Thursday, 15 March 2018

Treat the person not the scan

When learning clinical medicine, (junior) doctors can often show an over-reliance on blood tests and scans, rather than focussing on the patient and their holistic care. This can lead in turn to more intensive investigation, which is both costly and incurs extra risk, as well as in turn creating more ‘abnormal results’.
An important report has been published in pre-symptomatic Alzheimer’s this week, in the journal Lancet Neurology. The research team at the Salpêtrière Hospital in Paris studied over 300 older adults with subjective, but no objective, memory complaints. The participants completed detailed neuropsychological and cognitive assessment, structural and functional brain scans (MRI and PET), brain-wave tests (EEG), genetic testing and lumbar punctures. These tests were repeated every 6-12 months for over 2 years. They set out to see if they could identify particular markers that would identify who would develop prodromal Alzheimer’s. They separated their cohort into two groups: one with normal amyloid scans and one with evidence of amyloid build up in the brain. (Amyloid is one of two major abnormal proteins that are thought to cause this form of dementia)
With two years of follow up, only four individuals converted to prodromal Alzheimer’s. All four had some evidence of amyloid build up at the beginning of the study, although with such small numbers it is difficult to say this wasn’t due to chance. All four were also older than most (average age 80.2 years compared to 76.8 years), and ¾ had the genetic variant that confers the highest risk of Alzheimers, APOE-ε4, compared to 33/83 who were tested and didn’t progress. Importantly, evidence of amyloid in the brain did not seem to be a good discriminator for likelihood of progression from ‘the worried well’ to prodromal Alzheimers. In fact, the strongest findings from this study were that CSF and imaging markers of increased amyloid were associated with each other!
What does this mean for Parkinson’s? Firstly, we don’t have an equivalent brain scan, i.e. one that shows build up of α-synuclein with which to predict risk. Secondly, with these complex conditions one marker that doesn’t test the function of the individual will be hard pressed to be hugely predictive. Thirdly, one of the biggest limitations of this study is that the follow up was only 2 years. Given all these individuals had normal memory at the beginning, and most were highly educated, it is perhaps not suprising that so few converted to the prodromal stage.

This figure is worth considering as an alternative model of thinking about the earliest stages of Alzheimer’s and perhaps Parkinson’s

Two hypothetical models of the natural history of Alzheimer's disease
(A) Model 1 illustrates the dominant view of progressive deterioration: in Alzheimer's disease, cognition is progressively impaired from the preclinical phase (characterised by amyloid β deposition followed by tau pathology), to the prodromal clinical stage (with subtle cognitive changes), then the clinical stages of MCI and dementia. (B) Model 2 represents an alternative view of preclinical compensation that we have based on our data for brain β-amyloidosis. Cognition remains stable in the preclinical phase of the disease despite underlying brain lesions, until brain compensatory mechanisms are overwhelmed, leading to clinical disease. MCI=mild cognitive impairment. AD=Alzheimer's disease.


Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study.

Bruno Dubois et al
Lancet Neurology 2018, 17 (4), 335-346

BACKGROUND:Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease.

METHODS:The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid β deposition on18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and18F-FDG and18F-florbetapir PET every 24 months. We assessed associations of amyloid β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type.

FINDINGS:From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid β deposition and the remainder did not. The amyloid β subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β1-42concentration in CSF significantly correlated with mean18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β1-42to amyloid β1-40(r=-0·61, p<0·0001), and identified amyloid β deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid β deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]).

INTERPRETATION:Brain β-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent.

FUNDING:Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

Wednesday, 7 March 2018

An overview of sleep and circadian dysfunction in Parkinson's disease

A relationship between Parkinson's disease and sleep has been recognised for many years. Patients with PD suffer from REM sleep behaviour disorder, excessive daytime somnolence, insomnia, reversal of sleep-wake cycle, and some if not all of these can predate the diagnosis of PD.

There is a fascinating literature emerging on the role the circadian rhythm plays in Parkinson's disease. Circadian rhythm not only regulates our body clock but also has a major bearing on our mood, appetite, bowel habit etc. I started thinking a few years ago about whether abnormalities in circadian rhythm could explain much about the pre-diagnostic phase of PD. I wondered whether the structures in the brain that control circadian rhythm were affected early in PD... I later learned from colleagues that they were not. Now I am starting to wonder whether abnormalities in circadian rhythm are not simply an early manifestation of Parkinson's, but instead an actual risk factor for Parkinson's...

Research shows that normal circadian function is important for maintaining normal processes that go on with cells... it is plausible that when circadian rhythm goes awry brain cells stop clearing proteins so effectively and these then start to accumulate... or that mitcohondria in brain cells don't work so effectively when there is disordered circadian rhythm. Some of my recent research looks directly at the nature of the relationship between circadian rhythm and Parkinson's [watch this space!] but for now I agree with the authors of this review... normalising circadian rhythm may be an important therapeutic target for Parkinson's disease...

- Alastair Noyce

J Sleep Res. 2018 Mar 1. doi: 10.1111/jsr.12673. [Epub ahead of print]
Mantovani S, Smith SS, Gordon R, O'Sullivan JD;jsessionid=D053C900C0F2B819BB00734F213B98FB.f02t02

Sleep and circadian alterations are amongst the very first symptoms experienced in Parkinson's disease, and sleep alterations are present in the majority of patients with overt clinical manifestation of Parkinson's disease. However, the magnitude of sleep and circadian dysfunction in Parkinson's disease, and its influence on the pathophysiology of Parkinson's disease remains often unclear and a matter of debate. In particular, the confounding influences of dopaminergic therapy on sleep and circadian dysfunction are a major challenge, and need to be more carefully addressed in clinical studies. The scope of this narrative review is to summarise the current knowledge around both sleep and circadian alterations in Parkinson's disease. We provide an overview on the frequency of excessive daytime sleepiness, insomnia, restless legs, obstructive apnea and nocturia in Parkinson's disease, as well as addressing sleep structure, rapid eye movement sleep behaviour disorder and circadian features in Parkinson's disease. Sleep and circadian disorders have been linked to pathological conditions that are often co-morbid in Parkinson's disease, including cognitive decline, memory impairment and neurodegeneration. Therefore, targeting sleep and circadian alterations could be one of the earliest and most promising opportunities to slow disease progression. We hope that this review will contribute to advance the discussion and inform new research efforts to progress our knowledge in this field.

Tuesday, 6 March 2018

Seeing is believing

People with Parkinson's often have subtle cognitive changes and a particular area of difficulty is in visuo-perceptual problems. Patients commonly report visual hallucinations - from very subtle "passage hallucinations" - the sense that there is some movement in the periphery of vision to more complex "formed" hallucinations of animals and people. It is now clear that the visual problems affect all aspects of the visual pathway, from the retina to higher processing areas in the brain. 

This understanding underpins the work presented here by one of our collaborators, Dr Rimona Weil. She has developed online visual tasks which are sensitive to some of these issues. Her 6 tests covered different aspects of visual processing; the test for object invariance, the ability to detect an image despite distortion is shown in the image below. Also tested were peripheral vision, the ability to detect hidden images, to detect biological motion, relative sizes of shapes and mental rotation. 

Image from the Cats-and-Dogs Test, which assesses object invariance. From

Interestingly, not all the tests differentiated Parkinson's patients from healthy participants. The distorted image was particularly sensitive to detect differences between groups but the results from mental rotation and subjective size perception were similar. 

The importance of these findings - that a short online test performed remotely can detect differences between Parkinson's patients and healthy older people - opens up many possibilities. These kinds of tools are likely to find a role in remote monitoring of patients, especially those who find it difficult to attend clinic. Here at PREDICT-PD we are interested in using these tests for screening and will be working with Dr Weil to find out whether any of the changes in visual processing are present before diagnosis of Parkinson's. 


Assessing cognitive dysfunction in Parkinson's disease: An online tool to detect visuo-perceptual deficits.

Weil RS, Schwarzkopf DS, Bahrami B, Fleming SM, Jackson BM, Goch TJC, Saygin AP, Miller LE, Pappa K
, Pavisic I, Schade RN, Noyce AJ, Crutch SJ, O'Keeffe AG, Schrag AE, Morris HR

People with Parkinson's disease (PD) who develop visuo-perceptual deficits are at higher risk of dementia, but we lack tests that detect subtle visuo-perceptual deficits and can be performed by untrained personnel. Hallucinations are associated with cognitive impairment and typically involve perception of complex objects. Changes in object perception may therefore be a sensitive marker of visuo-perceptual deficits in PD.

We developed an online platform to test visuo-perceptual function. We hypothesised that (1) visuo-perceptual deficits in PD could be detected using online tests, (2) object perception would be preferentially affected, and (3) these deficits would be caused by changes in perception rather than response bias.

We assessed 91 people with PD and 275 controls. Performance was compared using classical frequentist statistics. We then fitted a hierarchical Bayesian signal detection theory model to a subset of tasks.

People with PD were worse than controls at object recognition, showing no deficits in other visuo-perceptual tests. Specifically, they were worse at identifying skewed images (P < .0001); at detecting hidden objects (P = .0039); at identifying objects in peripheral vision (P < .0001); and at detecting biological motion (P = .0065). In contrast, people with PD were not worse at mental rotation or subjective size perception. Using signal detection modelling, we found this effect was driven by change in perceptual sensitivity rather than response bias.

Online tests can detect visuo-perceptual deficits in people with PD, with object recognition particularly affected. Ultimately, visuo-perceptual tests may be developed to identify at-risk patients for clinical trials to slow PD dementia. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Tuesday, 27 February 2018

Substantia nigra fractional anisotropy changes confirm the PD at-risk status of patients with idiopathic smell loss

In my opinion idiopathic anosmics are an under-researched group (PARS study aside). It is good to see others taking a particular interest in them... at PREDICT-PD we are very in interested in idiopathic anosmia and are about to start reassessing the people that we have recruited with unexplained smell loss. Particularly interesting that there are MRI differences between the groups....

Parkinsonism Relat Disord. 2018 Feb 17. pii: S1353-8020(18)30076-2. doi: 10.1016/j.parkreldis.2018.02.026. [Epub ahead of print]
Haehner A, Schöpf V, Loureiro A, Linn J, Reichmann H, Hummel T, Kitzler HH.

INTRODUCTION: Individuals with unexplained smell loss constitute an at-risk population for the development of Parkinson's disease (PD). Currently, no specific MRI patterns are known for early PD diagnosis. In this study, we measured the fractional anisotropy (FA) in the substantia nigra (SN) in PD patients, in patients with idiopathic smell loss, and in healthy controls.

METHODS: All subjects underwent extensive olfactory testing and MR imaging data were obtained to explore SN diffusion characteristics. The SN regions were manually identified by two independent raters on the individual imaging data.

RESULTS: FA measurements in the SN revealed significant group differences, with reduced values clearly distinguishing PD patients and patients with idiopathic smell loss from healthy controls.

CONCLUSION: These findings indicate a reduced intrinsic integrity of the SN in PD at-risk subjects and support the risk status of patients with idiopathic smell loss.

Thursday, 15 February 2018

Do subjects with minimal motor features have prodromal PD?

This is a study of potentially vital importance to our understand of the prodrome(s) of PD. Here the authors show that people with mild parkinsonian signs (subtle bradykinesia, tremor, rigidity, gait disturbance) have Parkinson's disease pathology at post-mortem. The authors observed no PD pathology in participants without mild parkinsonian signs, moderate PD pathology in those with mild parkinsonian signs and frank PD pathology in those with a clinical diagnosis of PD. Some caution should be exercised that the group with mild parkinsonian signs was significantly older than the other two groups, but the pattern of pathology was not typically age-related.

Their observation add further weight the notion that there is a significant motor aspect to the phase of PD before diagnosis, as suggested by our group and others... (the citations in this paper relating to the previous literature on prodromal motor symptoms are a little light if you ask me ! 😀)... 

However this new study could turn out to be a landmark one. I (and some others) have long been asserting that the term 'premotor' may not be an appropriate one. Unless we have laid eyes on people with idiopathic anosmia, RBD or other non-motor prodromal features, then we can't be sure that there are no motor signs. The really important thing to work on now is characterising what specifically starts to change in terms of motor function in those that will eventually go on to get a diagnosis of PD? This is a major focus of the PREDICT-PD study over the next 3 years... and we are exploring this in a variety of ways...

Ann Neurol. 2018 Feb 8. doi: 10.1002/ana.25179. [Epub ahead of print]
Chu Y, Buchman AS, Olanow CW, Kordower JH.

BACKGROUND: Understanding the pathological changes underlying mild motor features of the eldery and defining a patient population with prodromal Parkinson's disease (PD) are of great clinical importance. It remains unclear, however, how to accurately and specifically diagnose prodromal PD. We examined whether older adults with minimal parkinsonian motor features have nigrostriatal degeneration and α-synuclein pathology consistent with prodromal PD.

METHODS: Brain sections were obtained from older adults with a clinical diagnosis of PD (N=21) and without a clinical diagnosis of PD (N=27) who underwent motor examination proximate to death. Cases without PD were further dichotomized into no motor deficit (n=9) or minimal motor features (n-18) groups using a modified Unified Parkinson's Disease Rating Scale. We performed quantitative unbiased stereological analyses of dopaminergic neurons/terminals and α-synuclein accumulation in the nigrostriatal system.

RESULTS: In all subjects with minimal motor features, there were significant reductions in dopaminergic neurons and terminals in the substantia nigra and putamen that was intermediate between subjects with no motor deficit and PD. Phosphorylated α-synuclein inclusions were observed in the substantia nigra that were of similar density to what was seen in PD. Furthermore, there was greater Lewy neuritic pathology in the putamen relative to PD patients. Lastly, neurons with α-synuclein inclusions displayed reductions in tyrosine hydroxylase expression that was comparable in subjects with both minimal motor features and PD.

INTERPRETATION: Minimal motor features in older adults may represent prodromal PD and identify at risk individuals for testing putative neuroprotective interventions that could slow or prevent PD progression.

This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

Friday, 2 February 2018

Parkinson's in the community

This article, which comes from a large UK study of Parkinson's Disease (PRoBaND), is an important snapshot of the impact of Parkinson's across the country today. The authors focus particularly on the most common genetic risk factor for Parkinson's - the GBA mutation. This mutation is of particular interest as it is associated with a rarer syndrome - Gaucher's Disease. In this disease, which is a lysosomal storage disorder, lipids accumulate in cells and there is disruption of the normal lysosomal function which is to digest and dispose of unwanted materials. The implication from this association is that a similar process may be involved in Parkinson's Disease.

However, most people with Parkinson's do not have this mutation. Here, over 2000 patients were recruited from across the country and of these, 1893 patients underwent genetic testing. In total a minority, 142 of these patients had mutations in the GBA gene. Of these, the majority, around 2/3 had mutations not linked with Gaucher's Disease, while the other 1/3 has mutations exactly the same as those seen in Gaucher’s disease. There were differences between carriers of these two different types of mutation, with those who had the Gaucher's Disease mutations more likely to have a severe form of the disease - younger at onset, with faster progression and higher medication requirements. While previous studies have reported more cognitive impairment in GBA carriers, this was not bourne out by this study.

We still have a long way to go in connecting the dots in genetics - a number of patients had mutations whose significance is unknown and only 10% of patients had any mutations in this gene. It may be that GBA-related Parkinson's represents a slightly different disease which may have different underlying pathology and treatment options from other forms. However, the connection between lysosomal storage disorders and Parkinson's is increasingly strong and the hope is that these connections will allow us to unlock mechanisms and develop specific treatments.

J Neurol Neurosurg Psychiatry. 2018 Jan 29. pii: jnnp-2017-317348. doi: 10.1136/jnnp-2017-317348.

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.

Malek N, Weil RS, Bresner C, Lawton MA, Grosset KA, Tan M, Bajaj N, Barker RA, Burn DJ, Foltynie T, Hardy J, Wood NW, Ben-Shlomo Y, Williams NW, Grosset DG, Morris HR; PRoBaND clinical consortium.

To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function.

We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia.

We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage.

Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD.

Tuesday, 30 January 2018

Seeing the future

We are proud to announce another research paper from the Predict-PD stable. We have published our data from the imaging substudy of the first phase of our research.

50 individuals who had gone through the website had a scan showing dopamine-releasing areas in the brain (known as a DAT-SPECT or DATSCAN) and transcranial ultrasound. The DATSCAN is the closest we have to a scan that gives proof of Parkinson’s in the brain. Ultrasound shows an area in the region most affected by Parkinson’s that is brighter in people with Parkinson’s compared to healthy people.

Our findings show that the reductions in the dopamine scan were correlated with risk scores, worse movement scores both on clinical assessment and using the keyboard tapping test, and worse sense of smell. The ultrasound scan also correlated with risk score and motor score on clinical assessment.

These findings show that the risk score calculated from the responses on the website are associated with changes on brain scans that are associated with established Parkinson’s. This is exciting news, not just for us, but it has established that there are hard changes in the brains of those at the highest risk that are very likely to be the earliest signs of Parkinson’s. These scans may well be used to prove eligibility for people to be included  in future drug trials to slow, stop or prevent the diagnosis.

What are the next steps? I’ll be repeating this on a larger sample, and not just using DATSCAN and ultrasound but MRI too, which will give a highly detailed map of the strucutre of the brain. I look forward to sharing these results with you in the next few years.


Dopamine reuptake transporter–single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson's disease
Alastair J. Noyce MRCP, PhD, John Dickson PhD, Richard N. Rees MRCP, Jonathan P. Bestwick MSc, Ioannis U. Isaias MD, PhD, Marios Politis MD, PhD, Gavin Giovannoni FRCP, PhD, Thomas T. Warner FRCP, PhD, Andrew J. Lees FRCP, MD, Anette Schrag FRCP, PhD

  • First published: 30 January 2018

Objective: The objective of this study was to examine whether prediagnostic features of Parkinson's disease (PD) were associated with changes in dopamine reuptake transporter–single-photon emission computed tomography and transcranial sonography.
Methods: Prediagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents. A total of 46 participants were included in analyses of prediagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter–single-photon emission computed tomography and nigral hyperechogenicity on transcranial sonography.
Results: The striatal binding ratio was associated with PD risk estimates (P = .040), University of Pennsylvania Smell Identification Test (P = .002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (P = .024), tapping speed (P = .024), and MDS-UPDRS motor scores (P = .009). Remotely collected assessments explained 26% of variation in the striatal binding ratio. The inclusion of MDS-UPDRS motor scores did not explain additional variance. The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (P < .001) and MDS-UPDRS scores (P = .03) only.
Conclusions: The dopamine reuptake transporter–single-photon emission computed tomography results correlated with motor and nonmotor features of prediagnostic PD, supporting its potential use as a marker in the prodromal phase of PD. Transcranial sonography results also correlated with risk scores and motor signs.

Treat the person not the scan

When learning clinical medicine, (junior) doctors can often show an over-reliance on blood tests and scans, rather than focussing on the ...