sep 25. pii: S0531-5565(14)00271-X. doi: 10.1016/j.exger.2014.09.014. [Epub ahead of print]
Abdullah R, Basak I, Patil K, Alves G, Larsen JP, Møller SG.


Parkinson's disease is a chronic, progressive neurodegenerative disorder with increased prevalence in the aging population. It is estimated that approximately 1.5 million individuals in the US alone suffer from Parkinson's disease and with the extension of life expectancy this number is expected to rise dramatically within the next twenty-five years. The majority of Parkinson's disease cases are sporadic. But mutations in genes such as α-synuclein, Parkin, PINK1, DJ-1 and LRRK2, have been conclusively associated with both early- and late-onset of the disease. Although the genetics of Parkinson's disease is starting to become unraveled, the interplay between genetic and environmental factors is largely unknown as are the underlying mechanisms that trigger the disease as the brain ages. The risk of Parkinson's disease increases dramatically in individuals over the age of 60 and it is estimated that more than 1% of all seniors have some form of the condition. In this review, we will highlight some of the central proteins associated with Parkinson's disease and how they may be linked to processes and factors associated with age.

Monday, 29 September 2014

Parkinson's disease: chameleons and mimics

Pract Neurol. 2014 Sep 24. pii: practneurol-2014-000849. doi: 10.1136/practneurol-2014-000849. [Epub ahead of print]
Ali K, Morris HR.

Parkinson's disease (PD) is a common neurodegenerative condition that usually presents with symptoms related to asymmetric bradykinesia, resting tremor, rigidity and postural instability. Making the correct diagnosis can be challenging as many conditions-including tremor, gait and atypical parkinsonian disorders-can mimic PD. PD can present with unanticipated motor and non-motor symptoms, and so can masquerade as a number of rheumatological, neurological, sleep and mood disorders. Careful clinical assessment, informed by well-validated diagnostic criteria, is important in the initial diagnostic formulation. In uncertain or ambiguous cases, follow-up with monitoring of the treatment response usually gives the correct diagnosis, as validated in postmortem follow-up studies. 'Premotor' PD-a range of non-motor symptoms, particularly sleep disorders and constipation, which can occur up to 20 years before PD motor onset-is common. The presence of non-motor features in early disease sometimes supports the diagnosis of PD. Here we give an overview of the diagnosis of PD and its most important chameleons and mimics, and review the recent advances in structural and functional imaging in parkinsonism.

Sunday, 28 September 2014

Glucocerebrosidase mutations in primary parkinsonism

Parkinsonism Relat Disord. 2014 Sep 9. pii: S1353-8020(14)00325-3. doi: 10.1016/j.parkreldis.2014.09.003. [Epub ahead of print]
Asselta R, Rimoldi V, Siri C, Cilia R, Guella I, Tesei S, Soldà G, Pezzoli G, Duga S, Goldwurm S.

Mutations in the lysosomal glucocerebrosidase (GBA) gene increase the risk of Parkinson's Disease (PD). We determined the frequency and relative risk of major GBA mutations in a large series of Italian patients with primary parkinsonism.

We studied 2766 unrelated consecutive patients with clinical diagnosis of primary degenerative parkinsonism (including 2350 PD), and 1111 controls. The entire cohort was screened for mutations in GBA exons 9 and 10, covering approximately 70% of mutations, including the two most frequent defects, p.N370S and p.L444P.

Four known mutations were identified in heterozygous state: 3 missense mutations (p.N370S, p.L444P, and p.D443N), and the splicing mutation IVS10+1G>T, which results in the in-frame exon-10 skipping. Molecular characterization of 2 additional rare variants, potentially interfering with splicing, suggested a neutral effect. GBA mutations were more frequent in PD (4.5%, RR = 7.2, CI = 3.3-15.3) and in Dementia with Lewy Bodies (DLB) (13.8%, RR = 21.9, CI = 6.8-70.7) than in controls (0.63%). but not in the other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP, 2%), and Corticobasal Degeneration (CBD, 0%). Considering only the PD group, GBA-carriers were younger at onset (52 ± 10 vs. 57 ± 10 years, P < 0.0001) and were more likely to have a positive family history of PD (34% vs. 20%, P < 0.001).


GBA dysfunction is relevant for synucleinopathies, such as PD and DLB, except for MSA, in which pathology involves oligodendrocytes, and the tauopathies PSP and CBD. The risk of developing DLB is three-fold higher than PD, suggesting a more aggressive phenotype.

Saturday, 27 September 2014

Parkinson's disease: no milk today?

Front Neurol. 2014 Sep 5;5:172. doi: 10.3389/fneur.2014.00172. eCollection 2014.
Kistner A, Krack P.


Several prospective epidemiological studies on large cohorts have consistently reported an association between milk intake and a higher incidence of Parkinson's disease (PD). Pesticide contamination of milk and milk's urate-lowering effects have been put forward as risk factors to explain epidemiological data. This has led to considerable uncertainty among physicians and avoidance of dairy products by PD patients. However, neither factor stands up to the rational and detailed examination of the literature carried out in this mini-review. We suggest that changes in eating behavior related to pre-motor PD are an alternative potential explanation of correlations observed between milk intake and PD occurrence. Despite clear-cut associations between milk intake and PD incidence, there is no rational explanation for milk being a risk factor for PD. Based on current knowledge, limiting the consumption of dairy products does not seem to be a reasonable strategy in the prevention of the development and progression of PD.

Friday, 26 September 2014

Does Anxiety Cause Freezing of Gait in Parkinson's Disease?

Interesting observation... certainly freezing provokes anxiety but I hadn't thought of it occurring in reverse order...

PLoS One. 2014 Sep 24;9(9):e106561. doi: 10.1371/journal.pone.0106561. eCollection 2014.
Ehgoetz Martens KA, Ellard CG, Almeida QJ.


Individuals with Parkinson's disease (PD) commonly experience freezing of gait under time constraints, in narrow spaces, and in the dark. One commonality between these different situations is that they may all provoke anxiety, yet anxiety has never been directly examined as a cause of FOG. In this study, virtual reality was used to induce anxiety and evaluate whether it directly causes FOG. Fourteen patients with PD and freezing of gait (Freezers) and 17 PD without freezing of gait (Non-Freezers) were instructed to walk in two virtual environments: (i) across a plank that was located on the ground (LOW), (ii) across a plank above a deep pit (HIGH). Multiple synchronized motion capture cameras updated participants' movement through the virtual environment in real-time, while their gait was recorded. Anxiety levels were evaluated after each trial using self-assessment manikins. Freezers performed the experiment on two separate occasions (in their ON and OFF state). Freezers reported higher levels of anxiety compared to Non-Freezers (p<0.001) and all patients reported greater levels of anxiety when walking across the HIGH plank compared to the LOW (p<0.001). Freezers experienced significantly more freezing of gait episodes (p = 0.013) and spent a significantly greater percentage of each trial frozen (p = 0.005) when crossing the HIGH plank. This finding was even more pronounced when comparing Freezers in their OFF state. Freezers also had greater step length variability in the HIGH compared to the LOW condition, while the step length variability in Non-Freezers did not change. In conclusion, this was the first study to directly compare freezing of gait in anxious and non-anxious situations. These results present strong evidence that anxiety is an important mechanism underlying freezing of gait and supports the notion that the limbic system may have a profound contribution to freezing in PD.

Thursday, 25 September 2014

Assessment and management of fracture risk in patients with Parkinson's disease

Not relevant to prediction I know but still an interest of mine. Some useful information here and I'll try to ignore that they didn't mention an excellent systematic review published this year (http://jnnp.bmj.com/content/85/10/1159) !!

Age Ageing. 2014 Sep 18. pii: afu122. [Epub ahead of print]
Lyell V, Henderson E, Devine M, Gregson C.


Parkinson's disease (PD) is associated with substantially increased fracture risk, particularly hip fracture, which can occur relatively early in the course of PD. Despite this, current national clinical guidelines for PD fail to adequately address fracture risk assessment or the management of bone health. We appraise the evidence supporting bone health management in PD and propose a PD-specific algorithm for the fracture risk assessment and the management of bone health in patients with PD and related movement disorders. The algorithm considers (i) calcium and vitamin D replacement and maintenance, (ii) quantification of prior falls and fractures, (iii) calculation of 10-year major osteoporotic and hip fracture risks using Qfracture, (iv) application of fracture risk thresholds, which if fracture risk is high (v) prompts anti-resorptive treatment, with or without dual X-ray absorptiometry, and if low (vi) prompts re-assessment with FRAX and application of National Osteoporosis Guidelines Group (NOGG) guidance. A range of anti-resorptive agents are now available to treat osteoporosis; we review their use from the specific perspective of a clinician managing a patient population with PD. In conclusion, our current evidence base supports updating of guidelines globally concerning the management of PD, which presently fail to adequately address bone health.

Wednesday, 24 September 2014

The use of botulinum toxin in the treatment of sialorrhea in parkinsonian disorders

Useful because it avoids the cognitive side effects that many medications cause which targeting the same symptom. Beware retrospective data as opposed to gold standard RCT data...

Neurol Sci. 2014 Sep 20. [Epub ahead of print]
Gómez-Caravaca MT, Cáceres-Redondo MT, Huertas-Fernández I, Vargas-González L, Carrillo F, Carballo M, Mir P.


Drooling is a common symptom in parkinsonian disorders. Our aim was to assess the safety and effect of botulinum toxin when applied to parotid glands without ultrasound guidance for sialorrhea in parkinsonian disorders in a retrospective study with a long-term follow-up. We evaluated 53 patients (64.2 % male and 35.8 % female) with a mean age of 70.18 ± 9.25 years who were treated in our centre between 2007 and 2013. We analysed the mean dose, latency, effect duration, response and adverse effects of treating sialorrhea by injecting botulinum toxin type A (Botox) into the parotid glands without ultrasound guidance. A total of 41 patients with Parkinson's disease, 6 with progressive supranuclear palsy, 4 with multiple system atrophy and 2 with corticobasal degeneration were included. The mean duration of the disease at onset was 10.51 ± 6.81 years and the mean sialorrhea duration was 1.99 ± 1.55 years. The initial dose used for each parotid gland was 14.53 ± 3.95 units of Botox, with a mean dose of 22.17 ± 8.76 units. There was an improvement after treatment in 65.22 % of patients with an average score of 6.85 ± 1.58 points on a scale from 0 to 10. The duration of the treatment effect was 4.38 ± 2.11 months, with a latency period of 10.06 ± 9.63 days. Adverse effects were mild and infrequent. Botulinum toxin is a safe and effective therapy for the treatment of sialorrhea in parkinsonian disorders and there is no requirement for ultrasound guidance. It has a rapid onset and lasting effect without requiring a high dosage.

Tuesday, 23 September 2014

Effects of cognitive training in Parkinson's disease: A randomized controlled trial

Good short term effects shown here...

Parkinsonism Relat Disord. 2014 Sep 16. pii: S1353-8020(14)00321-6. doi: 10.1016/j.parkreldis.2014.08.023. [Epub ahead of print]
Petrelli A, Kaesberg S, Barbe MT, Timmermann L, Fink GR, Kessler J, Kalbe E.

In Parkinson's Disease (PD), cognitive dysfunctions which can reduce patients' quality of life occur frequently. Data on non-pharmacological intervention effects on cognitive functions in patients with PD are rare. The aim of this study was to examine the effects of different cognitive group trainings (structured vs. unstructured) on cognition, depression, and quality of life in non-demented PD patients.

In this randomized controlled trial, 65 non-demented patients with PD according to UK Brain Bank criteria (Hoehn & Yahr I-III) were allocated to one of two cognitive cognitive multi-component treatments ("NEUROvitalis", a structured training, or the unstructured training "Mentally fit" with randomly assembled cognitive tasks, each including 12 group-sessions à 90 min over 6 weeks) or a waiting list control group (CG). A neuropsychological test battery was performed before and after the training.

Compared to the CG, patients from the "NEUROvitalis" group improved in short-term memory (word list learning "Memo": p < .01) and working memory (digit span from "DemTect": p < .05), whereas depression scores where reduced in the "Mentally fit" group (Becks Depression Inventory-II: p < .05). The "NEUROvitalis" group improved significantly more in working memory than the "Mentally fit" group (DemTect: p < .05).


Cognitive and affective functions can be improved by cognitive trainings in PD patients. Specific effects (e.g. on memory and working memory versus depression) seem to be dependent on the type of training. Further research is needed to define long-term effects and the efficacy in PD patients with different extent of cognitive and neuropsychiatric symptoms.

Monday, 22 September 2014

R2* mapping for brain iron: Associations with cognition in normal aging


Ghadery C, Pirpamer L, Hofer E, et al

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer´s disease. MR-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged and older adults from the Austrian Stroke Prevention Family Study (ASPS-Fam). MR imaging and R2* mapping in the basal ganglia and neocortex was done at 3T. Comprehensive neuropsychological testing assessed memory, executive function and psychomotor speed.
We found the highest iron concentration in the globus pallidus, and pallidal as well as putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load-dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance.

We conclude that higher R2*-determined iron in the basal ganglia correlate with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined.

Sunday, 21 September 2014

The role of iron in brain ageing and neurodegenerative disorders

Lancet Neurol. 2014 Oct;13(10):1045-1060. doi: 10.1016/S1474-4422(14)70117-6.
Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L.


In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood-brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.

Saturday, 20 September 2014

Midlife migraine and late-life parkinsonism: AGES-Reykjavik Study

Neurology. 2014 Sep 17. pii: 10.1212/WNL.0000000000000840. [Epub ahead of print]
Scher AI, Ross GW, Sigurdsson S, Garcia M, Gudmundsson LS, Sveinbjörnsdóttir S, Wagner AK, Gudnason V, Launer LJ.

In the present study, we tested the hypothesis that having migraine in middle age is related to late-life parkinsonism and a related disorder, restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED).

The AGES-Reykjavik cohort (born 1907-1935) has been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of Parkinson disease (PD), family history of PD, and RLS/WED.

Subjects with midlife migraine, particularly migraine with aura (MA), were in later life more likely than others to report parkinsonian symptoms (odds ratio [OR]MA = 3.6 [95% CI 2.7-4.8]) and diagnosed PD (ORMA = 2.5 [95% CI 1.2-5.2]). Women with MA were more likely than others to have a parent (ORMA = 2.26 [95% CI 1.3-4.0]) or sibling (ORMA = 1.78 [95% CI 1.1-2.9]) with PD. Late-life RLS/WED was increased for headache generally. Associations were independent of cardiovascular disease and MRI-evident presumed ischemic lesions.


These findings suggest there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism. Additional genetic and longitudinal observational studies are needed to identify candidate pathways that may account for the comorbid constellation of symptoms.

Friday, 19 September 2014

Parkinson disease and smoking revisited: Ease of quitting is an early sign of the disease

Really like this study not least because it fits what I think about smoking and PD...

Neurology. 2014 Sep 12. pii: 10.1212/WNL.0000000000000879. [Epub ahead of print]
Ritz B, Lee PC, Lassen CF, Arah OA.

To assess whether being able to quit smoking is an early marker of Parkinson disease (PD) onset rather than tobacco being "neuroprotective," we analyzed information about ease of quitting and nicotine substitute use.

For this case-control study, we identified 1,808 patients with PD diagnosed between 1996 and 2009 from Danish registries, matched 1,876 population controls on sex and year of birth, and collected lifestyle information. We estimated odds ratios and 95% confidence intervals with logistic regression adjusting for matching factors and confounders.

Fewer patients with PD than controls ever established a smoking habit. Among former smokers, those with greater difficulty quitting or using nicotine substitutes were less likely to develop PD, with the risk being lowest among those reporting "extremely difficult to quit" compared with "easy to quit." Nicotine substitute usage was strongly associated with quitting difficulty and duration of smoking, i.e., most strongly among current smokers, followed by former smokers who had used nicotine substitutes, and less strongly among former smokers who never used substitutes.


Our data support the notion that patients with PD are able to quit smoking more easily than controls. These findings are compatible with a decreased responsiveness to nicotine during the prodromal phase of PD. We propose that ease of smoking cessation is an aspect of premanifest PD similar to olfactory dysfunction, REM sleep disorders, or constipation and suggests that the apparent "neuroprotective" effect of smoking observed in epidemiologic studies is due to reverse causation.

Thursday, 18 September 2014

Lower plasma Apolipoprotein A1 levels are found in Parkinson's disease and associate with apolipoprotein A1 genotype

Mov Disord. 2014 Sep 16. doi: 10.1002/mds.26022. [Epub ahead of print]
Swanson CR, Li K, Unger TL, Gallagher MD, Van Deerlin VM, Agarwal P, Leverenz J, Roberts J, Samii A, Gross RG, Hurtig H, Rick J, Weintraub D, Trojanowski JQ, Zabetian C, Chen-Plotkin AS.


The discovery of novel plasma-based biomarkers could lead to new approaches in the treatment of Parkinson's disease (PD). Here, we explore the role of plasma apolipoprotein A1 (ApoA1) as a risk marker for PD and evaluate the influence of APOA1 promoter variation on plasma ApoA1 levels. Plasma ApoA1 and the single-nucleotide polymorphism, rs670, were assayed in a discovery cohort (cohort 1) of 301 PD patients, 80 normal controls (NCs), and 165 subjects with other neurodegenerative diseases, as well as a cohort (cohort 2) of 158 PD patients from a second clinical site. Additionally, rs670 was genotyped in a third cohort of 1,494 PD and 925 NC subjects from both clinical sites. Compared to both normal and disease controls, PD patients have lower plasma ApoA1 (P < 0.001 for both comparisons). Moreover, in PD patients, plasma ApoA1 levels are correlated with genotype at the APOA1 promoter polymorphism, rs670. Specifically, lower plasma ApoA1 levels were found in rs670 major allele (G) homozygotes in both cohort 1 (P = 0.009) and in a replication cohort (cohort 2; n = 158 PD patients; P = 0.024). Finally, evaluating rs670 genotype frequencies in 1,930 PD cases versus 997 NCs, the rs670 GG genotype shows a trend toward association (odds ratio: 1.1; P = 0.10) with PD. Our results are compatible with a model whereby circulating ApoA1 levels may be useful in risk-stratifying subjects for the development of PD, with higher ApoA1 levels suggesting relative protection. Future studies evaluating modulation of ApoA1 as a novel therapeutic strategy in PD are warranted.

Osteoporosis in neurodegeneration

We wondered about some commonality in pathways when we were writing our recent meta-analysis on bone health...

J Trace Elem Med Biol. 2014 Aug 29. pii: S0946-672X(14)00164-3. doi: 10.1016/j.jtemb.2014.08.010. [Epub ahead of print]
Roos PM


Osteoporosis affects bone microarchitecture and reduces bone mass. There are more than 200 million people with osteoporosis worldwide, and the prevalence is slowly increasing. The highest prevalences are found in Scandinavia and USA, also slowly increasing. A parallel increase in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis has been noted since the middle of this century. Osteoporosis is more common in patients with each of these neurodegenerative conditions than in the general population. Several metals with neurotoxic properties accumulate in bone and can substitute for calcium in hydroxyapatite, the main mineral component of bone. Especially cadmium, but also lead, aluminum and arsenic affect bone mineral density negatively. Metals with neurotoxic properties have also been found in brain and cerebrospinal fluid from patients with Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and multiple sclerosis, and markers for neurodegeneration such as amyloid beta peptide and amyloid precursor protein have been detected in bone tissue from patients with osteoporosis. A common mechanism contributing to the pathogenesis of both neurodegeneration and osteoporosis can be suspected. The hypothesis that neurodegenerative disorders are associated with osteoporosis is presented and discussed.

Correlation between decreased CSF α-synuclein and Aβ1-42 in Parkinson disease

More on CSF biomarkers for PD...

Neurobiol Aging. 2014 Aug 4. pii: S0197-4580(14)00512-0. doi: 10.1016/j.neurobiolaging.2014.07.043. [Epub ahead of print]
Buddhala C, Campbell MC, Perlmutter JS, Kotzbauer PT.


Accumulation of misfolded α-synuclein (α-syn) protein in Lewy bodies and neurites is the cardinal pathologic feature of Parkinson disease (PD), but abnormal deposition of other proteins may also play a role. Cerebrospinal fluid (CSF) levels of proteins known to accumulate in PD may provide insight into disease-associated changes in protein metabolism and their relationship to disease progression. We measured CSF α-syn, amyloid β1-42 (Aβ1-42), and tau from 77 nondemented PD and 30 control participants. CSF α-syn and Aβ1-42 were significantly lower in PD compared with controls. In contrast with increased CSF tau in Alzheimer disease, CSF tau did not significantly differ between PD and controls. CSF protein levels did not significantly correlate with ratings of motor function or performance on neuropsychological testing. As expected, CSF Aβ1-42 inversely correlated with [11C]-Pittsburgh compound B (PiB) mean cortical binding potential, with PiB+ PD participants having lower CSF Aβ1-42 compared with PiB- PD participants. Furthermore, CSF α-syn positively correlated with Aβ1-42 in PD participants but not in controls, suggesting a pathophysiologic connection between the metabolisms of these proteins in PD.

Wednesday, 17 September 2014

Cholinesterase inhibitors for Parkinson's disease: a systematic review and meta-analysis.

J Neurol Neurosurg Psychiatry. 2014 Sep 15. pii: jnnp-2014-308764. doi: 10.1136/jnnp-2014-308764. [Epub ahead of print]
Pagano G, Rengo G, Pasqualetti G, Femminella GD, Monzani F, Ferrara N, Tagliati M.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder frequently associated with a wide variety of non-motor symptoms related to non-dopaminergic pathways. Although the depletion of dopamine is the key neurochemical impairment in PD and anticholinergic medications are used for symptomatic treatment, significant deficits in cholinergic transmission are also present and have been associated with cognitive decline and gait dysfunction. Therefore, use of a cholinesterase inhibitor (ChI) might improve cognitive function and reduce the risk of falls in patients with PD, although it could plausibly worsen motor features. Our objective was to conduct a systematic review of prospective, randomised controlled trials, in order to assess the efficacy and safety of ChIs compared with placebo in patients with PD.

MEDLINE, Web of Science, CENTRAL and Scopus databases were searched to identify studies published before 5 May 2014 and including patients with PD treated with ChIs. From 945 references identified and screened, 19 were assessed for eligibility and 4 trials were included for a total of 941 patients with PD. ChIs significantly slowed Mini-Mental State Examination decline without effect on risk of falls. Tremor rates and adverse drug reactions favoured the placebo group. Alzheimer Disease Assessment Scale-cognitive subscale, global assessment and behavioural disturbance improved in the ChI group without effect on disability. There was no significant difference between the groups for Unified Parkinson Disease Rating Scale III. A significantly reduced death rate was observed in the treated cohort as compared with placebo.


ChIs are effective in the treatment of cognitive impairment in patients with PD, but do not affect risk of falls. The choice of treatment has to be balanced considering the increased tremor and adverse drug reactions.

Prediction of Parkinson's disease subsequent to severe depression: a ten-year follow-up study

Interesting study looking at prodromal markers and conversion in patients with a major depressive episode...

J Neural Transm. 2014 Sep 14. [Epub ahead of print]
Walter U, Heilmann R, Kaulitz L, Just T, Krause BJ, Benecke R, Höppner J.


Major depressive disorder (MDD) has been associated with an increased risk of subsequent Parkinson's disease (PD) in case-control and cohort studies. However, depression alone is unlikely to be a useful marker of prodromal PD due to its low specificity. In this longitudinal observational study, we assessed whether the presence of other potential markers of prodromal PD predicts the subsequent development of PD in MDD patients. Of 57 patients with severe MDD but no diagnosis of PD who underwent a structured interview, olfactory and motor investigation and transcranial sonography at baseline, 46 (36 women; mean age 54.9 ± 11.7 years) could be followed for up to 11 (median, 10) years. Three patients (2 women; age 64, 65 and 70 years) developed definite PD after 1, 7, and 9 years, respectively. The combined finding of mild asymmetric motor slowing, idiopathic hyposmia, and substantia nigra hyperechogenicity predicted subsequent PD in all patients who could be followed for longer than 1 year. Out of the whole study cohort, only the subjects with subsequent PD presented with the triad of asymmetric motor slowing, idiopathic hyposmia, and substantia nigra hyperechogenicity in combination with at least two out of four reportable risk factors (family history of PD, current non-smoker, non-coffee drinker, constipation) at baseline investigation. Post-hoc analysis revealed that additional rating of eye and eye-lid motor abnormalities might further improve the prediction of PD in larger cohorts. Findings of this pilot-study suggest that MDD patients at risk of subsequent PD can be identified using an inexpensive non-invasive diagnostic battery.

Tuesday, 16 September 2014

The predictive value of transcranial sonography in clinically diagnosed patients with early stage Parkinson's disease: comparison with DAT PET scans

This is helpful and underlines why TCS is not a diagnostic test per se. That doesn't prevent it being a useful tool in seeking support for a diagnosis of PD and a potentially valuable risk marker for PD. There are gender, age and ethnic differences in the adequacy of bone window that can limit some studies findings... 

Neurosci Lett. 2014 Sep 9. pii: S0304-3940(14)00736-8. doi: 10.1016/j.neulet.2014.08.053. [Epub ahead of print]
Liu P, Li X, Li FF, Ou-Yang QH, Zhang HX, Feng T.


Early and correct diagnosis of Parkinson's disease (PD) is critical for patient counseling and therapeutic management. The diagnostic accuracy of transcranial sonography of substantia nigra (SN-TCS) for early stage PD patients remains controversial. Dopamine transporter (DAT) imaging is sensitive to detect presynaptic dopamine neuronal dysfunction, and has been studied as a diagnostic tool for degenerative parkinsonism. To investigate the predictive value of SN-TCS for the DAT PET scans in clinically diagnosed early stage PD patients, we performed the SN-TCS and DAT Positron Emission Computed Tomography (PET) Imaging examinations on 53 patients. Using the DAT PET results as clinical gold standard, the sensitivity and specificity of TCS was 68.75% and 40% respectively. The positive predictive value (PPV) of an abnormal TCS for an abnormal PET scan was 91.67%. However, the negative predictive value (NPV) for a normal PET scan was only 11.76%. The false negative rate was 31.25%. In 35 patients, the result of the SN-TCD was in accordance with the result of the DAT PET scan (Kappa=0.042, P>0.05). The consistency between SN-TCS and PET scans was poor. We conclude that SN-TCS would not be used as a diagnostic tool for early stage PD patients. Negative result of TCS could not exclude the diagnosis of PD. Further tests like DAT-PET is needed for validation. On the other hand, positive SN-TCS will reduce the added diagnostic value of a presynaptic neuronimaging scan.

Cost of deep brain stimulation for the treatment of Parkinson's disease by surgical stimulation sites

  1. Kevin T. Stroupe PhD1,2,*,
  2. Frances M. Weaver PhD1,2,
  3. Lishan Cao MS1,
  4. Dolores Ippolito MPH1,
  5. Brandon R. Barton MD, MS3,4,
  6. Inger E. Burnett-Zeigler PhD5,
  7. Robert G. Holloway MD, MPH6,
  8. Barbara G. Vickrey MD, MPH7,8,
  9. Tanya Simuni MD9 and
  10. Kenneth A. Follett MD, PhD10

To assess costs and effectiveness of deep brain stimulation (DBS) of the internal globus pallidum (GPi) versus subthalamic nucleus (STN) from the provider and societal perspectives for Parkinson's disease (PD) patients in a multicenter randomized trial.

All costs from randomization to 36 months were included. Costs were from Department of Veterans Affairs (VA) and Medicare databases and clinical trial data. Quality adjusted life years (QALYs) were from Quality of Well Being questionnaires.

Provider costs were similar for the 144 GPi and 130 STN patients (GPi: $138,044 vs. STN: $131,822; difference = $6,222, 95% confidence interval [CI]: –$42,125 to $45,343). Societal costs were also similar (GPi: $171,061 vs. STN: $167,706; difference = $3,356, 95% CI: –$57,371 to $60,294). The GPi patients had nonsignificantly more QALYs.


The QALYs and costs were similar; the level of uncertainty given the sample size suggests that these factors should not direct treatment or resource allocation decisions in selecting or making available either procedure for eligible PD patients.

Saturday, 13 September 2014

Cerebrospinal fluid Alpha-synuclein as A Biomarker for Parkinson's disease Diagnosis: A Systematic review and Meta-analysis

Alpha-syn - insufficient on its own... at least when measured through standard means

Int J Neurosci. 2014 Sep 9:1-26. [Epub ahead of print]
Gao L, Tang H, Nie K, Wang L, Zhao J, Gan R, Huang J, Zhu R, Feng S, Duan Z, Zhang Y, Wang L.


Abstract To date, there are no definitive biomarkers for Parkinson's disease (PD) diagnosis. The detection of cerebrospinal fluid (CSF) alpha (α)-synuclein in PD patients has yielded promising but inconclusive results. To determine the performance of CSF α-synuclein as a diagnostic biomarker of PD and whether CSF α-synuclein can discriminate PD from other neurodegenerative diseases, a systematic search of all relevant studies investigating reproducible CSF α-synuclein quantification methods was conducted in electronic databases. A total of 17 studies, that included 3311 patients were included in this systemic review and meta-analysis. The mean CSF α-synuclein concentration was significantly lower in PD patients compared to normal/neurological controls [weighted mean difference (WMD) -0.31; 95% CI, -0.45, -0.16; p < 0.0001] and patients with Alzheimer's disease (AD) [WMD -0.15; 95% CI, -0.26, -0.04; p < 0.0001]. There was no significant difference between PD patients and dementia with Lewy bodies (DLB) patients [WMD -0.03; 95% CI, -0.16, 0.09; p = 0.58] or patients with multiple system atrophy (MSA) [WMD 0.05; 95% CI, -0.04, 0.13; p = 0.25]. Sensitivity and specificity of CSF α-synuclein in the diagnosis of PD was 0.88 (95% CI, 0.84-0.91) and 0.40 (95% CI, 0.35-0.45), respectively. The positive and negative likelihood ratios of CSF α-synuclein in the diagnosis of PD were 1.41 (95% CI, 1.24-1.60), and 0.29 (95% CI, 0.15-0.56), respectively. The corresponding summary receiver operating characteristic (SROC) curve showed an area under the curve (AUC) of 0.73. The concentration of CSF α-synuclein may be a biomarker for the diagnosis of PD. The use of α-synuclein alone however is not sufficient as a single biomarker and it must therefore be used in conjunction with other documented and reliable biomarkers.

Friday, 12 September 2014

A personal account of being diagnosed with Parkinson's by someone I know

Clearly written account by Roddy Lee which will resonate with others with PD. Raising awareness is so so important...


Basal ganglia echogenicity in tauopathies

Can be useful potentially for differentiating PD from PSP-P...

J Neural Transm. 2014 Sep 10. [Epub ahead of print]
Sadowski K, Serafin-Król M, Szlachta K, Friedman A.


Accumulating data confirm the usefulness of transcranial sonography (TCS) in the diagnosis of Parkinson's disease. The relevance of basal ganglia abnormalities depicted by TCS in atypical parkinsonian syndromes still needs further assessment. In the present study, 20 patients with progressive supranuclear palsy (PSP) and 13 patients with corticobasal syndrome (CBS) were studied with the use of transcranial sonography. Echogenicity of the substantia nigra (SN) and lenticular nucleus (LN) were assessed. 0/20 patients with PSP and 8/12 (66.6 %) patients with CBS were characterized with SN hyperechogenicity. LN hyperechogenicity was observed in 9/20 patients diagnosed with PSP and 0/11 of CBS patients. The combination of SN isoechogenicity and LN hyperechogenicity reached 100 % sensitivity and positive predictive value for the diagnosis of PSP. The results of this study point out that CBS has to be taken into consideration when SN hyperechogenicity is depicted in a patient with parkinsonian syndrome. Normal echogenicity of the SN coexisting with LN hyperechogenicity practically excludes CBS.

Tuesday, 9 September 2014

Dietary fat intake and risk for Parkinson's disease

Mov Disord. 2014 Sep 3. doi: 10.1002/mds.26032. [Epub ahead of print]
Dong J, Beard JD, Umbach DM, Park Y, Huang X, Blair A, Kamel F, Chen H.


Previous epidemiological studies have generated inconsistent results regarding the associations between dietary fat intakes and risk for Parkinson's disease (PD). We therefore prospectively examined these associations in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. A 124-item food frequency questionnaire was administered at baseline in1995 to 1996, and PD diagnosis was self-reported at the follow-up survey in 2004 to 2006. A total of 1,087 cases with a PD diagnosis between 2000 and 2006 and 299,617 controls were included in the analyses. Overall, intakes of fats and other macronutrients were not associated with PD risk. However, we found a weak positive association between n-6 polyunsaturated fatty acids (PUFA) and the risk for PD. After adjusting for potential confounders, the odds ratio (OR) and 95% confidence interval (CI) between extreme quintiles of n-6 PUFA intake was 1.23 (95% CI = 1.02-1.49, P for trend = 0.02). A similar association was observed for the intake of linoleic acid. Results were similar among men and among women. Our study suggests that fat intake in general is not related to the risk for PD. The weak positive association between intake of n-6 PUFA and PD risk needs further investigation.

Sunday, 7 September 2014

Lifetime exposure to estrogens and Parkinson's disease in California teachers

Previous studies in other cohorts/samples have found similar things, but not all...

Parkinsonism Relat Disord. 2014 Aug 19. pii: S1353-8020(14)00299-5. doi: 10.1016/j.parkreldis.2014.08.003. [Epub ahead of print]
Gatto NM, Deapen D, Stoyanoff S, Pinder R, Narayan S, Bordelon Y, Ritz B.

Parkinson's disease (PD) is consistently observed to occur less frequently in women than men, prompting investigation into whether estrogen protects against neurodegeneration of dopaminergic neurons.

We used baseline data in the California Teachers Study, a prospective cohort of women, to investigate whether reproductive factors indicating higher long-term estrogen levels are associated with PD using a nested case-control approach. We identified 228 PD cases and 3349 unaffected controls frequency matched by age and race.

Women who reported using combined estrogen/progesterone therapy or progesterone only formulations had a 57% increase in PD risk (OR = 1.57, 95% CI = 1.06, 2.34) compared to never having used HT. Compared to women with menopause at 50-52 years, menopause at younger (<35-46 years: OR = 0.59, 95% CI = 0.37, 0.94) and older ages (≥53 years: OR = 0.54, 95% CI = 0.36, 0.83) had lower PD risk. A derived composite estrogen summary score for women's exposure to both endogenous and exogenous estrogens throughout life indicated that women with presumed higher cumulative lifetime levels of estrogen (a score of 3-5) had a significantly reduced PD risk [(OR = 0.57, 95% CI = 0.35, 0.91) relative to those with lower lifetime estrogen exposure or a composite estrogen summary score of 0-1].


These results provide some support for the hypothesis that lifelong high estrogen is protective in PD, suggesting that the level and persistence of exposure over the long term may be important in PD risk reduction.

Saturday, 6 September 2014

APOE, MAPT, and SNCA Genes and Cognitive Performance in Parkinson Disease

JAMA Neurol. 2014 Sep 1. doi: 10.1001/jamaneurol.2014.1455. [Epub ahead of print]
Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Hurtig HI, Van Deerlin VM, Ritz B, Rausch R, Rhodes SL, Factor SA, Wood-Siverio C, Quinn JF, Chung KA, Peterson AL, Espay AJ, Revilla FJ, Devoto J, Hu SC, Cholerton BA, Wan JY, Montine TJ, Edwards KL, Zabetian CP.

Cognitive impairment is a common and disabling problem in Parkinson disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important nonmotor feature.

To determine whether common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.

We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.

Nine variables derived from 7 psychometric tests.

The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10-6; corrected P [Pc] = 6.0 × 10-5), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10-5; Pc = 9 × 10-5); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.


Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer disease than PD.

Friday, 5 September 2014

Which features of Parkinson's disease predict earlier exit from the workforce?

Evidence to further back up how markedly anxiety and depression can affect all aspects of daily life in PD patients...

Parkinsonism Relat Disord. 2014 Aug 20. pii: S1353-8020(14)00303-4. doi: 10.1016/j.parkreldis.2014.08.005. [Epub ahead of print]
Armstrong MJ, Gruber-Baldini AL, Reich SG, Fishman PS, Lachner C, Shulman LM.

Few objective data exist regarding predictors of leaving the workforce (LWF) in Parkinson's disease (PD).

Employed PD patients were followed prospectively. Baseline demographics, disease duration, and measures of disease severity, cognition, disability, and mental health were compared between patients working at last follow-up versus those who left the workforce using student's t-tests and multivariate analyses controlling for age, gender, and PD duration.

Of 419 employed patients, 224 had left the workforce by last follow-up. Patients who left the workforce were more likely to be older, female, have lower-income, and have longer PD duration. LWF patients had greater baseline depression, anxiety, and overall psychiatric distress. PD severity did not differ between groups.


Demographics, disease duration, and mental health contribute to LWF, but not motor severity. Age, gender and income contributions are difficult to modify but important to recognize. Worse baseline mental health is associated with LWF, suggesting a potential target for intervention.

Thursday, 4 September 2014

A population-based study of the association between bullous pemphigoid and neurologic disorders

J Am Acad Dermatol. 2014 Aug 29. pii: S0190-9622(14)01783-6. doi: 10.1016/j.jaad.2014.07.052. [Epub ahead of print]
Brick KE, Weaver CH, Savica R, Lohse CM, Pittelkow MR, Boeve BF, Gibson LE, Camilleri MJ, Wieland CN.

Bullous pemphigoid (BP) has been associated with neurologic disorders.

We sought to analyze the association between BP and neurologic disorders.

We retrospectively identified residents of Olmsted County, Minnesota, with a first lifetime diagnosis of BP between January 1, 1960, and December 31, 2009. Three age- and sex-matched Olmsted County, Minnesota, residents without BP were selected as control subjects for each patient. We compared history of or development of neurologic disorders (dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, cerebrovascular disease, and seizures) between groups using case-control and cohort designs.

In all, 87 patients with BP were identified and matched to 261 control subjects. The odds of a previous diagnosis of any neurologic disorder or a history of dementia were significantly increased among cases compared with controls (odds ratio 6.85; 95% confidence interval [CI] 3.00-15.64; P < .001; and odds ratio 6.75; 95% CI 2.08-21.92; P = .002, respectively). Both Parkinson disease (hazard ratio 8.56; 95% CI 1.55-47.25; P = .01) and any type of neurologic disorder (hazard ratio 2.02; 95% CI 1.17-3.49; P = .01) were significantly more likely to develop during follow-up in patients with than without BP.

Small geographic area and retrospective study design are limitations.


Findings confirmed an association of BP with neurologic disorders, especially dementia and Parkinson disease.

Wednesday, 3 September 2014

Montreal Cognitive Assessment for the screening and prediction of cognitive decline in early Parkinson's disease

More evidence supporting the MoCA as the cognitive screening test of choice in early PD...

Parkinsonism Relat Disord. 2014 Aug 14. pii: S1353-8020(14)00298-3. doi: 10.1016/j.parkreldis.2014.08.002. [Epub ahead of print]
Kandiah N, Zhang A, Cenina AR, Au WL, Nadkarni N, Tan LC.

Early diagnosis of cognitive impairment in PD would allow appropriate monitoring and timely intervention to reduce the progression to dementia (PDD).

To study the usefulness of the Montreal Cognitive Assessment (MoCA) in the screening for mild cognitive impairment (PD-MCI) and its predictive utility in determining longitudinal cognitive decline in PD.

Prospective longitudinal study of patients with mild PD. PD-MCI and PDD was diagnosed based on the Movement Disorder taskforce (MDS) criteria. Receiver Operating Characteristic analyses and Cox regression analyses were performed.

95 patients; mean age 66.37 (SD 7.86); mean H&Y score of 1.99 (SD 0.45) were studied. At baseline, 34 patients fulfilled the MDS criteria for PD-MCI. MoCA, compared to the MMSE had a high discriminatory power in detecting PD-MCI [Area Under Curve (AUC) of 0.912, p < 0.001]. A MoCA score of ≤26 provided a sensitivity of 93.1% for the diagnosis of PD-MCI. In the longitudinal cohort over 2 years, baseline MOCA was useful in predicting cognitive decline (AUC of 0.707, p = 0.05). With Cox regression analyses, a 1-point lower score on baseline MoCA was associated with a 34% increased risk of cognitive decline [Hazard ratio (HR) 1.34; 95% CI: 1.03-1.74: p = 0.029]. A baseline MoCA ≤26 was highly predictive of progressive cognitive decline (HR 3.47, 95% CI: 2.38-5.07; p < 0.01).


MoCA is a reliable tool in predicting cognitive decline in early PD. A MoCA score of ≤26 significantly increases the risk for progressive cognitive decline.

Tuesday, 2 September 2014

Predictors of dementia in Parkinson disease: A prospective cohort study

Useful prospective study which supports some of the observations made in the clinic...

Neurology. 2014 Aug 29. pii: 10.1212/WNL.0000000000000842. [Epub ahead of print]
Anang JB, Gagnon JF, Bertrand JA, Romenets SR, Latreille V, Panisset M, Montplaisir J, Postuma RB.

We investigated an array of possible markers of early dementia in Parkinson disease.

We performed a comprehensive assessment of autonomic, sleep, psychiatric, visual, olfactory, and motor manifestations in 80 patients with Parkinson disease who were dementia-free at baseline. After 4.4 years' follow-up, patients were evaluated for dementia. Predictive variables were assessed using logistic regression adjusting for disease duration, follow-up duration, age, and sex.

Of 80 patients, 27 (34%) developed dementia. Patients destined to develop dementia were older and more often male (odds ratio [OR] = 3.64, p = 0.023). Those with baseline mild cognitive impairment had increased dementia risk (OR = 22.5, p < 0.001). REM sleep behavior disorder at baseline dramatically increased dementia risk (OR = 49.7, p = 0.001); however, neither daytime sleepiness nor insomnia predicted dementia. Higher baseline blood pressure increased dementia risk (OR = 1.37 per 10 mm Hg, p = 0.032). Orthostatic blood pressure drop was strongly associated with dementia risk (OR = 1.84 per 10 mm Hg, p < 0.001); having a systolic drop of >10 mm Hg increased dementia odds 7-fold (OR = 7.3, p = 0.002). Abnormal color vision increased dementia risk (OR = 3.3, p = 0.014), but olfactory dysfunction did not. Among baseline motor variables, proportion of gait involvement (OR = 1.12, p = 0.023), falls (OR = 3.02, p = 0.042), and freezing (OR = 2.63, p = 0.013), as well as the Purdue Pegboard Test (OR = 0.67, p = 0.049) and alternate tap test (OR = 0.97, p = 0.033) predicted dementia.


Cardiovascular autonomic dysfunction, REM sleep behavior disorder, color discrimination ability, and gait dysfunction strongly predict development of dementia in Parkinson disease.

Monday, 1 September 2014

Olfactory dysfunction in incidental Lewy body disease and Parkinson's disease.

Small number of pathologically defined PD and ILBD cases who had smell testing in life. Reassuring that 50% of ILBD cases had olfactory dysfunction if this is the precursor...

Parkinsonism Relat Disord. 2014 Aug 16. pii: S1353-8020(14)00304-6. doi: 10.1016/j.parkreldis.2014.08.006. [Epub ahead of print]
Driver-Dunckley E, Adler CH, Hentz JG, Dugger BN, Shill HA, Caviness JN, Sabbagh MN, Beach TG; the Arizona Parkinson Disease Consortium.

Olfactory dysfunction in Parkinson's disease (PD) is well-established and may represent one of the earliest signs of the disease.

The objective of this study was to evaluate the relationship of olfactory dysfunction, using the University of Pennsylvania Smell Identification Test (UPSIT), to clinical and pathological parameters of clinicopathologically diagnosed PD (n = 10), incidental Lewy body disease (ILBD) (n = 13), and identically assessed controls who lacked a neurodegenerative disease (n = 69).

Mean UPSIT scores were significantly lower in PD (16.3, p < 0.001) and ILBD (22.2, p = 0.004) compared to controls (27.7). Using an UPSIT cutoff score of <22 (the 15th percentile) the sensitivity for detecting PD was 9/10 (90%) and ILBD 6/13 (46%), while the specificity was 86% (Controls with score of <22 = 10/69).


These results add to the growing body of evidence suggesting that olfactory testing could be useful as a screening tool for identifying early, pre-motor PD.

Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2),...