Premotor Phase Of Parkinson's Disease Research Articles

Striatal cholinergic interneurons regulate cognitive and affective dysfunction in partially dopamine-depleted mice.

Early non-motor symptoms such as mood disorders and cognitive deficits are increasingly recognised in Parkinson's disease (PD). They may precede the characteristic motor symptomatology caused by dopamine (DA) neuronal loss in the substantia nigra pars compacta (SNc). It is well known that striatal cholinergic interneurons (ChIs) are emerging as key regulators of PD motor symptom, however, their involvement in the cognitive and affective alterations occurring in the premotor phase of PD is poorly understood. We used optogenetic photoinhibition of striatal ChIs in mice with mild nigrostriatal 6-hydroxydopamine (6-OHDA) lesions and assessed their role in anxiety-like behaviour in the elevated plus maze, social memory recognition of a congener and visuospatial object recognition. In transgenic mice specifically expressing halorhodopsin (eNpHR) in cholinergic neurons, striatal ChIs photoinhibition reduced the anxiety-like behaviour and reversed social and spatial short-term memory impairment induced by moderate DA depletion (e.g., 50% loss of tyrosine hydroxylase TH-positive neurons in the SNc). Systemic injection of telenzepine (0.3mg/kg), a preferential M1 muscarinic cholinergic receptors antagonist, improved anxiety-like behaviour, social memory recognition but not spatial memory deficits. Our results suggest that dysfunction of the striatal cholinergic system may play a role in the short-term cognitive and emotional deficits of partially DA-depleted mice. Blocking cholinergic activity with M1 muscarinic receptor antagonists may represent a possible therapeutic target, although not exclusive, to modulate these early non-motor deficits.

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson's Disease.

Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0–6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.

TREATMENT AND REHABILITATION IN NON-MOTORS SYMPTOMS OF PARKINSON’S DISEASE

Parkinson's disease (PD) is the second most common neurodegenerative disease. The cardinal clinical features of PD are motor and include bradykinesia, rigidity, and resting tremor with an asymmetric pattern. Apart from these, various nonmotor symptoms (NMS) also occur in PD and constitute a major clinical symptoms. NMS can present at any stage of the disease including early and pre-motor phase of PD. Management of PD requires recognition of both motor and nonmotor symptoms as well as an understanding of the relationship between these symptoms and how they can be affected by treatments for PD. Therapy should be individualized for each patient, as treatments for the motor symptoms of PD can improve some nonmotor symptoms while they can worsen others. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with antiparkinsonian drugs . Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs in association with rehabilitation programs . In the future, development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration are the best hope of ameliorating non-motor symptoms

Cardiac stress test is normal in pre-motor Parkinson's disease.

Cardiac sympathetic denervation is an early nonmotor feature of Parkinson's disease (PD). The aim of the current study was to trace evidence for cardiac dysfunction abnormalities in the premotor phase of PD. We retrospectively reviewed treadmill ergometric tests of a large cohort (n = 16,841) between 2000 and 2012, that attended the Executive Screening Survey (ESS) at Sheba Medical Center. Heart rate and blood pressure profiles as well as exercise capacity were compared between subjects who later developed PD and age- and sex-matched subjects (ratio 1:2) who did not. We identified 28 subjects (24 males) who developed PD at follow-up. The PD group was older than the group of subjects who did not develop PD on first ergometric test (64.82 ± 8.82 vs. 48.91 ± 10.60 years, P < 0.001). The time between the first ergometric test and motor symptoms onset was 4.64 ± 2.86 years. Patients who later developed PD had lower maximal heart rate (P < 0.001) and lower heart rate reserve than healthy controls (P < 0.001); however, compared with age- and sex-matched subjects, subjects who developed PD had similar exercise capacity and heart rate profile during rest, exercise, and recovery, even 1 year before diagnosis. In this study, we did not detect significant signs of sympathetic dysfunction during the premotor phase of PD.

Hyposmia and cardiovascular dysautonomia correlatively appear in early-stage Parkinson's disease

ObjectiveOlfactory dysfunction is considered to precede motor symptoms and early markers of Parkinson's disease (PD), while the relative time at which cardiovascular dysautonomia appears in PD is not well understood. To assess the appearance of cardiovascular dysautonomia in PD, we evaluated its relation to olfactory dysfunction in early-stage PD patients. MethodsTwenty-three non-demented PD patients within 2 years from the onset of motor symptoms were enrolled. We evaluated olfactory dysfunction by the Odor Stick Identification Test for Japanese (OSIT-J) and analyzed its relationship to the results of other cardiovascular autonomic tests and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy. ResultsThere was a correlation between olfactory scores and increased blood pressure in both the norepinephrine (r = 0.75, p < 0.0001, n = 21) and dobutamine (r = 0.57, p = 0.0087, n = 20) infusion tests and cardiac MIBG uptake (r = 0.42, p = 0.049, n = 23). The fall in orthostatic blood pressure during the head-up tilt test was not correlated with the olfactory scores, but the Valsalva maneuver revealed that OSIT-J scores correlated with the pressure recovery time from phase III to the return of blood pressure to baseline (r = 0.54, p = 0.037, n = 15) and with the magnitude of blood pressure overshoot during phase IV (r = 0.67, p = 0.0016, n = 20). ConclusionOur results demonstrate that extensive components of the cardiovascular sympathetic system as well as the olfactory system are correlatively impaired in the early stage of PD, suggesting that degeneration of broad aspects of the cardiovascular sympathetic system occurs concurrently with olfactory system degeneration during the premotor phase of PD.

In Vivo Detection of Monoaminergic Degeneration in Early Parkinson Disease by 18F-9-Fluoropropyl-(+)-Dihydrotetrabenzazine PET

PET with (18)F-9-fluoropropyl-(+)-dihydrotetrabenzazine ((18)F-DTBZ), a novel radiotracer targeting vesicular monoamine transporter type 2 (VMAT2), has been proven as a useful imaging marker to measure dopaminergic integrity. The aim of this study was to evaluate the capability of (18)F-DTBZ PET in detecting the monoaminergic degeneration in early Parkinson disease (PD) in vivo. Seventeen age-matched healthy subjects and 30 PD patients at early stage of disease (duration of disease ≤ 5 y) with mild and unilateral motor symptoms underwent (18)F-DTBZ PET scans. The severity of disease, including Unified Parkinson Disease Rating Scale and modified Hoehn and Yahr Stage (mHY), were recorded at off-medication states. The standardized volumes of interest were applied to the spatial normalized image for quantification analysis. The specific uptake ratios (SURs) were calculated according to the formula (specific volumes-of-interest counts/occipital cortex counts) - 1. SUR measurements were summarized for each brain region. The mean duration of disease in the PD group was 3.2 ± 2.1 y (range, 0.5-5 y). The mean mHY was 1.0 ± 0.1 (range, 1-1.5). The SURs of bilateral caudate, anterior putamen, posterior putamen, substantia nigra, and nucleus accumbens were significantly lower in PD patients than those of healthy subjects. The reduction of SURs was most severe in the contralateral (the brain regions that are located opposite to the symptomatic side) posterior putamen (-81%), followed by the ipsilateral posterior putamen (-67%). Receiver-operating-characteristic curve analysis showed that the SURs of the bilateral posterior putamen and contralateral anterior putamen had a sensitivity of 100% and specificity of 100% in differentiating PD patients from healthy subjects. (18)F-DTBZ PET was as an excellent tool for the early diagnosis of PD. The obvious decline of (18)F-DTBZ uptake in the ipsilateral (asymptomatic) striatum suggested that (18)F-DTBZ PET might serve as an in vivo biomarker to detect the monoaminergic degeneration in the premotor phase of PD.

Preceding pain symptoms and Parkinson's disease: a nationwide population‐based cohort study

Painful sensations are recently reported to be a non-motor feature of Parkinson's disease (PD). The non-steroidal anti-inflammatory drug ibuprofen is a common painkiller and was reported to be associated with a decreased risk of PD. The aim of the present study was to examine the relationship amongst preceding pain symptoms, use of ibuprofen and risk of PD in a nationwide population-based cohort. The data of participants who were free of PD at baseline were obtained from two large National Health Interview Surveys (NHIS) in Taiwan, conducted in 2001 and 2005. The information regarding pain status included severity and location of pain. Information regarding pain status, use of ibuprofen, comorbidity of depression and PD-associated risk/protective behaviors was adjusted using proportional hazards models. Amongst 33388 participants, 32 cases of incident PD were identified after a mean follow-up of 3years. After adjusting for the use of ibuprofen and other PD risk factors, subjects with preceding pain symptoms had a higher incidence of PD than those without pain at baseline, and the hazard ratio was 1.79 (95% CI: 0.71-4.51, P=0.21) for mild pain and 2.88 (95% CI: 1.05-7.86, P=0.04) for moderate or severe pain. The PD risk increased by 34% with each additional increment in pain score [hazard ratio = 1.34 (1.03-1.75), P=0.03], showing a dose-response relationship. These findings support the hypothesis that pain is associated with PD in the pre-motor stage of the disease. Further research is needed to clarify the role of sensory system involvement in the pre-motor phase of PD.

Progress in defining the premotor phase of Parkinson's disease

Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset.Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD.

Diagnosing premotor Parkinson's disease using a two-step approach combining olfactory testing and DAT SPECT imaging

Extranigral neuropathological changes may precede the degeneration of nigrostriatal dopaminergic neurones in Parkinson's disease (PD). Therefore, non-motor disturbances are an interesting target for the development of tests aimed at identifying individuals with premotor PD. An impaired sense of smell occurs with high prevalence in the clinical motor stages of PD patients and has also been reported in first-degree relatives of PD patients. In a prospective study in 361 asymptomatic first-degree relatives of PD patients, we studied the value of a two-step approach, combining olfactory testing and dopamine transporter (DAT) SPECT imaging, in detecting patients in the premotor phase of PD. Unexplained hyposmia alone was associated with a 12.5% risk of developing PD within a five year period. Cox regression analysis revealed that odour discrimination performance was most strongly correlated with the risk of future PD. Furthermore, all relatives that later developed PD had both hyposmia and abnormally reduced striatal DAT binding at baseline. The results of our studies provide the proof-of-principle that a two-step approach of olfactory testing and DAT SPECT imaging may serve to diagnose PD in its premotor phase. Yet, the low positive predictive value of hyposmia indicates that a wider application of this approach for screening purposes would require too many DAT SPECT scans in healthy individuals. Therefore, future studies in larger populations are necessary to further characterize premotor PD and identify additional genetic and/or clinical susceptibility markers to be used in conjunction with olfactory testing as additional screening steps toward diagnosing PD in its earliest stages.

Diagnosis and the premotor phase of Parkinson disease

Clinical, neuroimaging, and pathologic studies have provided data suggesting that a variety of nonmotor symptoms can precede the classic motor features of Parkinson disease (PD) by years and, perhaps, even decades. The period when these symptoms arise can be referred to as the "premotor phase" of the disease. Here, we review the evidence supporting the occurrence of olfactory dysfunction, dysautonomia, and mood and sleep disorders, in this premotor phase of PD. These symptoms are well known in established PD and when presenting early, in the premotor phase, should be potentially considered as an integral part of the disease process. Even though information on the premotor phase of PD is rapidly accumulating, the diagnosis of premotor PD remains elusive at this time. Should a safe and effective treatment with disease-modifying or neuroprotective potential in PD become available, identifying individuals in the premotor phase will become a serious priority.