Parkinsonism & Related Disorder

2016 vol 22 (一月號)

Medical Scientific Liaison, MSL Willy Wen,文偉立 GSK Neuroscience (2012~) Taipei Medical University Pharmacy (2006-2009)

Highlights •Patients with Parkinson's disease (PD) may develop several non-motor symptoms. •Rapid eye movement sleep behavior disorder (RBD) is commonly associated with PD. •RBD may have associations with visual hallucinations (VH) and cognitive impairment (CI). •Presence of either VH or CI may be a risk factor for development of the other. •Interactions of VH, RBD and CI may have important clinical significance.

Evidence from •Clinical and epidemiological studies •Neuroimaging studies •Cholinergic dysfunction •Synucleinopathies

爭點1: RBD and VH in PD: a continuum or two distinct phenomena? Cont’d

1. Degeneration of process: (continuum) • REM, RBD to the Braak stage 2,3. • VH to the Braak stage 6. • Cognitive impairment in PD to the Braak stage 4,5,6.

2. Evidence from clinical and epidemiological studies (High prevelence,2 y/o) • Vivid dreams and nightmares found in RBD and PD.(Pappert 1999) Double frequency in PD with

RBD.(Gjerstad 2008) Higher risk of emergence of VH in PD with RBD after 2 year follow-up.(Sinforiani 20008)

• RBDSQ score of ≥6: 38% of PD with RBD develop VH at follow up 2 years, whereas none of PD w/o RBD. (Poryazoya 2013)

• Polysomnography: Reduced sleep efficiency, total REM sleep duration, and REM sleep percentage in PD with VH. (Comella 1993)

3. Evidence from neuroimaging studies (GM atrophy but not overlap that much)

• iRBD: reduced gray matter volume, as thalamus (Salons 2014), putamen (Ellmore 2010), cerebellum tegmental portion of pons and parahippocampal regions (Hanyu 2012)

• PD with VH: GM atrophy in dorsal and ventral visual pathways (Goldman 2014), frontal regions (Watanabe 2013), limbic regions and hippocampus (Ibarretxe-Bilbao 2010; Ibarretxe-Bilbao 2008).

爭點1: RBD and VH in PD: a continuum or two distinct phenomena? Cont’d

1. Evidence from cholinergic dysfunction (Be seen in RBD,VH, CI in PD)

• Short latency afferent inhibitoin by TMS.

• Nardone et al N=23 PD, (with RBD 10; w/o 13)

• Managanelli et al, N=22 PD (with VH 10; w/o 12)

2. Neuropsychological evaluation (highly associated, but need robust studies)

• Deficits in visuo-spatial learning, executive function and verbal memory in both “PD with RBD or VH” and “iRBD”. (Ferini-Stramni 2004; Massicotte-Marquez 2008)

• It may be: the emergence of RBD and VH in PD association with visuoperceptive functions.

爭點2: VH and CI in PD: does one predict the other?

1. Evidence from the clinical and epidemiological studies (high coexsist)

• PD=45, 24 with VH & 21 w/o VH (Ramirez-Ruiz 2007)

• 45% with VH developed MCI

• With VH 82%, compare to w/o VH 30% .

• Impairments in verbal memory and attention (Hepp 2013).

• VH is a Risk factors for dementia in PD, follow-up 4.4 years with 34% (Anang 2014).

• CALM-PD trial (n=301), lower MMSE at baseline to develop hallucination (Biglan

2007).

2. Evidence from neuroimaging studies (overlapping)

• Hippocampal and para-hippocampal atrophy.

• Lingual gyrus, posterior cingulate gyrus .

爭點3 : RBD and CI in PD: a tug of war between causation and association?

1. Evidence from clinical and epidemiological studies. (RBD is earlier)

• RBD had impaired episodic verbal memory, executive functions, visuoperceptual functions. (Vendtte 2007)

• Higher prevalence of MCI in patients with iRBD (50%) , or PD with RBD(73%) , PD w/p RBD (11%) and Control (8%)(Gagnon 2009)

• 4 Year follow up, 48% of PD with RBD development dementia compare to PD w/o RBD. (Postuma 2012)

2. Role of cholinergic dysfunction (close association)

• Reported cholinergic dysfunctions in VH, RBD, and PDD.

PubMed and PsycINFO database from the year 1995 to July 2015

Reminding: IF detect one, figure others two.

10-item self rated RBDSQ

MMSE

Highlights •Hedonic range for olfactory perception is severely reduced in PD. •Complex olfactory impairment in PD consists of hyposmia and reduced hedonic perception. •Reduced hedonic olfactory perception correlates with anhedonia but not with global depression in PD.

確認PD depression 是否跟 嗅覺喪失有關聯

Aromatic testing: 22 compounds

Pleasant Un-Pleasant

Highlights •A total of 31 non-demented PD patients and 20 age-matched controls were studied. •Patients were sub-classified into groups of PD with mild cognitive impairment (PD-MCI) and cognitively normal PD (PD-CN). •The degree of hyposmia self-awareness was calculated as the difference between subjective and objective olfactory impairment. •PD-MCI patients tended to rate their olfactory function higher on the olfactory questionnaire than PD-CN group. •The loss of awareness of hyposmia is closely associated with mild cognitive impairment in PD patients.

cognitive impairment (PD-MCI); cognitively normal (PD-CN)

I. Kawasaki et al. / Parkinsonism and Related Disorders 22 (2016) 74e79

If PD with MCI, they cannot detect their olfactory deficit.

Fig. 2. Mean olfactory deficit unawareness score. PD-MCI, Parkinson's disease with mild cognitive impairment; PD-CN, Parkinson's disease and cognitively normal; HC, healthy controls. The error bars represent the standard errors of the means (SEMs). Asterisks denote **p < 0.01 and ***p < 0.001.

I. Kawasaki et al. / Parkinsonism and Related Disorders 22 (2016) 74e79

cognitive impairment (PD-MCI); cognitively normal (PD-CN)

Highlights •We conducted a door-to-door survey to investigate the ET and its NMS in Shanghai. •The prevalence of ET in individuals (≥50 years old) was 0.306%. •The prevalence of ET in a rural area of Shanghai China is low. •ET patients had a lower MMSE score compared with the healthy controls. •Prevalence of certain NMSs was higher among ET patients.

Ethnic?

Study populations

1. 1-day workshop to train local doctors in Malu

2. The 9-question screening instrument. (Yes/No)

1. sustained bilateral arm extension

2. bilateral finger-nose-finger maneuver

3. drawing spirals with both the dominant and non-dominant arms.

3. Tremor severity was assessed using the Fahn-Tolosa-Marin essential tremor rating scale (FTMRS).

Northwestern Shanghai, and Only the residents aged 50 and above were recruited.

Step 1: Train Local Doctor Step 2: movement disorder

specialists

When ET compare to Health control

Single Question Screening Restless legs symptoms (Ondo 2006)

Depression** (not significant) HAMD might not uesful

Olfactory Impairment not present in ET

Highlights •Motor complications affected over 50% in the first 5 years of Parkinson's disease. •Dopamine depletion is indicated as an important cause. •Early levodopa treatment was not associated with motor complications. •Motor complications were mild in the majority and reversible in more than 35%. •No patients required advanced treatment during the first 5 years after diagnosis.

Actual L-dopa dose > Initial treatment with L-dopa

drug-naïve Parkinson's disease

Demographic at baseline of stduy

• 36/189 never use L-dopa – 5 (13.9%) motor fluctuation

– 4 (11.1%) dyskinesia

• Levodopa treated group – 49.7 % motor fluctuation

– 27.5 % dyskinesia

• Risk of develop Motor complication – MF, HR 1.84 p=0.023 (only)

– Dysknesia, HR 0.88 p=0.744

Prevelence and cumulative rate follow up 5 years

Severity of Motor complications

• Severe MF ≤5.1 %

• Severe dyskinesia ≤ 0.6%

• Painful dyskinesia ≤ 1.8%

Reversal of Dyskinesia (39/158)

• 19 of 39 (49%) had no dysknesia at final visit

• Patient with persistent motor flucutation were Younger.

Baseline Risk factors for dyskinesia

• Female ;

• Higher baseline UPDRS motor

Baseline Risk factors for motor fluctuations

• Lower age

• Higher baseline UPDRS motor

BW HR 0.99 p=0.239

Highlights •CuPiD's Smartphone-delivered gait training system is feasible for at-home use in PD. •Gait improvements were found after 6 weeks of training and retained 4 weeks later. •The CuPiD-system was equally effective for gait training as standard physiotherapy. •PD people's balance improved more after training with than without the CuPiD-system.

combined with a smartphone application (CuPiD-system)

CuPiD system the audiobiofeedback (ABF-gait app) The FOGtraining (FOG-cue app)

Figure 1. 2A illustrates the CuPiD system with the foot-mounted IMUs and the single large touchscreen button on the smartphone; 2B

shows a schematic overview of the ABF-gait app with at the top a recording of a clinical optimal reference walk, which was

captured under the therapist's supervision. The median value is then used as the reference value (full horizontal line). The pre-set

therapeutic window (dotted horizontal lines) are the percentages above and below the reference value as determined by the

therapist.

http://www.google.com.tw/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjCgOH1wMbKAhXF2hoKHRPTA9kQjRwIBw&url=http://www.cupid-project.eu/biofeedback&psig=AFQjCNHXNSmJOlyIDWr_n7hGMoGxCg2DJA&ust=1453864324339629

電信管制射頻器材管理辦法

1. 大哥大無線手機進口時應檢附那些證件，又該證件應向那個單位申請？

答: 進口大哥大無線手機應檢附電信管制射頻器材進口許可證，該證件應向國家通訊傳播委員會（NCC）申請。

五、為簡化民眾得攜帶自用之無線電信終端設備及低功率射頻電機進口之管制程序，增訂郵寄進口二部以內者或自行攜帶進口五部以內之器材，得免請領進口許可證，並刪除不需電臺執照之電信管制射頻器材為供自用應辦理審驗之規定。（修正條文第十八條及第十九條）

•Visual and auditory cueing improve functional performance in Parkinson's disease (PD) but need attention-dependent process. •TC may be processed faster, with minimal attentional demand investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks. •simple (seated heel tapping) & complex (straight linewalking with or without a secondary motor task + holding a tray with two cups of water. •Baseline gait parameters established in three 15-min walking line

Step 1: pre-synchronization Heel tapping 30 times

With preferred condense

Step 2: Synchronization Heel tapping with TC condense

and 30 times

Step 3: Continuation Heel tapping w/o TC but follow

the previous TC condense

Experiment 2 Walking 150 m 4 m hallway

Experiment 1 Heel Tapping

Step 1: pre-synchronization With preferred condense

Step 2: Synchronization with TC condense and 30 times

Step 3: Continuation w/o TC but follow the previous

TC condense

A,B: Heel tapping. C,D Waling 15-m line

第二次有跟拍 第二次快拍

Highlights •PD and healthy controls modulated heel tapping and walking in response to TC. •Healthy controls modulated walking at slower, comfortable, and 10% faster pace. •PD patients modulated walking at slower and comfortable pace. •Secondary motor task slowed down cued heel tapping, but not walking. •TC effectiveness in increasingly challenging tasks warrants further investigation.

Highlights •A single session of bilateral motor cortical LF rTMS has no effect on LID. •Multiple bilateral motor cortical LF rTMS sessions are not a good treatment for LID. •Bilateral motor cortical LF rTMS sessions are well tolerated in Parkinson patients.

Insight: levodopa-induced dyskinesias can benefit from bilateral subthalamic deep brain stimulation (DBS)

(LF rTMS)

LF rTMS failed to treat Levodopa-induced dyskinesia.

the first study Unfortunately, bilateral LF rTMS of the MC is not a suitable treatment for levodopa-induced dyskinesias in late-stage Parkinson patients. It contrast with previous study (Brusa 2006;Koch 2005)

Highlights •We compared after-effects following locomotor adaptation in Parkinson's disease. •Participants with and without freezing of gait were included. •Magnitude of after-effects were smaller in the freezer group. •After-effects were similar between controls and the non-freezer group. •People who freeze may have less storage of adapted locomotor patterns.

freezers (PDtFOG); non-freezers (PD-FOG) 15min on a motor driven rotating disc

S.T. Nemanich, G.M. Earhart / Parkinsonism and Related Disorders 22 (2016) 93e97

Split-Belt Walking

Mohammadi et al showed a similar maladaptive response during split-belt walking, noting a significantly slower adaptation rate in PD+FOG compared to PD-FOG and controls

S.T. Nemanich, G.M. Earhart / Parkinsonism and Related Disorders 22 (2016) 93e97

Highlights •The heritable component of Multiple System Atrophy (MSA) is currently unknown. •We used Genome-Wide Complex Trait Analysis (GCTA) to estimate the heritable component of MSA due to common coding variability. •We estimate the heritability of MSA in pooled cases at 2.09–6.65%. •Common genetic variation appears to play a less prominent role in risk for MSA than in other complex neurodegenerative diseases

Using GWAS

GWAS study

1. These studies compare the DNA of participants having varying phenotypes for a particular trait or disease.

2. Participants in a GWAS study may be people with a disease (cases) and similar people without (controls), or they may be people with different phenotypes for a particular trait, for example blood pressure. This approach is known as phenotype-first, in which the participants are classified first by their clinical manifestation(s), as opposed to genotype-first.

3. Each person gives a sample of DNA, from which millions of genetic variants are read using SNP arrays. If one type of the variant (one allele) is more frequent in people with the disease, the variant is said to be associated with the disease.

4. The associated SNPs are then considered to mark a region of the human genome that may influence the risk of disease. In contrast to methods that specifically test one or a few genetic regions, the GWA studies investigate the entire genome.

5. The approach is therefore said to be non-candidate-driven in contrast to gene-specific candidate-driven studies. GWA studies identify SNPs and other variants in DNA associated with a disease, but that cannot on their own specify which genes are causal.

Highlights •Can MR spectroscopy track metabolic changes in Parkinson's Disease? •The study assesses the posterior cingulate cortex (PCC) and cognitive impairment. •There was no association with disease or cognitive ability at baseline or over time. •MR spectroscopy of PCC does not appear to be a useful clinical marker for cognitive impairment in PD.

Proton Magnetic Resonance Spectroscopy (MRS), May 2007 and August 2013

N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI).

No finding MR ratio changes after follow up 2-4 years

At baseline, relative to controls, PDD had significantly decreased NAA/Cr and increased Cho/Cr.

At follow-up (2-4 years), no significant changes in MRS metabolite ratios were detected

Highlights •PD patients exhibit a distinctive serum miRNA profile from healthy controls. •Five miRNA of 18 miRNA were identified to be differently expressed in PD patients' serum. •The 5-member serum miRNA panel can distinguish PD patients from health individuals.

Up-regluated: miR-195 Down-regulated: miR-185, miR-15b, miR-221 and miR-181a

H. Ding et al. / Parkinsonism and Related Disorders 22 (2016) 68e73

miRNA might be a easier and specific biomarkers.

H. Ding et al. / Parkinsonism and Related Disorders 22 (2016) 68e73

Highlights •Orthostatic hypotension (OH) is common in Lewy body disorders (LBD). •We identify a link between OH and hypoperfusion in parieto-occipital areas using perfusion MRI. •Supine hypertension (SH) was associated with hyperperfusion of frontal regions. •OH-defined parieto-occipital hypoperfusion relates to visuospatial-attention deficits in LBD.

A.D. Robertson et al. / Parkinsonism and Related Disorders 22 (2016) 80e86

proof-of-concept study N=15

Lower perfusion to temporal and Occipital compared to a matched small vessel disease.

Fig. 1. Regional cerebral blood flow (CBF) in Lewy body spectrum disorder patients (LBD) and non-demented adults with small vessel disease (SVD). Scatter and error bar plots of CBF in four cortical lobes. Regional CBF is normalized to whole brain grey matter (GM CBF). * indicates within-group difference between regions corrected for multiple comparisons (q ?0.05). Error bars reflect mean ± standard deviation.

A.D. Robertson et al. / Parkinsonism and Related Disorders 22 (2016) 80e86

Highlights •Depression is common in SCAs and depressive symptoms do not progress over 2 years. •Suicidal ideation is more prevalent in SCA3. •The effects of depression on ataxia progression vary across different SCA types. •Depression has negative impact on functional status and quality of life in all SCAs, after accounting for ataxia progression.

SCA 1, 2, 3 and 6 from Spinocerebellar Ataxias (CRC-SCA), n=300 July 2009eMay 2012

R.Y. 88 Lo et al. / Parkinsonism and Related Disorders 22 (2016) 87e92

Classfication Prevalence of depression

SCA1 24.5%

SCA2 20.3%

SCA3 25.2%

SCA6 17.8%

No association link between severity of depression and motor progression follow up 2 years.

R.Y. 88 Lo et al. / Parkinsonism and Related Disorders 22 (2016) 87e92

unlike ataxia severity, depressive symptoms do not seem to change over time or change along with the motor disability, at least within the 2-year observation.