Cognitive and Psychological Anomalies in Parkinsons Disease: An Insight into Non-Motor Characteristic Features

Corresponding Author:

Amarendranath Choudhury, PhD
Jaipal Homes, Hightension Road, Kondapur
Hyderabad-500084, India & Alumnus
Department of Life Science and Bioinformatics
Assam University, Silchar-788011, India
Tel: +91-7003017920

Abstract

While most of the clinical concerns for Parkinson’s disease (PD) are limited to the cardinal motor abnormalities, non-motor features like cognitive and psychological anomalies are also acquired ample of importance in last few decades. Progressive research has showcased several obvious incidences of cognitive and psychological anomalies in the pathophysiology of PD. It has been reported that, almost 30% PD sufferers show different degree of cognitive
impairment but lack of awareness or negligence makes it difficult to diagnose it, at the initial stage of the disease. As a result, cognitive and psychological impairments continue to increases progressively and deteriorate the quality of life of the patient. It is presumable that, early detection of PD can be achieved by the identification of specific set of cognitive and psychological anomalies and the similar scope might open up new avenue in the non-invasive diagnosis of PD. In the present review, we have accumulated all the timely documentation on cognitive and psychological anomalies in PD and highlighted most of the non-motor features with rational justification for the relevance of their study in the early diagnosis of PD.

Keywords

Parkinson’s disease, Cognition, Psychology, Depression, Anxiety, Memory

Introduction

Parkinson’s disease (PD) is a chronic, insidious neurodegenerative disorder characterized by classical symptoms like bradykinesia, rest tremor, rigidity, and postural disturbances [1]. The pathophysiological scenario of PD includes the cytotoxic aggregation of α-synuclein, which forms Lewy Body-the eosinophilic hollow structure, regarded as the ‘hall-mark’ feature for PD [2,3]. Besides motor abnormalities [4], PD also has been reported with few non-motor psychological [5] and cognitive anomalies [6], which are comparatively less highlighted in last ten decades, since PD discovery [7]. During clinical diagnosis by Aarsland et al. 19% cognitive deficit PD patient were identified, which is one of the notable findings exploring the association between PD and cognitive impairment [8]. Progressive research has showed that, cognitive impairment with or without dementia is also a predominant feature of PD [9]. Statistically, PD with dementia is having a global prevalence rate of 30%, which is evident in a cross-sectional study by Aarsland et al. and they also have suggested almost 80% life-long risk are there with similar types of patients [10].

It has been reported that, PD patients often face it troublesome to concentrate in deep thinking and feel distracted or disorganized in planning specific tasks [11,12]. Moreover, attention deficiencies are also common in PD patients when they were accessed for group discussion or conversation. Most of the time ‘missing information’ or ‘weak memory’ feeling appears among the sufferers of PD [13]. Another notable fact regarding memory impairments reflects among PD patients, while they try to express their feeling in verbal way. Lack of proper word selection, incomplete sentence throwing and stumbling during conversation is quite common in PD [14]. Anger and anxiety are also evident among PD patients while managing common household affairs, which frequently interfere in the quality of life of the sufferers [15]. Studies have shown that, stress and depression also quite common in PD [16] and sometimes adverse effect of prescribed medication deteriorates the scenario even worse [17,18]. Though, cognitive impairment and dementia both affect memory function but, cognitive impairment is considered as the far early stage of dementia and reports have shown that, most of the cases cognitive impairment develops dementia in the late stages of PD [19,20]. Majority of therapeutic interventions for Parkinsonian dementia are still under investigation and available drug Rivastigmine tartrate (Exelon^®) has been marketed with three adverse side effects like gastrointestinal adverse reactions, Allergic dermatitis and increased cholinergic activity [21].

Sometimes, researchers represent psychological and cognitive anomalies in PD as mild cognitive impairment and motor disabilities become predominant concerns to physicians [22]. Hence, the severity and apprehensions related to nonmotor symptoms gets lesser importance [23]. Though, proper scientific studies and justified application of such non-invasive cognitive and psychological tests could open up new possibilities to innovate early diagnostic tools for PD. Here in this present study, we have accumulated all the relevant information on cognitive impairment and psychological anomalies and highlighted the importance of such alterations in early diagnosis of PD (Figure 1).

Cognitive Impairments in Parkinson’s Disease

By definition, cognition is the conglomeration of several different mental skills and activities, which precipitates in the behavior and intelligence of an individual [24]. In mechanistic way, cognition is described as the synchronized processes of brain function that helps an individual to discover the ambient environment around itself and also assists to interact in a controlled and appropriate manner [25]. Proper cognitive assistance explores the sense of perceptions, stores it in memory and retrieves the same depending upon need and/or usage [26]. This is the generalized path to boost and enrich the memory ability, which reflects in the process of learning, planning, solving, thinking, and linguistic skill development [24,27].

Abnormalities in neuronal structure and function are highly responsible for dysregulation of said cognitive processes, which are evident in PD [28]. PD is well-known as a movement disorder clinically characterized by resting tremor, bradykinesia, postural instabilities [1,7]. However, recent progress of research and studies have highlighted the co-occurrence of nonmotor abnormalities in PD [5,29] and thereby, raising the concern to consider the cognitive impairments and psychological anomalies as an important feature for PD pathology [23,29]. In last decades, several experimental evidences have linked the occurrence of cognitive impairment with PD. In an earlier report, application of ‘Society Task Force guidelines’ on diagnostic criteria for the evaluation of mild cognitive anomalies in PD has been highlighted, which represents a novel approach justifying the relevance of such tool in PD [11,12]. Cooper et al. have reported the scenario of cognitive impairment on the untreated PD patient and found a significant correlation exists in between cognitive disabilities and motor impairments [30]. Exclusive works by Janvin et al. have represented the types and sub-types of cognitive impairments in PD patients, which further linked the cognitive impairment with the occurrence of dementia [31]. Neuropsychological and clinical heterogeneity of cognitive impairment in PD patient has also been documented with possible links supporting the disease progression towards severe dementia [32].

Movement Disorder Society’s special task force is the most appreciated approach in the said field of study, which has reviewed all the possible aspects of cognitive dysfunction in PD [12]. In a large scale clinical study with 873 idiopathic PD patients, Riedel et al. have reported that, cognitive impairment is a common incident in PD and having significance in the early diagnosis of the disease [33]. In a multicenter pooled analysis, Aarsland et al. have documented the occurrence of mild cognitive impairment in PD patient [34]. In ‘The Norwegian ParkWest Study’ by Aarsland et al. has found similar result in drug naïve PD patients [8]. Another ‘prospective longitudinal study’ has presented depression, cognitive decline, and physical impairments in patients with PD. The same article is also suggested a possible link relating the events in disease progress [35]. Several cognitive function assessment tools have been introduced in recent years. The Montreal cognitive assessment screening tool is one of the similar kinds, which were employed in the diagnosis of cognitive status of PD patient by several authors in recent years [36]. However, molecular pathological alterations are also linked with the incidence of cognitive deficiency in PD. Mattila et al. has documented a study, where α-synuclein aggregation and Lewy body formations were reported to be highly correlated with cognitive impairment in PD [37].

In an earlier report by Perry et al. documented the similar correlation with cholinergic system [38]. Beyer et al. have studied voxel-based morphometry in magnetic resonance imaging on PD patient and found cognitive impairment is linked with the progress of the disease [39]. However, herbal, dopaminergic medication and certain task test have found to be beneficial for cognitive impaired PD, as it showed improvement among sufferers [40]. Particularly, Hippocampal and prefrontal atrophy has been reported responsible for the cognitive impairment in PD [41]. Another study has claimed the possibility of cognitive impairment in Parkinson’s disease could be due to nondopaminergic lesions [42]. Pharmacological studies on cognitive improvement in PD have showed promising outcome in recent years [35]. Though, applications of most of the drugs are still debated. However, the efficacies of the drugs like Donepezil, Atomoxetine, and Citicoline cannot be ruled out owing to their promises [43]. Earlier it was believed that, the occurrence of cognitive impairment in PD is limited to mid-to-late stage of the disease progress but, recent progress of research have showed that, mild cognitive changes is quite common in early stages of PD and hence, opening an avenue of research scope for early diagnosis of the disease. Majority of cognitive impaired PD in late stage develop dementia but, early-to-middle stage of the disease is predominantly cognitive impairment, which accounts ½ to ¼th of the total PD population [19].

Types of Cognitive Impairments

Cognitive impairments in PD are of several types, which are mainly focused on particular functional disabilities. It is reported that, the severity of the cognitive impairment varies with the duration of the disease or even person to person. The functional anomalies related to behavior or intelligence is highly governed by the implication of cognitive attributes in human [44]. The major cognitive differences a physician trace in the early stage of PD includes abnormalities in execution of functions, attention difficulties, slow thinking, trouble in word selection, difficulties in remembering information, learning, hampered spatial learning and imaging capability [45,46].

▪ Difficulties in execution of function

These are the initial feelings of cognitive impairment to an individual suffering from early stage of PD [45,47]. In many instances, people often ignore the fact thinking it a transient effect of work pressure and stress. However, chronic ignorance deteriorates the situation even worse and several signs of cognitive disabilities start to express. Lack of abilities in making plans, goal formulation, process evaluation are the basic feature of function execution related cognitive abnormalities [45,48]. In the study by Koerts et al. difficulties in execution of function has been evaluated through ‘Cognitive Effort Test’ and explored the vulnerability of the PD patient in performing daily-life works [49].

▪ Attention deficiency

It is also known as attention deficit hyperactivity disorder (ADHD) which is another cognitive disability observed in PD [50]. Though, the actual relationship is still speculative but both the diseases act on same platform i.e., substantia nigra [51]. Generally, the symptoms of ADHD start at childhood ages of the sufferer and proceeds into adulthood [52]. Most of the cases attention deficiency has been observed in PD but, it is tough to evaluate whether the same patient had ADHD in childhood or not. Hence, the conclusive association is equivocal, except one report by Walitza et al. where ‘Wender Utah Rating Scale’ was used to monitor the ADHD score and it was found that, PD patients were suffering from increased attention deficit, hyperactivity and anxious and depressive behavior [50].

▪ Slow thinking

It is another feature in cognitive impaired PD patient. Comparatively such PD patients take longer time and efforts to complete tasks than a common people [14,53]. Reports have showed that, such slow process of thinking is associated with the injury or impairment in Fronto-striatal region of brain [54,55]. PD patients also find it difficult to find appropriate word to express the feelings [56]. Though, similar problems have been reported with many other diseases also [57]. Separate study, Merims and groups, Freedman and groups have reviewed the occurrence of such word-finding problem [58,59]. The same study also emphasized this phenomenon, as an inseparable part of PD, if mild motor abnormalities are present in the patients [60].

▪ Linguistic dysfunction

Another study highlighted the genetic background underlying linguistic dysfunction and explored that, lack of function or absence of apolipoprotein E epsilon4 allele is responsible for such behavior [61]. Language impairment in PD, also eloquently discussed in the work of Bastiaanse and Leenders, where detail about nature, dissociation, and progression of linguistic impairment in terms of syntactic, action-verb, and action semantic skill have been discussed [14]. Moreover, in a meta-analysis Henry et al. have showed that, verbal fluency significantly deteriorates in PD patients while compared with matched control [62]. Trouble in learning new things or remembering the information is also quite common in cognitive deficit PD patient [63].

▪ Hampered learning skill

Molecular mechanism of hampered learning skill is associated with dopamine depletion. It has been reported that, dopamine depletion in striatal region reduces the functional symmetry dorsolateral prefrontal circuit, which is extended towards orbito-frontal pathway-the region responsible for reward-based learning in human [40,64].

▪ Spatial memory functions

Cognitive deficient PD patients are reportedly lacking the ability to image the previously executed tasks and spatial memory functions [65,66]. Possin et al. executed a study for spatial memory function and found that, PD patients are having significantly lower ability to memorize or image spatial locations or shapes than randomly selected control people [67]. In another study, Pillon et al. found that lack of spatial recognition is linked with dopamine depletion and suggested striatofrontal dysfunction could be the crucial player in such cognitive impairment [68]. In a recent report, the very same dopamine involvement has been highlighted with special reference to modulation in hippocampal-striatal functions in PD [66]. Together, most of the cognitive impairments in PD are directly or indirectly influenced by dopaminergic homeostasis and such rationale justifiably put forwards the association between cognitive impairment and PD.

Psychological Abnormalities in Parkinson’s Disease

The report by Celesia and Wanamaker is one of the pioneer works focused on psychological aspects of PD [69]. In that particular report, the authors have documented the first ever clinical evidence of psychiatric abnormalities among 153 PD patients, majority of which were affected with variable degree of psychosis [69]. With the special emphasis on the non-motor characteristics of PD, the study also flagged up the well-known cross-talk between cognitive impairment and dementia [70]. Growing interests and studies on neuropsychiatric background of PD have unveiled several hitherto unexplored facts and such endeavors reflected in the progresses made so far in the therapeutics of PD [71]. McKeith and Cummings highlighted the behavioral as well as the psychological perspectives of PD [70] while, patterns of psychological problems in PD have been discussed by Macht et al. [72]. Both articles have emphasized the coincidence of psychological events as crucial characteristic features in the pathobiology of PD.

Similar notion was also evident from the studies by MacCarthy et al. where 136 PD patients were accessed for ‘Self-report measures’ and result was significantly positive for the statement of co-occurrence of motor and psychological abnormalities among the patients [73]. However, early and late onset of PD with psychological anomalies was a topic of debate since the origin of the concept. The study by Schrag et al. intercepted the fact in a questionnaire base study with 141 PD patients (75 early-onset, 66 late-onset) and found that, psychosocial factors play important role in the quality of life in young patients with PD [74]. Furthermore, study by Janvin et al. also highlighted the similar involvement of psychological abnormalities in PD patients and provided a timely note on the influences of dementia in PD pathology [75].

Types of Psychological Abnormalities

▪ Depression

Among several psychological abnormalities in PD, incidence of depression is most prevalent. Van Praag et al. reported the association between dopamine depletion and occurrence of psychological anomalies in PD, which was the first ever report of such kind [76]. Later on, Taylor et al. re-evaluated the interlinking relationships between depression and the occurrence of PD [77]. In the very next year, Rogers and colleague reported the same phenomena and provided a rational discussion on psychological anomalies in PD and other depressive illness [78]. Together, reports were in line with the crucial involvement of depression in the pathology of PD. However, actual scenario of PD pathology, in respect to depressive behavior, was lacking more justifiable evidences, and it is until the clinical study by Brown et al. that made it eloquent [79]. The study was based on a follow-up of 132 cases, and outcome of the study presented a resourceful discussion on depression and disabilities in PD. In another study, the very similar notion of depressive behavior in PD was presented by comparing the equivalent disabilities in control subjects [80].

In the succeeding decades, several research and studies were performed on depressive issues in PD. Among plenty of resources, review sumup by Dakof and Mendelsohn, Cummings, Brown et al. and Lieberman are noteworthy [81-84]. However, discussion on quality of life of PD patients with depression by Schrag is another piece of appreciable work [85]. Torbey et al. reviewed the ‘Depression rating scales in Parkinson’s disease’, which is having timely importance in PD research [86]. It has been reported that, variable degree of depression is quite common in PD. According to physicians, depression can occur without any Parkinsonian symptoms in pre-early stage of PD or even it can appear with certain intervals [87]. Neurochemical dysregulation mainly in nigro-striatal region has been postulated as the prime factor underlying long lasting depression in PD [88]. Modulation of dopamine, norepinephrine and serotonin production has been shown promising improvement in the depression oriented chronic illness and in PD also [89]. Some reports also have indicated the potential role of depression in the deterioration of the PD pathology [90]. Very common appearances of PD depression include long lasting sadness, lack of interest, unnecessary guilty feeling, less attention for self-care, loss of motivation, worry and self-criticism [84].

However, the incident of depression becomes complex and critical when mild symptoms of other closely related disease like dystonia and essential tremors are common with the patient [91]. Similar issue has been discussed by Miller et al and the authors have presented a meaningful discussion resourceful for healthcare professionals in PD [92]. Commonly prescribed antidepressants have been found effective for the PD patients and alongside the medication, exercise, yoga and meditation are advised for better outcome [93,94].

▪ Anxiety

Alterations in the neurochemicals are the reported and most valid cause underlying anxiety, which is also quite common in PD [95]. Anxiety or restlessness is defined as the random activity of any animal without particular goal [96]. Among several reports on PD with anxiety, the study by Stein et al. is notable and first of similar kind, where the authors studied 24 PD patients with DSM-III-R axis I syndromes and found that, anxiety was evident among 38% of the sufferers [96]. Another study by Dissanayaka et al. studied on 79 PD patients and evaluated the presence of anxiety using DSM-IV criteria [95]. The outcome of the study revealed that 25% of the PD patients were suffering from anxiety of different varieties like Panic disorder, generalized anxiety disorder and social phobia [95]. Possible relationship between anxiety and PD is a debated as well as intriguing fact, which was reviewed and discussed by Richard and colleague in several articles and book [97,98]. Together, available information are in line with the assertive notion on the coincidence of the occurrence of anxiety in PD patient.

▪ Fatigue

Fatigue is another psychological anomaly in PD, affecting about half of the PD sufferers worldwide [99]. Mild to severe fatigue is evident since the early stages of PD and it can persist till the disease progress [99,100]. There are many overlapping phenology of fatigue with depression and creates a great deal of confusion in particular incidence diagnosis [101]. Moreover, additional symptoms like stress and depression can make the situation even worse [101,102]. There are no conclusive mechanisms have been stated behind the occurrence of fatigue in PD. However, it is assumed that, motor abnormalities like tremor and stiffness might be the crucial factors for muscle tiredness, which is the initial cause of fatigue [103]. It has been reported that, PD patients with fatigue fights a lot for sleep but unable to do so despite severe tiredness [104]. On the other hand, lack of concentration is also found to be associated with mental fatigue [105].

Exclusive works by Van Hilten et al. and Friedman et al. have highlighted the incident of fatigue in PD patient [106,107]. Similar findings were also reported by Karlsen et al. and Abe et al. [108,109]. However, intriguing association between physical fatigue and mental fatigue was documented in 2001 by Lou et al. [105]. In a study of nine years follow up investigation, Friedman et al. have presented the scenario of fatigue in PD patients [107]. Other crucial works by Friedman and colleague have unveiled several aspects of fatigue in PD [104,107]. Documentation on the impact of fatigue on quality of life in patients with PD is available from the study by Havlikova and colleagues [110]. In a summary, fatigue plays an important role in the psychological events in PD and holds crucial determining role in the quality of life in PD patients. Despite several therapeutic hypotheses and approaches, the conclusive cure from fatigue in PD is still remained an unachieved goal. Management of secondary psychological symptoms like sleep disturbance and depression is assuming to be the only option to tackle the fatigue issue in PD, as it is closely tangling with such symptoms [111].

▪ Vision Changes and Hallucinations

Vision Changes and Hallucinations are also common in PD patients, which have been reported to deduct the quality and pace of life [112]. Blurred vision and dry eyes are the initial response towards alteration of vision in PD [113]. In some case alteration in vision occurs due to the dopamine deficiency mediated motor dysfunction [114] and such abnormalities are associated with psychological corners of PD. However, dryness in eye due to less eye blink frequency has been reported to be linked with PD [115]. Such dry eyes phenomenon is also responsible for other vision related complications like itching, burning, seborrheic blepharitis etc. [116,117] PD patients are also reported to have less sensitivity to colour and brightness contrast [118]. In late stage of PD, lack of sharp vision, altered colored vision and impaired ability to read and recognize objects have been reported [118,119].

In a mechanistic explanation, loss of dopaminergic neurons in retina and associated eye structures have been put forwarded [120]. Hallucination is also a reported psychological phenomenon evident in PD pathology [121]. It has been reported that, on an average 20-30% of PD patients, who are under medications, are the frequent sufferers from visual hallucination [121,122]. Most of the cases, hallucination is regarded as the side effect of the medication that, PD patients are taking in advanced stage of PD [121,123]. Misinterpretation of visual objects due to combined effect of medicine and poor vision is the underlying cause of visual hallucination in PD [86,90,91]. Such hallucination can be regarded as the events of peripheral vision, which includes sudden appearance of flash of light, smaller animals and disappearance of objects [124]. In advanced stages of hallucination, PD patients have been reported with the experience of sound and physical sensations, which drags the patient towards a persistent delusion [125]. In case of severe hallucination events in PD physicians are advised to prescribe comparatively lower dose of medicine like donepezil (Aricept^®), rivastigmine (Exelon^®), galantamine (Razadyne^®) or any other antipsychotic drugs [126].

The forerunner report about the incident of hallucination among advanced PD patients was documented in several articles by Goetz and Stebbins [127,128]. While, in the year 1996, visual hallucinations associated with Parkinson disease was reported by Sanchez-Ramos et al. [129]. After initial report of visual hallucination by Goetz and Stebbins, succeeding years Inzelberg and colleagues have reported about auditory hallucination [130]. Comparatively, the report on auditory hallucination is very few than visual hallucination, which have been studied and reported by several researchers in succeeding years [131]. In last decade, exclusive work by Pacchetti et al. is noteworthy, where the authors have presented a resourceful discussion on the relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in PD [132]. Together, the relationship between hallucination and PD pathology is a common fact and it needs care in terms of medical considerations to improve the quality of life of PD patients.

▪ Sleeping disturbance

Sleeping disturbance is regarded as one of the most troublesome feature in PD, which reduces the quality of life in PD patients [133-135].

Fragmented sleep due to rigidity or tremor is quite common in among the patients suffering from PD and such situation is also common when none of the PD symptoms are well-enough to recognize [133,136]. Timing of sleep also found to be disturbed in PD patients [133,137]. Some PD sufferers face difficult to sleep at night while, others suffer from drowsiness during day time [104,138]. Dysregulation in the ‘sleep-wake’ cycle, results into excessive daytime sleep, which could appear long before the expression of characteristic motoric symptoms of neurodegenerative diseases [134,139-141]. Sometimes medication creates destructive dreams or nightmares, which is also a cause underlying sleep disturbance in PD [142].

Rapid eye movement (REM) during sleep is also a feature of sleep disturbance in PD [143]. Moreover, such REM sleep is associated with the muscle activity and as result, the patient with REM sleep never feel sound sleep after acceptable hours of sleeping [133,144]. Regular events of such REM sleep make the patient weak and it has been reported to be a common phenomenon among one third of the PD patients [145]. Moreover, such sleeping disturbances also contribute in the deterioration in the PD pathology by tangling with stress, fatigue and cognitive issues [146]. It is noteworthy that, the incidence of sleeping disturbance can be controlled with the proper medication like clonazepam (Klonopin^®), Continuous Positive Airway Pressure device, melatonin supplement etc. [147]. There are several timely articles are there to get an deep insight into the pathophysiology of sleeping disturbance in PD. Chronologically, studies by Factor et al is the pioneer work relating PD pathology with sleep disturbance [148] while, Gagnon and colleagues have highlighted the REM sleep behaviors in PD [149].

Evaluation and measurement of actual scenario of sleeping status in PD got more clear insight with the use ‘Parkinson’s disease sleep scale’, which was used in a study by Chaudhuri and colleague to assessing the sleep and nocturnal disabilities in PD [150]. Several timely reviews have enriched the concept and knowledge on sleeping disturbance in PD among them exclusive work by Larsen et al. and Kumar et al. and Mahowald are notable for briefing the notion about the association between PD and sleeping disorders [151-153]. However, the links between hallucinations, REM sleep, and PD is a novel concept, which has been hypothesized by Arnulf and colleagues [153]. Besides sleep disturbance, olfactory dysfunction is also considered as a crucial non-motor symptom, which is having immense importance in PD pathology [154]. Further, it has been reported that, herbal or neurotransmitter replenishment therapy is having promising prospects regarding partial recovery from cognitive and psychological anomalies in PD and other metabolic disorders [155-161]. Together, available literatures clearly pointing out that, non-motor symptoms in PD hold crucial diagnostic possibilities. Further studies are the urgent need of time to establish accurate and rational testing protocols targeting cognitive and psychological anomalies, which in turn could meet the desired early diagnostic promises in PD.

Conclusion

PD is the second most prevalent neurodegenerative disorder classically characterized by motor abnormalities. Available reports are indicating that, the pathophysiology of the disease is not limited within the cardinal features like bradykinesia, resting tremor and postural instabilities; rather, plenty of nonmotor symptoms have been recognized in last two decades. Among non-motor symptoms, cognitive impairment and psychological anomalies have been mentioned frequently in several reports (Figure 1). The individual, who is going through the pain and sufferings of PD, is the only person can feel the chronic alterations of his/her abilities in terms of cognition, intelligence and psychological status. Most unfortunately, presence of cognitive or psychological abnormalities with or without PD makes the patient a social and economic burden. It is noteworthy that, large scale global organizations are working hand-in-hand to develop the awareness among caregivers about the issue. Research and studies are also in line to highlight various measures and guidelines for the estimation of cognitive impairment and psychological anomalies in PD. However, large scale mass application of such tool still not performed. The association and interlinked crosstalk between cognitive impairment and dementia is another frequently discussed issue in PD perspective, which also provides the deep insight into the pathobiology of PD. In summary, non-motoric features of PD could be a useful tool for the early diagnosis of PD, as those appears far early than the classical symptoms starts to express.

Acknowledgement

We sincerely acknowledge the continuous support and co-operation provided by Amit Kumar Banerjee.

References

1. Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron 39(6), 889-909 (2003).
2. Spillantini MG, Schmidt ML, Lee VM-Y, et al. Alpha-Synuclein in Lewy bodies. Nature 388(6645), 839-840 (1997).
3. Baba M, Nakajo S, Tu PH, et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol 152(4): 879-84 (1998).
4. Mazzoni P, Shabbott B, Cortés JC. Motor control abnormalities in Parkinson’s disease. Cold. Spring. Harb Perspect. Med 2(6), a009282 (2012).
5. Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson’s disease. Parkinsonism. Relat. Disord 13(6), 323-332 (2007).
6. Haaland KY, Harrington DL, O’brien S,et al. Cognitive-Motor Learning in Parkinson’s Disease. Neuropsychology 11: 180-186 (1997).
7. Goedert M, Spillantini MG, Del Tredici K, et al. 100 years of Lewy pathology. Nat. Rev. Neurol 9(1), 13-24 (2013).
8. Aarsland D, Brønnick K, Larsen JP, et al. Cognitive impairment in incident, untreated parkinson disease: The norwegian parkwest study. Neurology 72(13), 1121-1126 (2009).
9. Leverenz JB, Quinn JF, Zabetian C, et al. Cognitive impairment and dementia in patients with Parkinson disease. Curr. Top. Med. Chem 9(10), 903-912 (2009).
10. Aarsland D, Andersen K, Larsen JP, et al. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch. Neurol 60(3), 387-392 (2003).
11. Litvan I, Goldman JG, Tröster AI, et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force guidelines. Mov. Disord 27(3), 349-356 (2012).
12. Litvan I, Aarsland D, Adler CH, et al. MDS Task Force on mild cognitive impairment in Parkinson’s disease: critical review of PD-MCI. Mov. Disord 26 (10), 1814-1824 (2011).
13. Attard A, Coulson NS. A thematic analysis of patient communication in Parkinson’s disease online support group discussion forums. Comput. Human. Behav 28(2), 500-506 (2012).
14. Bastiaanse R, Leenders KL. Language and Parkinson’s Disease. Cortex 45(8), 912-914 (2009).
15. Lawrence AD, Goerendt IK, Brooks DJ. Impaired recognition of facial expressions of anger in Parkinson’s disease patients acutely withdrawn from dopamine replacement therapy. Neuropsychologia 45(1), 65-74 (2007).
16. Hemmerle AM, Herman JP, Seroogy KB. Stress, depression and Parkinson’s disease. Exp. Neurol 233(1),79-86 (2012).
17. Jahanshahi M, Wilkinson L, Gahir H, et al. Medication impairs probabilistic classification learning in Parkinson’s disease. Neuropsychologia 48(4), 1096-1103 (2010).
18. Politis M, Wu K, Loane C, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci. Transl. Med 2(38), 38ra46 (2010).
19. Pagonabarraga J, Kulisevsky J. Cognitive impairment and dementia in Parkinson’s disease. Neurobiol. Disease 590-596 (2012).
20. Aarsland D, Beyer MK, Kurz MW. Dementia in Parkinson’s disease. Curr. Opin. Neurol 21(1), 676-82 (2008).
21. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl. J. Med 351(24), 2509-2518 (2004).
22. Knopman DS, Petersen RC. Mild cognitive impairment and mild dementia: A clinical perspective. Mayo. Clin. Proc 89(10), 1452-1459 (2014).
23. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nat. Rev. Neurosci 18(7) 435-450 (2017).
24. Wu L, Y-M L. Factors associated with Parkinson’s disease patients with hyposmia in Chines e han population: a case-control study. Biomed. Res 27(2) 513-516 (2016).
25. Wasserman EA, Zentall TR. Comparative Cognition: Experimental Explorations of Animal Intelligence. (2012).
26. Craik FIM, Bialystok E. Cognition through the lifespan: Mechanisms of change. Trends. Cogn. Sci 10(3), 131-138 (2006).
27. Cacioppo JT, Petty RE. The need for cognition. J. Pers. Soc. Psychol 42(1), 116-131(1982).
28. Lin C, Bian Y, Han X, et al. Gray Matter Reduction in Currently Depressed Patients of Major Depressive Disorder: A Meta-Analysis. Neuropsychiatry 7(5), 596-605(2017).
29. Todorova A, Jenner P, Ray Chaudhuri K. Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected. Pract. Neurol 14(5), 310-22 (2014).
30. Cooper JA, Sagar HJ, Jordan N, et al. Cognitive impairment in early, untreated Parkinson’s disease and its relationship to motor disability. Brain 114 ( Pt 5), 2095-2122 (1991).
31. Janvin CC, Larsen JP, Aarsland D, et al. Subtypes of mild cognitive impairment in Parkinson’s disease: Progression to dementia. Mov. Disord 21(9), 1343-1349 (2006).
32. Kehagia AA, Barker RA, Robbins TW. Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson’s disease. Lancet. Neurol 9(12), 1200-1213 (2010).
33. Riedel O, Klotsche J, Spottke A, et al. Cognitive impairment in 873 patients with idiopathic Parkinson’s disease: Results from the German Study on Epidemiology of Parkinson’s Disease with Dementia (GEPAD). J. Neurol 255(2), 255-264 (2008).
34. Aarsland D, Bronnick K, Williams-Gray C, et al. Mild cognitive impairment in Parkinson disease: A multicenter pooled analysis. Neurology 75(12), 1062-1069 (2010).
35. Starkstein SE, Mayberg HS, Leiguarda R, et al. A prospective longitudinal study of depression, cognitive decline, and physical impairments in patients with Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 55(5), 377-382 (1992).
36. Gill DJ, Freshman A, Blender J a, et al. The Montreal cognitive assessment as a screening tool for cognitive impairment in Parkinson’s disease. Mov. Disord 23(7), 1043-1046 (2008).
37. Mattila PM, Rinne JO, Helenius H, et al. Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease. Acta. Neuropathol 100(3), 285-290 (2000).
38. Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 48(5), 413-21 (1985).
39. Beyer MK, Janvin CC, Larsen JP, et al. A magnetic resonance imaging study of patients with Parkinson’s disease with mild cognitive impairment and dementia using voxel-based morphometry. J. Neurol. Neurosurg. Psychiatry 78(3), 254-259 (2007).
40. Cools R, Barker RA, Sahakian BJ, et al. Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb. Cortex 11(12), 1136-1143 (2001).
41. Brück a, Kurki T, Kaasinen V, et al. Hippocampal and prefrontal atrophy in patients with early non-demented Parkinson’s disease is related to cognitive impairment. J. Neurol. Neurosurg. Psychiatry 75(10), 1467-1469 (2004).
42. Pillon B, Dubois B, Cusimano G, et al. Does cognitive impairment in Parkinson’s disease result from non-dopaminergic lesions? J. Neurol. Neurosurg. Psychiatry 52(2), 201-206 (1989).
43. Leroi I, Brandt J, Reich SG, et al. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson’s disease. Int. J. Geriatr. Psychiatry 19(1), 1-8 (2004).
44. O’Callaghan C, Lewis SJG. Cognition in Parkinson’s Disease. Int. Rev. Neurobiol 133(1), 557-583 (2017).
45. Klimkeit EI, Mattingley JB, Sheppard DM, et al. Motor preparation, motor execution, attention, and executive functions in attention deficit/hyperactivity disorder (ADHD). Child. Neuropsychol 11(2), 153-173 (2005).
46. Saldert C, Ferm U, et al. Semantic trouble sources and their repair in conversations affected by Parkinson’s disease. Int. J. Lang. Commun. Disord 49(6), 710-721 (2014).
47. Morris RG, Downes JJ, Sahakian BJ, et al. Planning and spatial working memory in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 51(6), 757-66 (1988).
48. Kudlicka A, Clare L, Hindle J V. Executive functions in Parkinson’s disease: Systematic review and meta-analysis. Mov. Disord 26(13), 2305-2315 (2011).
49. Koerts J, van Beilen M, Tucha O, et al. Executive functioning in daily life in Parkinson’s disease: Initiative, planning and multi-task performance. PLoS. One 6(12), e29254 (2011).
50. Walitza S, Melfsen S, Herhaus G, et al. Association of Parkinson’s disease with symptoms of attention deficit hyperactivity disorder in childhood. J. Neural. Transm. Suppl 72,311-315 (2007).
51. Nutt JG, Carter JH, Carlson NE. Effects of methylphenidate on response to oral levodopa: a double-blind clinical trial. Arch. Neurol 643(3), 19-323 (2007).
52. Lange KW, Reichl S, Lange KM, et al. The history of attention deficit hyperactivity disorder. ADHD. Atten Deficit. Hyperact. Disord 2(4), 241-255 (2010).
53. Kahneman D. Thinking Fast and Slow. Igarss 1-5 (2014).
54. Owen AM, James M, Leigh PN, et al. Fronto-striatal cognitive deficits at different stages of parkinson’s disease. Brain 115( Pt 6), 1727-1751 (1992).
55. O’Callaghan C, Naismith SL, Hodges JR, et al. Fronto-striatal atrophy correlates of inhibitory dysfunction in parkinson’s disease versus behavioural variant frontotemporal dementia. Cortex 49(7), 1833-1843 (2013).
56. Monetta L, Pell MD. Effects of verbal working memory deficits on metaphor comprehension in patients with Parkinson’s disease. Brain. Lang 101(1), 80-89 (2007).
57. Sasikumar K, George Priya Doss C AK. Analysis of physiological signal variation between autism and control group in south indian population. Biomed. Res 26(3), 525-529 (2015).
58. Merims D, Giladi N. Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson’s disease. Parkinsonism. Relat. Disorders 14(4), 273-280 (2008).
59. Freedman M, Stuss DT. Theory of Mind in Parkinson’s disease. J Neurol Sci 310(1), 225-227 (2011).
60. Merims D, Freedman M. Cognitive and behavioural impairment in Parkinson’s disease. Int. Rev. Psychiatry 20(4), 364-373 (2008).
61. Tröster AI, Fields JA, Paolo AM, et al. Absence of the apolipoprotein E epsilon4 allele is associated with working memory impairment in Parkinson’s disease. J. Neurol. Sci 248(1-2), 62-67 (2006).
62. Henry JD, Crawford JR. Verbal fluency deficits in Parkinson’s disease: a meta-analysis. J. Int. Neuropsychol. Soc 10(4), 608-22 (2004).
63. Robbins TW, Cools R. Cognitive deficits in Parkinson’s disease: A cognitive neuroscience perspective. Mov. Disord 29(5), 597-607 (2014).
64. Lange KW, Robbins TW, Marsden CD, et al. l-Dopa withdrawal in Parkinson’s disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction. Psychopharmacology (Berl) 107(2-3), 394-404 (1992).
65. Pillon B, Ertle S, Deweer B, et al. Memory for spatial location is affected in Parkinson’s disease. Neuropsychologia 34(1), 77-85 (1996).
66. Thurm F, Schuck NW, Fauser M, et al. Dopamine modulation of spatial navigation memory in Parkinson’s disease. Neurobiol. Aging 38, 93-103 (2016).
67. Possin KL, Filoteo JV, Song DD, et al. Spatial and object working memory deficits in Parkinson’s disease are due to impairment in different underlying processes. Neuropsychology 22(5), 585-595 (2008).
68. Pillon B, Deweer B, Vidailhet M, et al. Is impaired memory for spatial location in Parkinson’s disease domain specific or dependent on “strategic” processes? Neuropsychologia 36(1), 1-9 (1998).
69. Celesia GG, Wanamaker WM. Psychiatric disturbances in Parkinson’s disease. Dis. Nerv. Sys 33(9), 577-583 (1972).
70. McKeith I, Cummings J. Behavioural changes and psychological symptoms in dementia disorders. Lancet. Neurol 4(11), 735-742 (2005).
71. Leroi I, Burns A. Behavioural and psychological symptoms of dementia associated with Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 78(1), 2–3 (2007).
72. Macht M, Schwarz R, Ellgring H. Patterns of psychological problems in Parkinson’s disease. Acta. Neurol. Scand 111(2), 95-101 (2005).
73. MacCarthy B, Brown R. Psychosocial factors in Parkinson’s disease. Br. J. Clin. Psychol 28( Pt 1), 41-52 (1989).
74. Schrag A, Hovris A, Morley D, et al. Young- versus older-onset Parkinson’s disease: Impact of disease and psychosocial consequences. Mov. Disord 18(11), 1250-1256 (2003).
75. Janvin C, Aarsland D, Larsen JP, et al. Neuropsychological profile of patients with Parkinson’s disease without dementia. Dement. Geriatr. Cogn. Disord 15(3), 126-131 (2003).
76. Praag HM, Korf J, JPWF L, et al. Dopamine metabolism in depressions, psychoses, and Parkinson’s disease: the problem of the specificity of biological variables in behaviour disorders. Psychol. Med 5(2), 138-146 (1975).
77. Taylor AE, Saint-cyr JA, Lang AE, et al. Parkinson’s disease and depression: A critical re-evaluation. Brain 109(Pt 2), 279-292 (1986).
78. Rogers D, Lees AJ, Smith E, et al. Bradyphrenia in parkinson’s disease and psychomotor retardation in depressive illness: An experimental study. Brain 110 ( Pt 3), 761-776 (1987).
79. Brown RG, MacCarthy B, Gotham AM, et al. Depression and disability in Parkinson’s disease: a follow-up of 132 cases. Psychol. Med 18(1), 49-55 (1988).
80. Ehmann TS, Beninger RJ, Gawel MJ, et al. Depressive Symptoms in Parkinson’s Disease: A Comparison With Disabled Control Subjects. J. Geriatr. Psychiatry. Neurol 3(1), 3-9 (1990).
81. Cummings JL. Depression and Parkinson’s disease: a review. Am. J. Psychiatry 149(4), 443-454 (1992).
82. Dakof G a., Mendelsohn G a. Parkinson’s disease: The psychological aspects of a chronic illness. Psychol. Bull 99(4), 375-387 (1986).
83. Brown R, Jahanshahi M. Depression in Parkinson’s disease: a psychosocial viewpoint. Adv. Neurol 65, 61-84 (1995).
84. Lieberman A. Depression in Parkinson’s disease - A review. Acta. Neurologica. Scandinavica 1-8 (2006).
85. Schrag A. Quality of life and depression in Parkinson’s disease. J. Neurol. Sci 248(1-2), 151-157 (2006).
86. Torbey E, Pachana NA, Dissanayaka NNW. Depression rating scales in Parkinson’s disease: A critical review updating recent literature. J. Affect. Disord 184, 216-224 (2015).
87. Starkstein SE, Petracca G, Chemerinski E, et al. Depression in classic versus akinetic-rigid Parkinson’s disease. Mov. Disord 13(1), 29-33 (1998).
88. Remy P, Doder M, Lees A, et al. Depression in Parkinson’s disease: Loss of dopamine and noradrenaline innervation in the limbic system. Brain 12(Pt 6), 1314-1322 (2005).
89. Esposito E, Di Matteo V, Di Giovanni G. Serotonin-dopamine interaction: an overview. Progress in Brain Research 172, 3-6 (2008).
90. Gantz SC, Levitt ES, Llamosas N, et al. Depression of serotonin synaptic transmission by the dopamine Precursor L-DOPA. Cell. Rep 12(6), 944-954 (2015).
91. Chou YH, Fu TS, Hung CI. Depression: An Important Factor Related to Other Pains among Patients with Chronic Low Back Pain. Neuropsychiatry (London) 7(5), 651-8 (2017).
92. Miller KM, Okun MS, Fernandez HF, et al. Depression symptoms in movement disorders: Comparing Parkinson’s disease, dystonia, and essential tremor. Mov. Disord 22(5), 666-672 (2007).
93. Zhang Y, Zhang C, Cheng Z, et al. Serum levels of brain-derived neurotrophic factor and clinical efficacy of mirtazapine in geriatric patients with major depression. Biomed. Res 26(2), 338-342 (2015).
94. Ahmad M, Butt MS, Umar B, et al. Prevalence of postpartum depression in an urban setting. Biomed. Res 26 (4), 765-770 (2015).
95. Dissanayaka NNW, Sellbach A, Matheson S, et al. Anxiety disorders in Parkinson’s disease: prevalence and risk factors. Mov. Disord 25(7), 838-845 (2010).
96. Stein MB, Heuser IJ, Juncos JL, et al. Anxiety disorders in patients with Parkinson’s disease. Am. J. Psychiatry 147(2), 217-220 (1990).
97. Richard IH, Szegethy E, Lichter D, et al. Parkinson’s disease: a preliminary study of yohimbine challenge in patients with anxiety. Clin. Neuropharmacol 22(3), 172-175 (1999).
98. Richard IH, Justus AW, Greig NH, et al. Worsening of motor function and mood in a patient with Parkinson’s disease after pharmacologic challenge with oral rivastigmine. Clin. Neuropharmacol 25(6), 296-299 (2002).
99. Herlofson K, Kluger BM. Fatigue in Parkinson’s disease. J. Neurological. Sciences 38-41 (2017).
100. Chen CT, Cheng KY, Chang WN, et al. Clinical Factors Associated with Fatigue in Parkinson’s. Neuropsychiatry (London) 7(5), 684-90 (2017).
101. Skorvanek M, Gdovinova Z, Rosenberger J, et al. The associations between fatigue, apathy, and depression in Parkinson’s disease. Acta. Neurol. Scand 131(2), 80-87 (2015).
102. Lou JS. Fatigue in Parkinson’s disease and potential interventions. NeuroRehabilitation 37(1), 25-34 (2015).
103. Fabbrini G, Latorre A, Suppa A, et al. Fatigue in Parkinson’s disease: Motor or non-motor symptom? Parkinsonism. Relat. Disord 19(2),148-152 (2013).
104. Friedman JH, Chou KL. Sleep and fatigue in Parkinson’s disease. Parkinsonism. Relat. Disord 10(1), S27-S35 (2004).
105. Lou JS, Kearns G, Oken B, et al. Exacerbated physical fatigue and mental fatigue in Parkinson’s disease. Mov. Disord 16(2): 190-196 (2001).
106. van Hilten JJ, Weggeman M, van der Velde EA, et al. Sleep, excessive daytime sleepiness and fatigue in Parkinson’s disease. J. Neural. Transm – Park. Dis. Dement. Sect 5(3), 235-244 (1993).
107. Friedman JH, Friedman H. Fatigue in Parkinson’s disease: A nine-year follow-up. Mov. Disord 16(6), 1120-1122 (2001).
108. Karlsen K, Larsen JP, Tandberg E, et al. Fatigue in patients with Parkinson’s disease. Mov. Disord 14(1), 237-241 (1999).
109. Abe K, Takanashi M, Yanagihara T. Fatigue in patients with Parkinson’s disease. Behav. Neurol 12 (3), 103-106 (2000).
110. Havlikova E, Rosenberger J, Nagyova I, et al. Impact of fatigue on quality of life in patients with Parkinson’s disease. Eur. J. Neurol 15(5), 475-480 (2008).
111. Del Sorbo F, Albanese A. Clinical management of pain and fatigue in Parkinson’s disease. Parkinsonism. Relat. Disord 18, S233-S236 (2012).
112. Urwyler P, Nef T, Killen A, et al. Visual complaints and visual hallucinations in Parkinson’s disease. Park. Relat. Disord 20(3), 318-322 (2014).
113. Kesler A, Korczyn AD. Visual disturbances in Parkinson’s disease. Pract. Neurol 6(1), 28-33 (2006).
114. Bodis-Wollner I. Visual deficits related to dopamine deficiency in experimental animals and Parkinson’s disease patients. Trends. Neurosci 13(7),296-302 (1990).
115. Biousse V, Skibell BC, Watts RL, et al. Ophthalmologic features of Parkinson’s disease. Neurology 62(2), 177-180 (2004).
116. Basso M a, Evinger C. An explanation for reflex blink hyperexcitability in Parkinson’s disease. II. Nucleus raphe magnus. J. Neurosci 16(22) 7318-7330 (1996).
117. Sauerbier A, Ray Chaudhuri K. Parkinson’s disease and vision. Basal. Ganglia 3(3),159-163 (2013).
118. Price MJ, Feldman RG, Adelberg D, et al. Abnormalities in color vision and contrast sensitivity in Parkinson’s disease. Neurology 42(4), 887-890 (1992).
119. Vitório R, Lirani-Silva E, Barbieri FA, et al. The role of vision in Parkinson’s disease locomotion control: Free walking task. Gait. Posture 35, 175-179 (2012).
120. Huang YM, Yin ZQ. Minor retinal degeneration in Parkinson’s disease. Med. Hypotheses 76(2), 194-196 (2011).
121. Nagano-Saito A, Washimi Y, Arahata Y, et al. Visual hallucination in Parkinson’s disease with FDG PET. Mov. Disord 19(7), 801-806 (2004).
122. Fénelon G, Mahieux F, Huon R, et al. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain 123 ( Pt 4), 733-745 (2000).
123. Turjanski N, Lloyd GG. Psychiatric side-effects of medications: Recent developments. Adv. Psychiatr. Treat 11(1), 58-70 (2005).
124. Nayani TH, David a S. The auditory hallucination: a phenomenological survey. Psychol. Med 26(1), 177-189 (1996).
125. Strasburger H, Rentschler I, Jüttner M. Peripheral vision and pattern recognition: A review. J. Vis 11(5), 13 (2011).
126. Wolters EC, Berendse HW. Management of psychosis in Parkinson’s disease. Curr. Opin. Neurol 14(1) 499-504 (2001).
127. Goetz CG, Stebbins GT. Mortality and hallucinations in nursing home patients with advanced Parkinson’s disease. Neurology 45(4), 669-671 (1995).
128. Goetz CG, Stebbins GT. Risk factors for nursing home placement in advanced Parkinson’s disease. Neurology 43(11), 2227-2229 (1993).
129. Sanchez-Ramos JR, Ortoll R, Paulson GW. Visual hallucinations associated with Parkinson disease. Arch. Neurol 53(12), 1265-1268 (1996).
130. Inzelberg R, Kipervasser S, Korczyn AD. Auditory hallucinations in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 64(4), 533-535 (1998).
131. Barnes J, David AS. Visual hallucinations in Parkinson’s disease: a review and phenomenological survey. J. Neurol. Neurosurg. Psychiatry 70(6), 727-733 (2001).
132. Pacchetti C, Manni R, Zangaglia R, et al. Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson’s disease. Mov. Disord 20(11), 1439-1448 (2005).
133. Wang CC, Liu TL, Hsiao RC, et al. The relationships of insomnia and short and long nocturnal sleep durations with quality of life and the moderating effects of sex and age in Taiwanese adolescents. Neuropsychiatry (London) 7(3), 217-23 (2017).
134. Priya MS KNG. Modified emotion recognition system to study the emotion cues through thermal facial analysis. Biomed. Res 28(20), 1-6 (2017).
135. Xinxue Gao, Yu Zhang, Xiuzhen Zhang, et al. Anti-depressant treatment-related changes in risk factors and their impact on the prognosis of sleep disturbances in patients with depression. Biomed. Res 28(14), 6435-6440 (2017).
136. dos Santos AB, Kohlmeier KA, Barreto GE. Are Sleep Disturbances Preclinical Markers of Parkinson’s Disease? Neurochem. Res 40(3), 421-427 (2015).
137. Suzuki K, Miyamoto M, Miyamoto T, et al. Sleep disturbances associated with Parkinson’s disease. Parkinsons. Dis 219056 (2011).
138. Schulte EC, Winkelmann J. When Parkinson’s disease patients go to sleep: Specific sleep disturbances related to Parkinson’s disease. J. Neurology (2011).
139. Dzirasa K, Ribeiro S, Costa R, et al. Dopaminergic control of sleep-wake states. J. Neurosci 26(41), 10577-10589 (2006).
140. Liu GM, Xu K, Li J LYet al. 7, 8-dithydroxycoumarins protect human neuroblastoma cells from Aβ-mediated neurotoxic damage via inhibiting JNK and p38MAPK pathways. Biomed. Res 27, 591-595 (2016).
141. Xia Feng, Ji Hong Xue, Kun Xia Xie, et al. Beneficial effect of Mangiferin against sleep deprivation-induced neurodegeneration and memory impairment in mice. Biomed. Res 28(2), 769-777 (2017).
142. Kataoka H, Ueno S. Nightmare-enacting behavior responding to zonisamide in early Parkinson’s disease. Case. Rep. Neurol 4(1), 31-33 (2012).
143. Ford AH, Duncan GW, Firbank MJ, et al. Rapid eye movement sleep behavior disorder in Parkinson’s disease: magnetic resonance imaging study. Mov. Disord 28(6), 832-836 (2013).
144. Arnulf I, Leu S, Oudiette D. Abnormal sleep and sleepiness in Parkinson’s disease. Curr. Opin. Neurol 21(4), 472-477 (2008).
145. Bliwise DL, Trotti LM, Juncos JJ, et al. Daytime REM sleep in Parkinson’s disease. Park. Relat. Disord. Elsevier. Ltd 19(1), 101-103 (2013).
146. Boeve BF, Silber MH, Ferman TJ. REM sleep behavior disorder in Parkinson’s disease and dementia with Lewy bodies. J. Geriatr. Psychiatry. Neurol 17(3), 146-157 (2004).
147. Iranzo A, Santamaria J, Tolosa E. The clinical and pathophysiological relevance of REM sleep behavior disorder in neurodegenerative diseases. Sleep. Medicine. Reviews 13(6),385-401 (2009).
148. Factor S a, McAlarney T, Sanchez-Ramos JR, et al. Sleep disorders and sleep effect in Parkinson’s disease. Mov. Disord 5(4): 280-285 (1990).
149. Gagnon JF, Petit D, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in probable Alzheimer disease. Sleep 29(10), 1321-1325 (2006).
150. Chaudhuri KR, Pal S, DiMarco A, et al. The Parkinson’s disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 73(6), 629-635 (2002).
151. Larsen JP, Tandberg E. Sleep disorders in patients with Parkinson’s disease: epidemiology and management. CNS. Drugs 15(4), 267-275 (2001).
152. Kumar S, Bhatia M, Behari M. Sleep disorders in Parkinson’s disease. Mov. Disord 17(4), 775-781 (2002).
153. Mahowald MW, Schenck CH, Bornemann M a C. Pathophysiologic mechanisms in REM sleep behavior disorder. Curr. Neurol. Neurosci. Rep 7(2), 167-172 (2007).
154. Park JW, Kwon DY, Choi JH, et al. Olfactory dysfunctions in drug-naïve Parkinson's disease with mild cognitive impairment. Parkinsonism. Relat. Disord S1353(17), 30787-30793 (2017).
155. Arnulf I, Bonnet AM, Damier P, et al. Hallucinations, REM sleep, and Parkinson’s disease: a medical hypothesis. Neurology 55(2), 281-288 (2000).
156. Lee CH, Huang GC CC. Bioactive compounds from natural product extracts in Taiwan cosmeceuticals-Mini review. Biomed. Res 28(1), 6561-6566 (2017).
157. VD R. The molecular crosstalk: oxidative stress, genomic instability and neurodegenerative disorders. Biomed. Res 28(1), 6446-6451 (2017).
158. Zhang W LS. Study on the determination of lactone contents in Ginkgo biloba leaves and their effects in schizophrenia. Biomed. Res 26(1), 31-36 (2015).
159. Nikam S, Nikam P AS. Role of free radical and antioxidant imbalance in pathogenesis of Parkinson’s disease. Biomed. Res 20(1), 55-58 (2009).
160. Hassanalilou T, Payahoo L, Shahabi P, et al. The protective effects of Morus nigra L. leaves on the kidney function tests and kidney and liver histological structures in streptozotocin-induced diabetic rats. Biomed. Res 28(1), 6113-6118 (2017).
161. Mazumdar S, Akter R, Talukder D. Antidiabetic and antidiarrhoeal effects on ethanolic extract of Psidium guajava (L.) Bat. leaves in Wister rats. Asian. Pac. J. Trop. Biomed 5(1), 10-14 (2015).