Parkinson's Disease and Movement Disorders Unit, Institut Clínic de Neurosciències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Hospital Clínic de Barcelona, Barcelona 08036, Spain.
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.
"Thus, disease-modifying therapies should be much more promising when instated in early premotor stages of PD. To this end, PD risk scores have been introduced [30, 31]. Stages 5 and 6, finally, are characterized by the involvement of the basal forebrain and cortical regions, including the entorhinal cortex and the cornu ammonis regions of the hippocampus. "
[Show abstract][Hide abstract] ABSTRACT: In Parkinson's disease (PD) and other synucleinopathies, chronic neurodegeneration occurs within different areas of the central nervous system leading to progressive motor and nonmotor symptoms. The symptomatic treatment options that are currently available do not slow or halt disease progression. This highlights the need of a better understanding of disease mechanisms and disease models. The generation of newborn neurons in the adult hippocampus and in the subventricular zone/olfactory bulb system is affected by many different regulators and possibly involved in memory processing, depression, and olfaction, symptoms which commonly occur in PD. The pathology of the adult neurogenic niches in human PD patients is still mostly elusive, but different preclinical models have shown profound alterations of adult neurogenesis. Alterations in stem cell proliferation, differentiation, and survival as well as neurite outgrowth and spine formation have been related to different aspects in PD pathogenesis. Therefore, neurogenesis in the adult brain provides an ideal model to study disease mechanisms and compounds. In addition, adult newborn neurons have been proposed as a source of endogenous repair. Herein, we review current knowledge about the adult neurogenic niches in PD and highlight areas of future research.
"Little is known about the progression and the natural history regarding the large range of NMS that complicate the journey of a patient with PD. The NMS are recognized to be present from the " pre-motor " stage  to the final palliative stage of PD . Interestingly , while motor progression in PD appears to follow a largely linear pattern, NMS are more complicated and while few remain static, other may improve and some may worsen . "
[Show abstract][Hide abstract] ABSTRACT: Background: Recent studies have demonstrated that, contrary to common perception non-motor symptoms (NMS) occur and may dominate early and untreated stage of Parkinson's disease (PD). Objective: The aim of this ongoing study was to describe the overall NMS profile and burden in drug naïve PD patients (DNPD) compared to a group of long-term PD patients (LTPD, disease duration ≥15 years). Methods: Cross sectional UK data from a multicenter (16 sites) collaboration were obtained and specifically NMS dataset from validated scales were analysed in DNPD and LTPD patients. The NMS scale (NMSS) was used as the primary outcome variable. Results: Out of a current database of 468 PD patients, 57 were DNPD (58% males, mean age 64.8 years, median Hoen and Yahr stage 1) and 25 were LTPD (44%, mean age 67.6 years, median Hoen and Yahr stage 3). DNPD patients had a significantly lower (p = 0.001) NMSS score (mean 45.5, range 1-150) compared to the LTPD patients (mean 74.0, range 6-155), but 26.3% had severe and 19.3% had very severe burden of NMSS using NMSS cutoff scores. In comparison, 20.0% of the LTPD patients had severe and 60.0% very severe burden of NMS (p = 0.003). Conclusions: NMS are common in DNPD patients and over 45% may have severe to very severe burden of NMS, which is a key determinant of quality of life. In LTPD patients not only the burden of "very severe" NMS is significantly higher, but there are also differences in the profile of expression of NMS.
"Braak et al. have proposed that pathologic involvement of PD starts from lower brainstem, peripheral and central ANS, and olfactory bulb, and progresses rostrally (Burke et al., 2008; Tolosa et al., 2009). Therefore, it has been suggested that non-motor features might precede the classical motor symptoms of PD (Tolosa et al., 2009). In this study, we examined SSR of forehead and extremities in addition to other associated parameters of ANS in early and advanced stage PD patients and controls, to see whether forehead SSR is impaired sooner than extremity SSR in PD. "
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate forehead sympathetic skin response (SSR) and demonstrate any differences with extremity SSR in determining autonomic nervous system (ANS) involvement in patients with Parkinson's disease (PD).
Twenty early stage, 20 advanced stage idiopathic PD patients and 20 healthy controls participated in this study. SSR of forehead, hands and feet, heart rate variability (HRV), orthostatic intolerance, QT intervals and dysautonomic symptoms were evaluated.
Absent forehead SSR was determined unilaterally in 4, bilaterally in 7 early stage patients, and unilaterally in 4, bilaterally in 8 advanced stage PD patients; there was significant difference between early and advanced stage PD and control groups in terms of the lack of SSR (p=0.000). Absent extremity SSR was determined in at least 1 extremity of 3 advanced stage PD patients, and none of the early stage PD patients. No difference was noted in HRV at rest between early and advanced stage PD and control groups (p=0.218); but HRV at deep breathing was lower in both early and advanced PD patients compared to controls (p=0.014, p=0.002, respectively).
Forehead SSR is more sensitive in determining ANS dysfunction not only in late but also in early stage of PD.
With further supportive research, forehead SSR might be used as a simple diagnostic electrophysiological test in the early diagnosis of ANS dysfunction enabling proper treatment and increasing the quality of life of PD patients.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 04/2014; 125(12). DOI:10.1016/j.clinph.2014.03.024 · 3.10 Impact Factor
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