Parkinsons Disease Case

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Abnormal alpha-synuclein proteins in particular have been implicated in the development of Lewy bodies and the progressive spread of PD. This is based on evidence alpha-synuclein misfolds in PD [BURKE]. and also makeup the primary component of Lewy bodies [BURKE].. These findings add further weight to the accumulating evidence for the Braak staging model. It suggests misfolded alpha-synuclein interact with normal alpha-synucleins within other cells to induce normally conformed alpha-synuclein molecule to take up the abnormal conformation in a prion-like process called protein templating [Visanji]. In this way and in combination with retrograde axonal transport, a hypothesized gastric peripheral origin [Visanji] of alpha-synuclein pathology can propagate cell to cell and via the vagus nerve reach the lower brainstem, spreading in a caudo-rostral fashion come to subsequently reach the midbrain, forebrain and cerebral cortex [Visanji]. This proposed pattern of spread dovetails with the progressive pathological manifestations seen in PD.

[pic 1][BURKE]

[BURKE] - A Critical Evaluation of The Braak Staging Scheme for Parkinson’s Disease http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605160/

NON-MOTOR Symptoms (NMS) and their predictive value

The structures of the basal ganglia involve five major neural pathways (motor, oculomotor, associative, limbic and orbitofrontal) [Galvez-Jimenez ], and are all disrupted in PD i.e not just dopaminergic loss but also a degeneration of non-dopaminergic transmitter symptoms [OBESO]. Consequently the wide variety\multitude of functions these pathways act in are impacted upon and give rise to a diverse range of NMS. Subcategories of NMS include neuropsychiatric, autonomic and sensory subtypes [TODOROVA]. Collectively it is the burden of non-motor rather than motor symptoms that determine the extent of reduction in quality of life (QOL) in PD patients and their carers. [YOON SANG-OH].

NMS are present throughout the course of the disease and some may precede the classical outward motor signs by decades and thus suggest a prodromal phase to PD. On average a PD patient may display between 8-12 non-motor symptoms and at least one NMS at time of diagnosis [ROBERTO ERRO]. Reported prevalence and incidence of NMS does greatly vary in the literature though those commonly described to precede motor symptoms include: drooling, constipation, urinary symptoms, hyposmia, cardiovascular dysfunction, sleep disorders, musculoskeletal pain, sexual dysfunction, cognitive and neuropsychiatric symptoms. [Maria C Rodriquez] [Jose-Alberto Palma] [GOLDMAN] [Anne Marie Bonnet]

[pic 2]

Progresion of Parkinsons - https://www.youtube.com/watch?v=pKdhEPEc20Q

Further possible NMS with PD progression may include: dysphonia, thermoregulation deficits, weight gain, orthostatic hypotension, bladder and bowel dysfunction. [J Jankovic] [Anne Marie Bonnet]

Hyposmia (85%)[goldman], constipation [80%][Verbaan], Fatigue (80%), and cardiovascular dysfunction [Jose-Alberto Palma] are thought to be virtually universal in PD and those most frequently described in the pre-motor phase (40%-60%) [Jose-Alberto Palma, Anne Marie Bonnet, [GOLDMAN] . The presence of rapid eye movement behaviour sleep disorder (RBD) has been associated with a significantly higher predictive risk for PD development [Goldman] above other NMS. Also a 2013 study found RBD to potentially ‘precede motor symptoms by up to 29 years’ [Schenck]

A study of psychiatric symptoms found ‘apathy, anxiety, and depression precede disease onset in 30%’ [SHIBA] of new patients. Another study reported ‘depression (37%), apathy (27%), sleep disturbances (18%), and anxiety (17%)’ [Aarsland].

Olfactory function has been observed to precede PD diagnosis by up to 8 years [GOLDMAN]. In the Honolulu-Asia Aging study an increased 5.2 risk for developing PD was reported for study subjects clustered in the lowest quartile following a smell identification test [Abbott]. Sexual dysfunction has been acknowledged in up to 79% of men and 75% of woman with PD. A retrospective analysis study of erectile dysfunction in PD found a 3.8-fold increased risk of developing PD at baseline [Jose-Alberto Palma]. The Honolulu-Asia Aging study reported a 2.7-4.1 times increased risk of PD for males whom experienced less than 1 bowel movement /day and also a potential pre-diagnostic presence of constipation symptom by more than 15 years [Abbott].

Depression and anxiety are common neuropsychiatric symptoms occurring in some 30% of cases [GOLDMAN]. Similarly depression, anxiety and apathy were found to precede PD onset in 30% of cases [Maria C Rodriquez]. Cognitive deficits have been reported to be present in 20%-40% of early PD patients and consistently increase in severity and prevalence with PD progression [Muslimovic]. Dementia in particular is regarded as one of the greatest sources of disability and a key determinant of QOL and significantly increases mortality [J Jankovic]. At diagnosis it affects some 25% in the early stages, increasing up to 80% of patients after 20 years [Fabiola De Marchi].

[Galvez-Jimenez ]Scientific Basis for the Treatment of Parkinson's Disease, Second Edition

By Nestor Galvez-Jimenez

[WIRDEFELDT] – epidemiology and etiology of Parkinsons disease

OBESO - http://www.nature.com/nm/journal/v16/n6/full/nm.2165.html

[SHIBA] - Anxiety disorders and depressive disoreders preceding Parkinson disease.

[Aarsland] – The spectrum of neuropsychiatric symptoms in patients with early untreated parkinsons

[Muslimovic] – Cognitive profile of patients with newly diagnosed parkinsons disease.

[Schenck] - CH, Boeve BF, Mahowald MW. Delayed emergence of a parkinsonian disorder or dementia in 81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (RBD): 16year update on a previously reported series. Sleep Med. 2013 Jan 21;PubMed.

[ROBERTO ERRO] – Non-motor Symptoms in Early Parkinson's Disease. http://www.medscape.com/viewarticle/777158_4

[36& ,37–41]

36 - Duncan GW, Khoo TK, Yarnall AJ, et al. Health-related quality of life in early Parkinson’s disease: the impact of nonmotor symptoms.