Christopher H. Hawkes

Parkinson's disease: a dual‐hit hypothesis

Accumulating evidence suggests that sporadic Parkinsons disease has a long prodromal period during which several non‐motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissners plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinsons disease is pathogenic access to the brain through the stomach and nose – hence the term ‘dual‐hit’.

Meta-analysis of early nonmotor features and risk factors for Parkinson disease.

To evaluate the association between diagnosis of Parkinson disease (PD) and risk factors or early symptoms amenable to population‐based screening.

Olfaction in Neurodegenerative Disorder

There has been an increase of interest in olfactory dysfunction since it was realised that anosmia was a common feature of idiopathic Parkinsons disease (PD) and Alzheimer‐type dementia (AD). It is an intriguing possibility that the first sign of a disorder hitherto regarded as one of movement or cognition may be that of disturbed smell sense. In this review of PD, parkinsonian syndromes, essential tremor, AD, motor neurone disease (MND) and Huntingtons chorea (HC) the following observations are made: 1) olfactory dysfunction is frequent and often severe in PD and AD; 2) normal smell identification in PD is rare and should prompt review of diagnosis unless the patient is female with tremor‐dominant disease; 3) anosmia in suspected progressive supranuclear palsy and corticobasal degeneration is atypical and should likewise provoke diagnostic review; 4) hyposmia is an early feature of PD and AD and may precede motor and cognitive signs respectively; 5) subjects with anosmia and one ApoE‐4 allele have an approximate 5‐fold increased risk of later AD; 6) impaired smell sense is seen in some patients at 50% risk of parkinsonism; 7) smell testing in HC and MND where abnormality may be found, is not likely to be of clinical value; and 8) biopsy of olfactory nasal neurons shows non‐specific changes in PD and AD and at present will not aid diagnosis.

Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease.

Increasing recognition that Parkinsons disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non‐motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.

Parkinson's disease: the dual hit theory revisited.

Accumulating evidence suggests that sporadic Parkinsons disease (sPD) has a long prodromal period during which several nonmotor features develop; in particular, impairment of olfaction, vagal dysfunction, and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexuses of the foregut. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (a) nasal, with anterograde progression into the temporal lobe; and (b) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissners plexus and via transsynaptic transmission reach the preganglionic parasympathetic motor neurons of the vagus nerve. This would allow retrograde transport into the medulla and from here into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sPD is pathogenic access to the brain through the foregut and nose—hence the term “dual hit.”

The prodromal phase of sporadic Parkinson's disease: Does it exist and if so how long is it?†

It is frequently assumed that idiopathic Parkinsons disease starts with several nonmotor symptoms and signs, but the evidence for this stage in the disease process is of variable quality. This review evaluates the more robust prospective or pathologically confirmed publications to establish whether there is a premotor period and if so what is its duration. The most informative studies are considered to be those concerned with olfaction, dysautonomia, and sleep disorder. Estimates for the duration of the prodromal phase vary from months to decades. It is concluded that there probably is an early phase in the disease where a variety of nonmotor features develop, but the sequence and time of onset of such features is not well established.

Olfactory tests in the diagnosis of essential tremor.

Most patients with tremor-dominant Parkinsons disease (PD) have impaired smell function but it is unclear whether this is true for subjects with essential tremor (ET). If ET patients do not exhibit meaningful smell loss, then olfactory testing may help to distinguish PD from ET. We assessed olfactory function in 59 ET and 64 tremor-dominant PD patients using the University of Pennsylvania Smell Identification Test (UPSIT) and olfactory event-related potential (OERP). UPSIT scores were compared to those from 245 healthy controls, and OERPs were compared to those from 74 controls. Unlike the PD test scores, those of ET patients were indistinguishable from controls when the effects of age, age of onset, gender, and smoking were taken into account. ET patients with a family history of tremor scored significantly better than controls on the UPSIT, and their rate of decline with age was slower. The effect was not observed on OERP. Smell testing may help to distinguish between ET and tremor-predominant PD, and patients with family history of tremor may represent a subgroup whose olfactory function is enhanced by some unknown mechanism.

Choreic syndrome and coeliac disease: a hitherto unrecognised association.

Coeliac disease has been associated with a variety of neurological conditions, most frequently cerebellar ataxia and peripheral neuropathy. To date, chorea has not been associated with coeliac disease. We present the case histories of 4 individuals with coeliac disease and chorea (4 women, average age of onset of chorea 61 years). Unexpectedly, most of these patients showed a notable improvement in their motor symptoms after the introduction of a gluten‐free diet.

Abnormality of taste and smell in Parkinson's disease

BACKGROUND Smell sense is impaired in classic Parkinsons disease (PD). An initial study found no change in taste threshold in non-demented PD subjects and pathological studies suggest that the first relay for taste, the nucleus of the solitary tract, is spared. We wished to determine if taste is abnormal in PD and whether it is associated with smell dysfunction. METHODS Taste threshold was estimated using the Rion electrogustometer and olfaction by the University of Pennsylvania Smell Identification Test (UPSIT) in 75 non-demented PD patients and 74 controls. RESULTS There was a significant impairment of taste threshold and severe disorder of smell identification in the PD group. Age, duration of symptoms, disability, and smoking had no important effect on threshold measurement and there was no correlation between taste and smell dysfunction. Sensitivity analysis suggested that a provisional diagnosis of PD would be confirmed if smell or taste were abnormal; conversely, the diagnosis would merit review if both modalities were normal. CONCLUSIONS Impaired taste appreciation was found in about 27% of patients with clinically defined PD. There were no important effects from age, disease severity or smell sense. Given the sparing of the first and second order taste neurones in PD, disorder of taste in PD most likely signifies involvement of the frontal operculum or orbitofrontal cortex, in keeping with advanced disease, although confounding by drug effects and changes in salivary constitution could not be excluded completely.

PREDICT-PD: Identifying risk of Parkinson's disease in the community: methods and baseline results

Objectives To present methods and baseline results for an online screening tool to identify increased risk for Parkinsons disease (PD) in the UK population. Methods Risk estimates for future PD were derived from the results of a systematic review of risk factors and early features of PD. Participants aged 60–80 years without PD were recruited by self-referral. They completed an online survey (including family history, non-motor symptoms and lifestyle factors), a keyboard-tapping task and the University of Pennsylvania Smell Identification Test. Risk scores were calculated based on survey answers. Preliminary support for the validity of this algorithm was assessed by comparing those estimated to be higher risk for PD with those at lower risk using proxies, including smell loss, REM-sleep behaviour disorder and reduced tapping speed, and by assessing associations in the whole group. Results 1324 eligible participants completed the survey and 1146 undertook the keyboard-tapping task. Smell tests were sent to 1065 participants. Comparing the 100 highest-risk participants and 100 lowest-risk participants, median University of Pennsylvania Smell Identification Test scores were 30/40 versus 33/40 (p<0.001), mean number of key taps in 30 s were 55 versus 58 (p=0.045), and 24% versus 10% scored above cut-off for REM-sleep behaviour disorder (p=0.008). Regression analyses showed increasing risk scores were associated with worse scores in the three proxies across the whole group (p≤0.001). Conclusions PREDICT-PD is the first study to systematically combine risk factors for PD in the general population. Validity to predict risk of PD will be tested through longitudinal follow-up of incident PD diagnosis.