University of Groningen

Radiotracer imaging in PD Eshuis, Sietske Aleida

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record

Publication date: 2009

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA): Eshuis, S. A. (2009). Radiotracer imaging in PD: value of in vivo presynaptic dopaminergic measures in animal models and human disease. [s.n.].

Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

Download date: 27-09-2021 Parkinson’s disease: symptoms and age 2dependency

S.A. Eshuis, K.L. Leenders Dept of neurology, University Medical Center, Groningen, The Netherlands

Abbreviated according to chapter 68: “Parkinson’s disease: symptoms and age dependency” appeared in Functional Neurobiology of Aging; Edited by Patrick R. Hof and Charles V. Mobbs, 2001 Publisher: Academic Press, San Diego, CA, USA Chapter 2

regel 1 regel 2 regel 3 regel 4 regel 5 regel 6 regel 7 regel 8 regel 9 regel 10 regel 11 regel 12 regel 13 regel 14 regel 15 regel 16 regel 17 regel 18 regel 19 regel 20 regel 21 regel 22 regel 23 regel 24 regel 25 regel 26 regel 27 regel 28 regel 29 regel 30 regel 31 regel 32 regel 33 regel 34 regel 35 regel 36 regel 37 regel 38 regel 39 30 Parkinson’s disease: symptoms and age dependency

Epidemiology of Parkinson’s Disease (PD) regel 1 regel 2 Parkinson’s disease is one of the most frequent neurodegenerative diseases, which mainly regel 3 affects the elderly. To estimate incidence and prevalence of PD, some problems need to regel 4 be mentioned. No perfect ante mortem diagnostic test for PD exists and the most reliable regel 5 diagnostic method is expert neurologic examination at regular time intervals. In autopsy regel 6 Chapter 2 studies, the diagnosis of PD before death has been found to be incorrect in about 24% regel 7 of cases39. Essential tremor may account for 10% - 40% of the false-positive diagnoses of regel 8 PD. In contrast PD may be misdiagnosed as depression, or in the very elderly, “normal” regel 9 aging. Other neurodegenerative disorders, like progressive nuclear palsy (PSP) or multiple regel 10 system atrophy (MSA) may not be distinguished easily from PD early in the course of regel 11 the disease. Many “atypical” parkinsonian syndromes were only recognised in the past regel 12 several decades and probably have been classified as PD in early reports. regel 13 regel 14 Incidence and prevalence of Parkinson’s disease regel 15 Several studies have been performed to estimate the frequency of PD. The overall incidence regel 16 is estimated to be 20 / 100 000 per year, and raises to about 1% of persons over 50 regel 17 years of age32, 78 and even higher when older9. regel 18 Prevalence of PD varies from 10 to 405 per 100 000 population. This variation may be regel 19 due to differences in case-finding procedures, in diagnostic criteria, in accessibility of regel 20 medical services and in the age distribution of populations. Most frequently prevalence is regel 21 about 100 - 187 per 100 00059. As for incidence, prevalence rises almost exponentially regel 22 after age 50. By the eighth decade, prevalence in Europe and North America is estimated regel 23 to be between 1000 and 3000 per 100 000 persons88. This is confirmed by the Rotterdam regel 24 Study: prevalence figures were 0.3% for those aged 55 to 64 years, 1.0% for those aged regel 25 65 to 74 years, 3.1% for those aged 75 to 84 years and 4.3% for those aged 85 to 94 regel 26 years. Among women aged 95 to 99 years, prevalence was 5.0%16. In some studies an regel 27 apparent decrease in late life is seen. This is probably due to ascertainment and diagnosis regel 28 difficulties in this population, rather than an actual decline in disease frequency. regel 29 regel 30 Mortality regel 31 In Hoehn and Yahr’s series mortality ratio in patients with primary parkinsonism regel 32 was 2.9 times that expected in the age-matched population38. In a more recent study regel 33 of parkinsonian patients the overall risk for death, adjusted for age and sex, was 2.0 regel 34 times that of persons without parkinsonism4. Since the introduction of more effective regel 35 antiparkinsonian medication, especially levodopa, mortality has decreased in younger regel 36 parkinsonian patients. However in older parkinsonian patients an increase during the last regel 37 few decades in mortality is found. In the United States between 1962 and 1984, mortality regel 38 regel 39 31 Chapter 2

regel 1 decreased for persons younger than age 70, but increased for persons of 75 years and regel 2 older49. This is confirmed by Morens et al67, who found that after age 60, PD-associated regel 3 mortality rates appeared to increase logarithmically. This increase in mortality rate was regel 4 not attributable to age alone. Increased age-related PD mortality was associated with regel 5 both absolute age and duration of illness longer than 10 years. Between the ages of 70 regel 6 and 89 years, parkinsonian patients had a two- to three-fold increase in the risk of dying, regel 7 corresponding to a mortality ratio of 2.567. In a study of Louis et al54 risk of mortality was regel 8 higher in parkinsonian patients (rate ratio = 2,7) after adjusting for baseline age, years of regel 9 education, sex, ethnicity and smoking status. It was even higher when PD was combined regel 10 with dementia (rate ratio = 4.9). In fact dementia is a significant predictor of death in PD57. regel 11 A high base-line score of extrapyramidal signs was most associated with increased risk regel 12 of mortality among the patients with PD. After subanalysis of the different extrapyramidal regel 13 signs, severe bradykinesia was the motor manifestation that most highly correlated with regel 14 increased mortality54. The Sydney multicentre study found increased mortality risk among regel 15 parkinsonian men, whereas this was not significantly different for women, compared to regel 16 the general Australian population. Predictors of mortality, according to this study, are age regel 17 at onset and progression rate. Several studies have shown that the effects of levodopa regel 18 on mortality are apparent in the early years of the disease. In contrast, despite levodopa regel 19 therapy, mortality is rising in a later stage of the disease12, 17. Data from the DATATOP cohort regel 20 suggests that carefully selected patients with early PD without co-morbidity have normal life regel 21 expectancy when adequately treated and frequently seen by consulting physicians1. This regel 22 is confirmed by Tanner and Ben-Shlomo88. For persons with PD diagnosed before the age regel 23 of 60, they found a relative survival similar to that of the general population, in contrast to regel 24 people with an older age at diagnosis, who showed a lower relative survival88 . regel 25 Pneumonia is the most common cause of death, probably due to immobility and increased regel 26 risk of aspiration1. Death from cerebrovascular disease is increased as well35. Some studies regel 27 have suggested a reduced risk of death from cancer in parkinsonian patients35, 42, but other regel 28 studies did not confirm this91. regel 29 regel 30 Regional and racial variation regel 31 Estimates of prevalence vary widely depending on geographical location. A Northwest regel 32 to Southeast gradient is suggested49 and PD prevalence appears to be highest in Europe regel 33 and North America, whereas rates in Japan, China and Africa are markedly lower. In regel 34 the USA PD prevalence is much lower among blacks. Already in 1972, Kessler found a regel 35 higher frequency of PD for whites compared with blacks43, 44. In a survey of PD in New regel 36 York, age-adjusted prevalence rates were lower for blacks than for whites and Hispanics. regel 37 Surprisingly however incidence rates were highest among black men, but these incidence regel 38 rates were otherwise comparable across sex and ethnic groups. By ethnic group, the regel 39 32 Parkinson’s disease: symptoms and age dependency

cumulative incidence was higher for blacks than for whites and Hispanics, but more regel 1 deaths occurred among incident black patients. These findings could result from a delay regel 2 in diagnosis due to limited access to appropriate health services among these people60. regel 3 Some studies however show similar rates for African-American, Asian-American and regel 4 European-American subjects67. In a study among a cohort of American men of Japanese or regel 5 Okinawan ancestry, epidemiological data are in general in accord with those from Europe regel 6 Chapter 2 and the United States. Incidence data are 5- to 10-fold higher at each age stratum than regel 7 age-specific incidence figures from China. These findings most likely cannot be explained regel 8 by methodological differences between Chinese and Western studies alone. However this regel 9 possibility cannot be ruled out, as the Chinese data have not been verified yet by other regel 10 studies67. Similar findings have been observed in a study in Mississippi, where black men regel 11 and women have PD prevalence rates more like white men and women than black men and regel 12 women in Nigeria79, 80. These data suggests that risk of developing PD is more a function regel 13 of environmental factors than racial ones. So different distributions of PD causing factors regel 14 across populations may contribute to geographic differences in epidemiological findings. regel 15 These factors could be differences in exposure to causative and protective influences, but regel 16 also genetic differences in susceptibility to disease. It could be that an environmental agent regel 17 might only act in genetically susceptible people. regel 18 regel 19 Gender differences regel 20 Males tend to have a modestly increased age-adjusted PD prevalence. Male-to-female ratio regel 21 range from 0.86 (in Japan) to 3.7 (Chinese studies). In a study in New York, age-adjusted regel 22 prevalence was lower for women compared with men across all ethnic groups. However regel 23 in another study, age-adjusted incidence did not differ between men and women in all regel 24 ethnic groups60. This is confirmed by the Rotterdam Study in which no significant gender regel 25 differences in prevalence were found16. regel 26 regel 27 regel 28 Symptoms regel 29 regel 30 Motor symptoms regel 31 The classic triad of symptoms of PD consists of tremor, rigidity and hypokinesia. Postural regel 32 impairment has been called the fourth major symptom of PD. The disease is a slowly regel 33 progressive disorder and signs and symptoms develop usually over several years. In the regel 34 early stages of the disease the signs and symptoms may be vague and non-specific in such regel 35 a way that a reliable diagnosis can not yet be made. regel 36 The typical parkinsonian tremor is a 3-6-Hz distal resting tremor. It consists of alternate regel 37 contractions of agonist and antagonist muscles, including flexors, extensors, pronators and regel 38 regel 39 33 Chapter 2

regel 1 supinators of the wrists and arms during rest. This may result in a pill rolling movement regel 2 of the hand. Often the typical parkinsonian rest-tremor starts on one side of the body. In regel 3 most patients the signs will develop in due course on both sides, but asymmetry will usually regel 4 persist throughout the disease. The legs or lower jaw may also be involved. The tremor regel 5 tends to disappear with action. Resting tremor is found in 79% - 90% of patients with PD regel 6 in clinical studies and in 76% - 100 % in autopsy-proven studies. Some patients have little regel 7 or no resting tremor but a predominant action or postural tremor. Tremor at rest may also regel 8 be induced by neuroleptic agents. regel 9 Rigidity can be present in all four limbs and in the trunk, but mainly affects the arms and regel 10 is often of the cogwheel type. The increase in tone is fairly equal in flexors and extensors, regel 11 but slightly more in flexors. It can be diagnosed in 89% - 99% of parkinsonian patients. regel 12 Bradykinesia means slowness of movements, whereas hypokinesia stands for poverty regel 13 of movement. Hypokinetic features include facial hypomimia, reduced eye blinking, regel 14 hypophonic speech and micrographia. There is difficulty in initiating movements, resulting regel 15 in start hesitation. Rapid repetitive movements are impaired. Bradykinesia is present in regel 16 77% to 98% of patients with PD, but it is not unique to PD. It can also occur as a result regel 17 of other extrapyramidal disorders, such as PSP, MSA, CBD and normal aging. Symptoms regel 18 can be gravitated by contralateral activation or concentration on mental or physical tasks. regel 19 Each one of these features can be present for a long time, before others develop. Symptoms regel 20 usually begin unilaterally or asymmetrical. Later they are bilateral or generalised. regel 21 Gait is impaired in patients with PD as well. The patients walk slowly with small shuffling regel 22 steps. Parkinsonian patients move in a rigid manner and turn en bloc. Their posture is regel 23 stooped, because of flexion of the shoulders, neck and trunk. In PD the center of gravity regel 24 is shifted forward. Walking can be hampered by stutter steps, resulting in start- and turn- regel 25 hesitation, and sudden “freezing”. This phenomenon refers to the patient’s feet stuck to regel 26 the ground while walking, rendering the patient unable to move with the lower body. It regel 27 especially happens on turns and in elevators or doorways. Freezing and related phenomena regel 28 are called motor blocks. It occurs in 32% of parkinsonian patients31. Retropulsion refers to regel 29 the phenomenon that the standing patient if pushed backward, is only able to regain his regel 30 balance slowly by small and slow steps or even fails to do so and falls. When walking, regel 31 patients may have problems stopping and legs are preceded by the flexed trunk, resulting regel 32 in frequent little short steps or propulsive gait. This pattern is characteristic of advanced PD. regel 33 In the beginning of the disease symptoms are unilateral, affecting only one side. Patients regel 34 appear to drag a leg when walking and arm swing is decreased at the affected side. In a regel 35 later stage, when the opposite side is affected as well, steps are short and the feet barely regel 36 clear the floor. Usually symptoms stay asymmetrical, in contrast to normal aging. In a later regel 37 stage parkinsonian patients may experience problems of autonomic dysfunction such as regel 38 constipation, incontinence, hypotension and impotence. If this occurs in an early stage of regel 39 PD, the diagnosis should be questioned28 . 34 Parkinson’s disease: symptoms and age dependency

Not only motor symptoms may occur. Another abnormality is for example an olfactory regel 1 disorder. In PD there is an increase of the olfactory detection threshold70, which is probably regel 2 due to the presence of Lewy bodies in the olfactory bulb and neuronal loss in the anterior regel 3 olfactory nucleus14, 69. Other features include increased saliva production and increased regel 4 sweating. regel 5 None of the 3 major symptoms has enough sensitivity or specificity to diagnose PD. For this regel 6 Chapter 2 reason a scheme has been made for diagnostic classification: The UK Parkinson’s Disease regel 7 Society Brain Bank clinical diagnostic criteria (see table 1: UK Parkinson’s Disease Society regel 8 Brain Bank 1993)15. regel 9 regel 10 Table 1 regel 11 regel 12 STEP 1 DIAGNOSIS OF PARKINSONIAN SYNDROME * bradykinesia (slowness of initiation of voluntary movement with regel 13 progressive reduction in speed and amplitude of repetitive actions) regel 14 * and at least one of the following: regel 15 - 4 - 6 Hz rest tremor - rigidity regel 16 - postural instability not caused by primary visual, vestibular, cerebellar regel 17 or proprioceptive dysfunction STEP 2 EXCLUSION CRITERIA FOR PARKINSON’S DISEASE regel 18 * history of repeated strokes with stepwise progression of parkinsonian regel 19 features regel 20 * history of repeated head injury * history of definite encephalitis regel 21 * oculogyric crises regel 22 * neuroleptic treatment at onset of symptoms * more than one affected relative regel 23 * sustained remission regel 24 * strictly unilateral features after 3 years * supranuclear gaze palsy regel 25 * cerebellar signs regel 26 * early severe autonomic involvement regel 27 * early severe dementia with disturbances of memory, language and praxis * Babinski sign regel 28 * presence of cerebral tumour or communicating hydrocephalus on CT scan regel 29 * negative response to large doses of levodopa (if malabsorption excluded) * MPTP exposure regel 30 STEP 3 SUPPORTIVE PROSPECTIVE POSITIVE CRITERIA FOR regel 31 PARKINSON’S DISEASE regel 32 (three or more required for diagnosis of definite Parkinson’s disease) * unilateral onset regel 33 * rest tremor present regel 34 * progressive disorder * persistent asymmetry affecting side of onset most regel 35 * excellent response (70 - 100%) to levodopa regel 36 * severe levodopa-induced chorea * levodopa response for 5 years or more regel 37 * clinical course of 10 years or more regel 38 regel 39 35 Chapter 2

regel 1 Non-motor symptoms regel 2 In PD there are several other nonmotor clinical features, like dementia, depression and regel 3 psychotic features. regel 4 regel 5 Dementia regel 6 In 20 to 40% of patients with PD cognitive impairment develops and the risk of dementia regel 7 in non-demented PD patients is almost twice that of age-matched non-demented elderly regel 8 controls. Prevalence however is estimated to be 10.9%61. Here it needs to be considered that regel 9 PD patients with dementia have a shorter life expectancy. Dementia in PD is characterized regel 10 by a severe dysexecutive syndrome without instrumental disorders like aphasia, apraxia regel 11 or agnosia. regel 12 In several studies the influence of age at onset on the presentation and course of PD has regel 13 been demonstrated. Young onset patients have little cognitive impairment even after a regel 14 disease duration of over 20 years73. Dementia mainly develops in patients with onset regel 15 after 70 years. In this cohort of patients prevalence of dementia is more than twice that regel 16 of younger patients61. Usually it develops after several years of disease duration. This in regel 17 contrast to diffuse Lewy body disease, where cognitive deficits occur very early (less than regel 18 2 years) or even precede motor symptoms19. Other risk factors for developing dementia regel 19 in PD are lack of education and severe motor deficits (UPDRS motor scores above 24)56. regel 20 Cognitive deficits however are usually less prominent than motor symptoms. regel 21 regel 22 Depression regel 23 Depression is estimated to occur in 30 - 60% of patients with PD at some point during regel 24 the disease. It has been suggested that there is a natural tendency for chronic, disabling regel 25 diseases to induce depression. However it appears that the prevalence of depression in regel 26 patients with PD is higher than in other chronic disorders. Besides, the depression is unrelated regel 27 to the severity of motor symptoms and depression can continue despite improvement in regel 28 motor symptoms after L-dopa therapy. It is possible that depression precedes the motor regel 29 symptoms of PD. There are some similarities between clinical and biochemical changes regel 30 in PD and depression. Clinical similarities include akinesia and psychomotor retardation, regel 31 while biochemical similarities include dysfunction in dopaminergic, noradrenergic and regel 32 serotonergic systems. Reduced serotonergic function is associated with psychomotor regel 33 retardation, reduced noradrenergic function with bradyphrenia and reduced dopaminergic regel 34 function with extrapyramidal symptoms, cognitive slowing and more severe symptoms of regel 35 depression51. regel 36 regel 37 regel 38 regel 39 36 Parkinson’s disease: symptoms and age dependency

Psychotic features regel 1 Psychotic symptoms may either be a manifestation of the disease itself, or it may be the regel 2 result of therapy with dopaminergic agents25. Psychosis may also occur as a reaction regel 3 to the disease and functional impairment (“reactive psychosis”) as well, although this is regel 4 probably a rare condition. About 30% of parkinsonian patients, treated with levodopa, regel 5 have experienced psychotic symptoms and the lifetime prevalence may approach 50%. regel 6 Chapter 2 Visual hallucinations are most common and the images are usually fully formed human or regel 7 animal figures. Usually insight is preserved2. regel 8 regel 9 regel 10 Pathology findings regel 11 regel 12 The most prominent lesion in PD is the degeneration of neuromelanin-containing neurons regel 13 in the pars compacta of the substantia nigra, which at post-mortem inspection turns visibly regel 14 pale. Also selected aminergic brain-stem nuclei (catecholaminergic and serotoninergic), regel 15 the cholinergic nucleus basalis of Meynert, hypothalamic neurons, small cortical neurons regel 16 (particularly in the cingulate gyrus and entorhinal cortex), olfactory bulb, sympathetic regel 17 ganglia and parasympathetic neurons may be involved in this progressive degenerative regel 18 process. regel 19 Not all dopaminergic neurons are equally susceptible. Within the substantia nigra pars regel 20 compacta, neuronal loss appears to be greatest in the ventrolateral part, followed by the regel 21 medial part and the dorsal part24. This has been confirmed by Damier and coworkers13. regel 22 It results in a regional loss of striatal dopamine50. The nigrostriatal dopaminergic neurons regel 23 which project to the putamen are more affected than those which project to the caudate regel 24 nucleus and nucleus accumbens. The latter one is believed to be responsible for akinesia regel 25 and rigidity. This pattern of cell loss seems to be rather unique to Parkinson’s disease and regel 26 is different of the pattern seen in normal aging. Neuronal loss of the medial nigral cells, regel 27 with enhanced involvement of projections to the caudate nucleus, could result in more regel 28 cognitive symptoms. Another possible clinical-pathological correlation may be based on regel 29 degenerative changes of the olfactory bulb, causing anosmia. Autonomic dysfunction may regel 30 be the result of lesions in the sympathetic and parasympathetic ganglia or degeneration in regel 31 the intermediolateral columns of the spinal cord75. Some believe that dementia in PD may regel 32 be the result of cell loss in the nucleus basalis of Meynert77. regel 33 The surviving, but dying catecholaminergic neurons may contain Lewy bodies, an important regel 34 pathological feature. Lewy bodies are spherical, eosinophylic cytoplasmic inclusions with regel 35 a dense core and peripheral halos, found in pigmented cells. In PD the most important regel 36 anatomical sites where these bodies are located are the substantia nigra and locus regel 37 ceruleus. They are not specific to PD. They appear as well in some other neurodegenerative regel 38 regel 39 37 Chapter 2

regel 1 disorders, like Alzheimer’s disease (AD). AD however is associated with cortical Lewy regel 2 bodies, particularly in frontal, temporal, anterior cingulate and insular regions, whereas regel 3 PD is associated with subcortical Lewy bodies, mainly in the substantia nigra. Lewy bodies regel 4 are also seen as an incidental finding in about 10% of people older than 60 years. Gibb regel 5 and Lees30 discovered that the age-specific prevalence of Lewy bodies in the brains of regel 6 persons without clinical PD increased from 3.8 to 12.8% between the sixth and ninth regel 7 decade of life. It has been suggested that the presence of incidental Lewy-bodies constitutes regel 8 actually a presymptomatic stage of PD30. McKeits however suggests a relationship between regel 9 this “incidental” pathology and dementia with Lewy bodies62. regel 10 The mechanisms of cell death in PD are still unknown. Several factors have been mentioned regel 11 to play a role in neuronal degeneration in PD, like mitochondrial dysfunction, oxidative regel 12 stress and excitotoxity and free radical production. It is believed that the neuronal death in regel 13 the pars compacta of the substantia nigra is apoptotic6, 7, but this has not been universally regel 14 accepted yet and necrosis has been suggested as well. regel 15 regel 16 regel 17 Other movement disorders in the elderly regel 18 regel 19 Aging is a unequivocal risk factor for PD87. It is also a major risk factor for several other regel 20 movement disorders and neurodegenerative diseases. regel 21 There are many causes of movement or gait disorders in the elderly, of which some can regel 22 easily be mistaken for PD. The many characteristics and patterns of gait disorders may look regel 23 difficult and require special expertise, but simple observation of the patient and its gait may regel 24 yield valuable information. The history from patients may reveal a stepwise progression, regel 25 suggesting vascular disease. Pain with walking usually excludes a neurodegenerative regel 26 cause of the gait disorder. Magnetic Resonance Imaging (MRI) may be used for screening regel 27 for hydrocephalus or multiple infarcts. Positron emission tomography (PET) scans of the regel 28 brain may for example help for diagnosing PD, MSA or PSP. Gait disorders in the elderly, regel 29 irrespective their underlying pathology, contribute to the risk of falling and fractures89. The regel 30 higher risk of falling limits the elderly in their mobility and independence, also because of regel 31 the fear of falling itself. Imms and Edholm surveyed in 1981 a group of older people (mean regel 32 age, 78 years) and found that half of them limited their activity because of their concerns regel 33 about mobility40. regel 34 Many signs of gait disorders, slowing down and stiffening up, are accepted as being part regel 35 of aging. However most of these signs may be signals of an underlying disease. Critchley regel 36 already warned in 1931 that “an abnormal gait in the aged is frequently the result of regel 37 disease outside the nervous system” (Critchley, 1931). In many cases gait disorders are regel 38 of orthopedic (osteoarthrosis, osteomalacia, unsuspected fractures), endocrinological regel 39 38 Parkinson’s disease: symptoms and age dependency

(hypothyroidism), psychological (depressive state, fear of falling) or general (general regel 1 muscle weakness) origin11. Circulatory or respiratory systems may play a role as well regel 2 in determining gait velocity because of the need to minimize energy expenditure23. The regel 3 incidence of subtle extrapyramidal signs on neurological examination of elderly persons regel 4 with no known neurologic or psychiatric disorder is high. Bennett et al4 showed that 35% regel 5 of people over 65 years old had these subtle changes, while around 3% in similarly aged regel 6 Chapter 2 persons had PD. In a community study in North Carolina, 15% of adults over 60 years of regel 7 age had some degree of difficulty with ambulation18. In Western Europe 20-25% of people regel 8 aged 80 or older, use mechanical aids for walking55. A review of the variety of conditions, regel 9 which can cause gait disorders or may be confused with PD, will be given here. regel 10 regel 11 Essential tremor (ET) regel 12 One of the commonest causes of misdiagnosis of PD is essential tremor (also known as regel 13 senile tremor, which is a misnomer). It is inherited as an autosomal dominant disorder regel 14 with incomplete penetrance. A familial incidence is common in about one-third to one- regel 15 half of cases. In the elderly however it is often sporadic32. The incidence of essential regel 16 tremor increases with climbing age. Considering prevalence Rautakorpi’s study76 reported regel 17 a prevalence of 12.5% in his population. In a study of a population aged 65 and older, regel 18 Louis et al53 found a prevalence of 4%. A higher prevalence of 23% in a population of regel 19 people older than 70 years has been observed by Elble22. regel 20 Essential tremor is an action tremor with a frequency of 8- to 12-Hz (the resttremor in regel 21 PD is 4- to 6-Hz). It may sometimes be present at rest as well, but generally increases regel 22 with activity. The amplitude increases with age. According to Marttila and Rinne essential regel 23 tremor accounted for 26% of cases of presumed PD58. This misdiagnosing can occur regel 24 because of many reasons. Both conditions frequently occur in the elderly. Parkinsonian regel 25 patients sometimes suffer from a postural action tremor of the hands, as seen in ET. Patients regel 26 with ET may have some bradykinesia and rigidity, which could be normal in the elderly. regel 27 Besides, some hallmarks of PD, like asymmetric manifestation and a resting component of regel 28 the tremor, can also be found in cases of ET. regel 29 However, there are also some striking differences between these two disorders. Essential regel 30 tremor frequently involves the head in contrast to tremor in PD. Conversely, a resttremor of regel 31 the leg or slow vertical jaw tremor is often seen in PD, but rarely in essential tremor. Also, regel 32 hypokinesia may be present in PD, but not in ET. regel 33 regel 34 Vascular parkinsonism regel 35 This results from multiple small cerebral infarcts, especially in the basal ganglia secondary regel 36 to hypertensive cerebrovascular disease. Some patients with vascular parkinsonism regel 37 present with a progressive gait disorder without a medical history of strokes83. Chronic regel 38 regel 39 39 Chapter 2

regel 1 hypertension leads to fibrinoid necrosis and occlusion of arterioles supplying the basal regel 2 ganglia. An akinetic rigid syndrome with urinary incontinence, dysarthria, abulia and regel 3 dementia may occur. The extrapyramidal signs may coexist with pyramidal dysfunction like regel 4 weakness, hyperreflexia, spasticity, pseudobulbar palsy, emotional lability and Babinski regel 5 signs. These pyramidal signs may be important in differentiating this disorder from PD. regel 6 The patient is slow and walks wide-based (unlike in PD) with short, shuffling, somewhat regel 7 irregular footsteps. Postural stability may be impaired. As in PD freezing and start hesitation regel 8 may occur. regel 9 However the upper body may show little or no parkinsonian features, thus no facial regel 10 hypomimia may occur. Another term used for this disorder is lower body parkinsonism. regel 11 Another striking difference with PD is usually the absence of tremor and no fatigue or regel 12 decrement of rapid alternating movements. In vascular parkinsonism symptoms are regel 13 symmetric in contrast to PD. However, if signs and symptoms are not clear cut, the regel 14 differential diagnosis may be difficult. regel 15 Computerised tomography shows multiple infarcts but sometimes misses small ones. regel 16 Magnetic resonance imaging demonstrates infarctions in the deep gray matter structures regel 17 and ischemic changes in periventricular white matter. According to Sudarsky, vascular regel 18 parkinsonism accounts for 15 - 16% of the gait disorders among elderly patients83, 84. regel 19 regel 20 Multiple system atrophy (MSA) regel 21 MSA refers to a sporadic, gradually progressive, idiopathic neurodegenerative process regel 22 of adult onset characterized by varying proportions of cerebellar dysfunction, autonomic regel 23 failure, pyramidal signs and parkinsonism, that is poorly responsive to L-dopa therapy. Cell regel 24 loss and gliosis (without Lewy bodies) are not only present in substantia nigra, but also regel 25 in multiple other structures, like striatum, olives, pons, cerebellum, intermediolateral cell regel 26 columns and Onuf’s nucleus in the spinal cord. Most commonly MSA begins in the early regel 27 50s, progresses more rapidly than PD and has a reduced life expectancy (median survival regel 28 = 9.3 years), this in contrast to PD (see above). regel 29 Parkinsonism occurs in 90% of patients with multiple system atrophy and is the dominant regel 30 motor disorder is 80% of patients. In contrast to PD, the parkinsonism in MSA is usually regel 31 bilateral. Unlike PD, tremor is often not the classical rest tremor, but an action tremor. regel 32 Cerebellar dysfunction and pyramidal signs both occur in about half of patients71, 90. regel 33 Cerebellar dysfunction as the dominant symptom occurs in about 20% of patients74. regel 34 Autonomic failure appears in almost all patients with MSA. In PD patients it may occur regel 35 as well, mostly in a late stage of disease, whereas in MSA it usually occurs earlier and regel 36 more severe. Indeed, in MSA, autonomic failure may precede the motor symptoms by regel 37 months or even years. Frequently, the first symptom is impotence in men and incontinence regel 38 in both men and women (PD usually causes just frequency increase and urgency due to regel 39 40 Parkinson’s disease: symptoms and age dependency

hyperreflexia of the detrusor). Postural hypotension is another common feature in MSA, regel 1 which may appear in PD as well, though less severe. Inspiratory stridor is present in about regel 2 30% of patients with MSA. When combined with parkinsonism it is highly suggestive of regel 3 the diagnosis MSA72. Other signs of autonomic failure are thermoregulation disturbances, regel 4 gastro-intestinal problems and phenomena of Raynaud. regel 5 The response to levodopa of patients with MSA is usually absent or poor. However, in regel 6 Chapter 2 about 30% of patients an initial response has been reported, usually temporary. Levodopa regel 7 induced dyskinesias are usually absent in MSA, so high doses of levodopa can be regel 8 administered. regel 9 Differentiating MSA from PD may be very difficult, especially in an early stage of disease. regel 10 There are some red flags suggesting non-idiopathic parkinsonism, like: regel 11 • Poor or no response to levodopa therapy regel 12 • Cerebellar, pyramidal or autonomic signs regel 13 • Symmetric start of symptoms regel 14 • Absence of classic rest tremor regel 15 • Early instability or falls regel 16 • Rapid clinical progression71, 74, 90. regel 17 Some diagnostic tests may include external urethral (or anal) sphincter EMG, standard tests regel 18 of cardiovascular autonomic function and imaging of the brain. Computed tomography regel 19 or magnetic resonance imaging sometimes shows cerebellar or brainstem atrophy. regel 20 Fluorodesoxyglucose positron emission tomography (PET) scanning may be useful as regel 21 well20, 86. regel 22 regel 23 Progressive supranuclear palsy (PSP) regel 24 PSP, or Steele-Richardson-Olszewski syndrome, is an idiopathic degenerative disease, not regel 25 uncommon in the elderly, which mimics PD. It occurs at a rate of 0.3 per 100.000 per regel 26 year34 and its prevalence is 1.46 per 100.000. Pathologic investigation shows cell loss regel 27 and neurofibrillary tangles, mainly in the brainstem, globus pallidus, nucleus subthalamicus regel 28 and nucleus dentatus. regel 29 The clinical picture includes the tetrad of supranuclear gaze paralysis, axial rigidity, regel 30 dementia and pseudobulbar palsy. It is associated with bradykinesia, severe postural regel 31 disorder and frequent falls. Supranuclear gaze paralysis affects vertical gaze more than regel 32 horizontal. Voluntary downgaze is slow and usually incomplete, but when the oculocephalic regel 33 reflex is performed, full down gaze is obtained. Pseudobulbar palsy is characterised by regel 34 dysphagia and dysarthria. Dementia is progressive and consists of slowing of cognition, regel 35 memory deficits and personality changes suggestive of frontal lobe dysfunction52. PSP may regel 36 be distinguished from PD by the absence of rest tremor, the extended neck posture, rigidity regel 37 more truncal than in limbs and abnormal eye movements. PSP patients have a stiff, broad- regel 38 regel 39 41 Chapter 2

regel 1 based gait with ataxia. In contrast to PD patients they do not turn en bloc, but pivot. During regel 2 pivoting they also tend to fall backwards. regel 3 regel 4 Cortico-basal degeneration (CBD) regel 5 This disorder presents with a unique pattern of progressive impairment. It appears in mid- regel 6 to late adult life, usually beginning after age 60. The duration of the illness until death is regel 7 about 6 to 8 years. Pathologic and histologic evaluation reveal frontoparietal atrophy and regel 8 neuronal loss, gliosis and swelling of the cell body with resistance to staining methods regel 9 (achromasia)45. regel 10 Prototypic findings are combined parkinsonian signs, other movement disorders and regel 11 higher cortical dysfunction, with marked asymmetry of involvement. The most common regel 12 extrapyramidal sign is rigidity, followed by bradykinesia. Sometimes tremor is present regel 13 as well, but does not resemble the parkinsonian tremor. Tremor in CBD is more rapid regel 14 (6-8Hz), is mainly during action, with varying amplitude. Other movement disorders regel 15 include myoclonus and dystonia. Higher cortical dysfunction includes dyspraxia, involving regel 16 the limbs, ocular and orofacial muscles, cortical sensory loss, dementia (which usually regel 17 occurs late in disease) and aphasia. A striking feature of CBD is the “alien hand/limb” regel 18 phenomenon81. regel 19 regel 20 Normal pressure hydrocephalus (NPH) regel 21 This disorder is often idiopathic, but has also been associated with many neurological regel 22 diseases. The classic triad of symptoms includes frontal dementia, urinary incontinence and regel 23 gait disorder with unsteadiness. It is associated with enlargement of the cerebral ventricles regel 24 on CT or MRI and a CSF pressure of 180 mm H2O or less. A dynamic test is necessary to regel 25 confirm the diagnosis of true (opposed to ex vacuo) hydrocephalus5. The removal of 50 regel 26 ml of cerebrospinal fluid may improve the symptoms of gait disorder85. Mental dysfunction regel 27 improves less than gait after a shunt. The patient walks wide-based with small steps, feet regel 28 glued to the floor, marked imbalance and difficulty initiating walking. Postural instability regel 29 with frequent falling may occur. Clinical signs may include hyperreflexia, extensor plantar regel 30 responses and extrapyramidal signs, including hypokinesia and freezing during walking. regel 31 Diagnosing NPH may be difficult since the three cardinal symptoms are common in the regel 32 elderly. Besides gait disorder may precede other symptoms for several years and can regel 33 be the only symptom for a long period. NPH is a common cause of gait disorders in the regel 34 elderly, while in dementia it accounts for only 0 - 5% of persons with dementia26. It should regel 35 account for 4 - 6.7% of the gait disorders in the elderly84, 85. regel 36 regel 37 regel 38 regel 39 42 Parkinson’s disease: symptoms and age dependency

Metabolic and endocrine disorders regel 1 Some of these disorders may produce akinetic-rigid syndromes. Hypothyroidism may regel 2 cause parkinsonism with motor slowing. Hypoparathyroidism, resulting in calcifications of regel 3 the basal ganglia, may produce a clinical syndrome consisting of parkinsonism, chorea, regel 4 cerebellar dysfunction or a mixed extrapyramidal-pyramidal syndrome, resembling the regel 5 lacunar state48. Metabolic and toxic disorders causes gait disorders in 2,5 % of the regel 6 Chapter 2 elderly83, 84. regel 7 regel 8 Drug-induced parkinsonism regel 9 Many drugs commonly prescribed in the geriatric practice can affect gait. It can be caused regel 10 by: regel 11 • drugs that deplete presynaptic dopamine stores, like reserpine or tetrabenazine regel 12 • neuroleptic drugs, like phenothiazines (chlorpromazine), butyrophenones regel 13 (haloperidol), thioxanthines (flupenthixol) and substituted benzamides (sulpiride) regel 14 • metoclopramide for gastrointestinal symptoms or migraine regel 15 • the atypical calcium blocking drug cinnarizine and flunarizine for vestibular regel 16 disorders or hypertension regel 17 • others, like fluoxetine and rarely valproate regel 18 Drug-induced parkinsonism results in bradykinesia and rigidity with facial amimia, regel 19 dysarthria and diminished or disappeared arm swing. Tremor is less common, but can be regel 20 identical to the classic rest tremor of PD. Moreover symptoms of drug-induced parkinsonism regel 21 usually are, just like in PD, asymmetrical. Drug-induced parkinsonism often resolves quickly regel 22 within weeks after stopping those drugs. Sometimes this will take months, especially after regel 23 depot neuroleptic medications. regel 24 regel 25 regel 26 Subclassification of PD regel 27 regel 28 The variance in expression of the clinical syndrome of PD is large and suggests the existence regel 29 of subtypes with distinct clinical patterns, especially concerning the age of symptom onset, regel 30 rate of disease progression and clinical manifestations. Probably this clinical heterogeneity regel 31 reflects a broad spectrum of manifestations of one pathological disorder: the lossof regel 32 pigmented neurons in the substantia nigra pars compacta and the presence of Lewy bodies regel 33 (intracytoplasmic inclusions). Several studies have tried to define clinical subgroups on the regel 34 basis of distinguishing features, like family history of PD, variable progression and age of regel 35 onset of symptoms of disease. regel 36 regel 37 regel 38 regel 39 43 Chapter 2

regel 1 Young-onset versus old -onset of PD regel 2 Friedman has compared clinical expression of patients with onset age of symptoms above regel 3 70 years with patients with onset age below 45 years27. In this study there were some striking regel 4 differences between these groups. The DATATOP (deprenyl and tocopherol antioxidative regel 5 therapy of parkinsonism)- study has investigated the variability in clinical expression by regel 6 comparing several factors, like early versus late onset of disease, benign versus malign regel 7 status, H/Y stage I versus H/Y stage II and tremor versus postural instability and gait regel 8 disorder (PIGD) type41. This study suggests that there are probably 2 different subtypes regel 9 of PD: early-onset and late-onset of disease. Patients with early onset of PD progress at a regel 10 slower rate, which has been confirmed by others33. Patients with young-onset of disease regel 11 are more sensitive to levodopa and to levodopa-induced dyskinesias, and dyskinesias regel 12 seem to appear earlier in those patients. Not only will they develop focal dystonia early in regel 13 the course of illness, but also end-of-dose phenomenon is more often observed in patients regel 14 with young-onset of disease29, 73. Similarly, motor fluctuations, such as the wearing-off regel 15 effect, tend to occur earlier in young-onset patients47. Initial symptom in this group is usually regel 16 tremor. This is in contrast to Friedmans results27 who found that young-onset patients usually regel 17 start with paraesthesia and have bradykinesia as dominant symptom. They tend to perform regel 18 better on neuropsychological tests, but this may be explained by their younger age. regel 19 Patients with late-onset of disease have a more aggressive form of PD with faster progression regel 20 and greater motor disability. They have as initial symptoms bradykinesia, postural regel 21 instability, rigidity and less often tremor, according to the DATATOP-study. This study also regel 22 suggests that motor deterioration in PD does not necessarily parallel cognitive decline and regel 23 it is postulated that cognitive impairment in PD results mainly from a nondopaminergic regel 24 deficit. According to Friedman27 old-onset patients with PD more often have tremor as regel 25 both presenting and dominant symptom. Old-onset parkinsonian patients more frequently regel 26 develop psychotic complications and less frequent dyskinesia as complication of levodopa regel 27 treatment than young-onset ones. Friedman found a striking difference in symptomatology regel 28 of psychotic complications. Whereas old-onset patients used to have simple, mostly visual regel 29 hallucinations with preserved insight, young-onset ones tend to develop paranoid behaviour regel 30 without preserved insight. The number of young-onset patients with psychotic complications regel 31 however was very low in this study. There was no striking difference in overall functioning regel 32 based on activities of daily living (ADL) between those two groups. According to Friedman27, regel 33 the lesion in young-onset PD concerns predominantly the dopaminergic system. This regel 34 monosystemic lesion may explain the greater susceptibility to dyskinesia (and the fact that regel 35 bradykinesia is the dominant symptom of this disease). Lower susceptibility to dyskinesia regel 36 in old-onset parkinsonian patients could be the result of age-related decline in the number regel 37 of dopaminergic receptors in striatum. In contrast old-onset patients are more susceptible regel 38 to developing psychotic complications, probably due to more widespread lesions of the regel 39 44 Parkinson’s disease: symptoms and age dependency

central nervous system resulting from ageing. Older people are in general more likely to regel 1 develop psychotic reactions to various external stimuli, e.g. infections, intoxications, etc regel 2 46. Age-related brain atrophy involving also other neurotransmitter systems is probably regel 3 the reason for the different symptoms in PD between old-onset and young-onset patients27. regel 4 Some studies have observed a higher frequency of a first-degree relative with PD in young- regel 5 onset patients3, 82, although other studies found no difference in the number of affected regel 6 Chapter 2 relatives among young- and old-onset cases29, 73. Others have noted an increased exposure regel 7 to farming and rural living in patients with young-onset of disease. Despite the differences regel 8 in clinical manifestation, the cellular morphology and frequency of Lewy bodies in the regel 9 substantia nigra are identical in young-and old-onset cases29. regel 10 regel 11 Other subtypes of PD regel 12 Several other studies have investigated the existence of possible subgroups of PD, including regel 13 young onset, tremor dominant, postural instability/gait disorder predominant, benign and regel 14 malignant forms. Comparing tremor-dominant versus postural instability/gait disorder- regel 15 dominant PD (PIGD), greater motor disability has been found in the latter group. Patients regel 16 with tremor as dominant symptom usually did not only have more severe tremor at rest, regel 17 but also more severe action- and postural tremor. PIGD patients had, in addition to their regel 18 greater postural and gait difficulties, more severe bradykinesia and rigidity41. regel 19 Some authors have divided patients into benign or malignant groups based on duration regel 20 of symptoms and stage of disease. Patients were arbitrarily considered to have a benign regel 21 form of PD if they were Hoehn and Yahr stage 2 or less, combined with parkinsonian regel 22 symptoms for 4 years or less. In contrast, patients with malignant PD were those with early regel 23 postural imbalance, while disease duration is less than 1 year. Patients with a benign form regel 24 of PD usually were younger at onset of disease and had tremor as dominant symptom. regel 25 Indeed, benign tremulous parkinsonism is considered to be a well-recognized subgroup regel 26 of patients with a relatively nonprogressive, long-term course of disease. The benign regel 27 group had an earlier onset than the malignant one and the latter one performed slightly regel 28 worse on the Mini Mental State Examination, although this difference was not statistically regel 29 significant after adjusting for age. To distinguish the benign form from the malignant one, regel 30 other factors may be important as well, like response to medication, genetic factors and regel 31 cognitive impairment82. Hely et al suggest that patients with a benign form of PD have mild regel 32 dyskinesia, if present, and that none of these patients had dementia or hallucinations. All regel 33 of them are responsive to drugs37. regel 34 Graham and Sagar have investigated the heterogeneity in PD, using a data-driven regel 35 approach36. They suggested the existence of three distinct subtypes: regel 36 • a motor only subtype, without intellectual impairment regel 37 • a motor and cognitive subtype regel 38 • a rapid progressive subtype regel 39 45 Chapter 2

regel 1 The latter group is characterized by an older age of disease onset than the other subtypes, regel 2 rapidly progressive motor and cognitive disability and more orthostasis. Because of the regel 3 rapid progression patients belonging to this subtype have a shorter life expectancy than regel 4 the other groups. This is confirmed by Louis et al54, who found that mortality increases with regel 5 climbing of the years, the development of dementia and the severity of motor disability. regel 6 Gender may be associated with a different progression of PD. According to the Sydney regel 7 multicentre study of Parkinson’s Disease, dyskinesia develops earlier in women during the regel 8 first 10 years of disease. After 10 years there is no significant difference in the prevalence regel 9 of dyskinesia, but women tend to have a higher score in Hoehn and Yahr stage37. regel 10 regel 11 regel 12 Brain metabolism in aging and Parkinson’s Disease regel 13 regel 14 During development and aging, the brain will change anatomically and physiologically to regel 15 support the behaviour of normal adults. Chugani et al8 have investigated the maturation regel 16 of the brain during the first years of life by using positron emission tomography (PET) and regel 17 2-deoxy-[18F]fluoro-D-glucose (FDG). They discovered that in the first 4 weeks of life (the regel 18 neonatal period), the most important region of metabolic activity is the primary sensorimotor regel 19 area, while high activity was also found in the thalamus, brainstem and cerebellar vermis. regel 20 The second postnatal month a small increase in metabolism in calcarine and temporal regel 21 cortices can be seen. Approximately 3 months after birth, considerable rises in metabolic regel 22 activity in the anterior parietal, temporal and calcarine cortices as well as in basal ganglia regel 23 and cerebellar cortex were found. By 1 year, the metabolic pattern resembled that in regel 24 adults, but absolute values were lower than adult ones. Adult rates were reached by 2 regel 25 years of age. Metabolic rates continued to rise until 3 - 4 years, so values exceeded those regel 26 of adults by a factor of approximately 2. These high values were maintained until age 8 regel 27 - 9. At this age, they begin to decline and by the end of the second decade adult values regel 28 are reached. The highest increases in metabolic activity were observed in the cerebral regel 29 cortices8. regel 30 Aging is associated with the degeneration of specific neural systems. Normal aging is regel 31 predominantly characterized by metabolic changes in the prefrontal cortex. By using regel 32 FDG-PET scans metabolism of these systems can be investigated. Moeller and coworkers65 regel 33 have tried to explore the metabolic topography of aging. They found various topographic regel 34 profiles. One was characterized by relative frontal hypometabolism associated with regel 35 covariate metabolic increases in the parietooccipital association areas, basal ganglia, regel 36 mid-brain and cerebellum. Another one revealed relative basal ganglia hypermetabolism regel 37 associated with covariate decreases in frontal premotor cortex65. Mielke et al also found a regel 38 decline of regional cerebral glucose metabolism in frontal areas63. regel 39 46 Parkinson’s disease: symptoms and age dependency

Although the most important lesion in PD is located in the substantia nigra and its regel 1 dopaminergic projections, lesions of the presynaptic nigrostriatal dopamine system regel 2 result in widespread abnormalities in regional brain metabolism. To define the metabolic regel 3 topography of parkinsonism the same strategy as above has been used. According to regel 4 the results of Eidelberg and coworkers21 the metabolic profile of PD is characterized by regel 5 increased activity in the lentiform nucleus, thalamus, pons and cerebellum whereas activity regel 6 Chapter 2 was decreased in the lateral frontal, paracentral and parietal association areas. Increase regel 7 in activity in the lentiform nucleus and thalamus in PD is consistent with experimental regel 8 animal studies64, 68. Increased metabolism in the ventral thalamus has been confirmed by regel 9 others10, 68. The subject scores for the metabolic profile in PD correlated with the individual regel 10 Hoehn and Yahr score and with rigidity and bradykinesia ratings, but not with tremor21, regel 11 68. The reproducibility of this unique pattern of regional metabolic covariation in patients regel 12 with PD has been assessed by Moeller et al66, 68. This topography appears to be highly regel 13 reproducible across patient populations and tomographs. regel 14 regel 15 regel 16 regel 17 regel 18 regel 19 regel 20 regel 21 regel 22 regel 23 regel 24 regel 25 regel 26 regel 27 regel 28 regel 29 regel 30 regel 31 regel 32 regel 33 regel 34 regel 35 regel 36 regel 37 regel 38 regel 39 47 Chapter 2

regel 1 Reference List regel 2 regel 3 1. Mortality in DATATOP: a multicenter trial in early Parkinson’s disease. Parkinson Study regel 4 Group. Ann Neurol 43:318-325, 1998 regel 5 2. Aarsland D, Larsen JP, Cummins JL, et al: Prevalence and clinical correlates of psychotic regel 6 symptoms in Parkinson disease: a community-based study. Arch Neurol 56:595-601, regel 7 1999 regel 8 3. Barbeau A, Pourcher E: New data on the genetics of Parkinson’s disease. Can J Neurol regel 9 Sci 9:53-60, 1982 regel 10 4. Bennett DA, Beckett LA, Murray AM, et al: Prevalence of parkinsonian signs and regel 11 associated mortality in a community population of older people. N Engl J Med regel 12 334:71-76, 1996 regel 13 5. Borgesen SE, Gjerris F: The predictive value of conductance to outflow of CSF in normal regel 14 pressure hydrocephalus. Brain 105:65-86, 1982 regel 15 6. Burke RE: Programmed cell death and Parkinson’s disease. Mov Disord 13 Suppl regel 16 1:17-23, 1998 regel 17 7. Burke RE, Kholodilov NG: Programmed cell death: does it play a role in Parkinson’s regel 18 disease? Ann Neurol 44:S126-S133, 1998 regel 19 8. Chugani HT, Phelps ME, Mazziotta JC: Positron emission tomography study of human regel 20 brain functional development. Ann Neurol 22:487-497, 1987 regel 21 9. Conley SC, Kirchner JT: Parkinson’s disease - the shaking palsy - Underlying factors, regel 22 diagnostic considerations, and clinical course. Postgraduate Medicine 106:39-+, regel 23 1999 regel 24 10. Crossman AR, Mitchell IJ, Sambrook MA: Regional brain uptake of 2-deoxyglucose regel 25 in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the regel 26 macaque monkey. Neuropharmacology 24:587-591, 1985 regel 27 11. Cunha U, Leduc M, Nayak US, et al: Why do old people stoop? Arch Gerontol regel 28 Geriatr 6:363-369, 1987 regel 29 12. Curtis L, Lees AJ, Stern GM, et al: Effect of L-dopa on course of Parkinson’s disease. regel 30 Lancet 2:211-212, 1984 regel 31 13. Damier P, Hirsch EC, Agid Y, et al: The substantia nigra of the human brain. II. Patterns of regel 32 loss of dopamine-containing neurons in Parkinson’s disease. Brain 122 ( Pt 8):1437- regel 33 1448, 1999 regel 34 14. Daniel SE, Hawkes CH: Preliminary diagnosis of Parkinson’s disease by olfactory bulb regel 35 pathology. Lancet 340:186, 1992 regel 36 15. Daniel SE, Lees AJ: Parkinson’s Disease Society Brain Bank, London: overview and regel 37 research. J Neural Transm Suppl 39:165-172, 1993 regel 38 regel 39 48 Parkinson’s disease: symptoms and age dependency

16. de Rijk MC, Breteler MM, Graveland GA, et al: Prevalence of Parkinson’s disease in the regel 1 elderly: the Rotterdam Study. Neurology 45:2143-2146, 1995 regel 2 17. Diamond SG, Markham CH, Hoehn MM, et al: Multi-center study of Parkinson mortality regel 3 with early versus later dopa treatment. Ann Neurol 22:8-12, 1987 regel 4 18. DOVENMUEHLE RH, BUSSE EW, NEWMAN EG: Physical problems of older people. J regel 5 Am Geriatr Soc 9:208-217, 1961 regel 6 Chapter 2 19. Dubois B, Pillon B: Cognitive deficits in Parkinson’s disease. J Neurol 244:2-8, 1997 regel 7 20. Eckert T, Barnes A, Dhawan V, et al: FDG PET in the differential diagnosis of parkinsonian regel 8 disorders. Neuroimage 26:912-921, 2005 regel 9 21. Eidelberg D, Moeller JR, Dhawan V, et al: The metabolic topography of parkinsonism. J regel 10 Cereb Blood Flow Metab 14:783-801, 1994 regel 11 22. Elble RJ: Tremor in ostensibly normal elderly people. Mov Disord 13:457-464, 1998 regel 12 23. Elble RJ, Hughes L, Higgins C: The syndrome of senile gait. J Neurol 239:71-75, 1992 regel 13 24. Fearnley JM, Lees AJ: Ageing and Parkinson’s disease: substantia nigra regional regel 14 selectivity. Brain 114 ( Pt 5):2283-2301, 1991 regel 15 25. Ferreri F, Agbokou C, Gauthier S: Recognition and management of neuropsychiatric regel 16 complications in Parkinson’s disease. CMAJ 175:1545-1552, 2006 regel 17 26. Fisher CM: Hydrocephalus as a cause of disturbances of gait in the elderly. Neurology regel 18 32:1358-1363, 1982 regel 19 27. Friedman A: Old-onset Parkinson’s disease compared with young-onset disease: clinical regel 20 differences and similarities. Acta Neurol Scand 89:258-261, 1994 regel 21 28. Gelb DJ, Oliver E, Gilman S: Diagnostic criteria for Parkinson disease. Arch Neurol regel 22 56:33-39, 1999 regel 23 29. Gibb WR, Lees AJ: A comparison of clinical and pathological features of young- and regel 24 old-onset Parkinson’s disease. Neurology 38:1402-1406, 1988 regel 25 30. Gibb WR, Lees AJ: The relevance of the Lewy body to the pathogenesis of idiopathic regel 26 Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745-752, 1988 regel 27 31. Giladi N, McMahon D, Przedborski S, et al: Motor blocks in Parkinson’s disease. regel 28 Neurology 42:333-339, 1992 regel 29 32. Gilmore R: Movement-Disorders in the Elderly. Geriatrics 39:65-&, 1984 regel 30 33. Goetz CG, Tanner CM, Stebbins GT, et al: Risk factors for progression in Parkinson’s regel 31 disease. Neurology 38:1841-1844, 1988 regel 32 34. Golbe LI: The epidemiology of PSP. J Neural Transm Suppl 42:263-273, 1994 regel 33 35. Gorell JM, Johnson CC, Rybicki BA: Parkinson’s disease and its comorbid disorders: regel 34 an analysis of Michigan mortality data, 1970 to 1990. Neurology 44:1865-1868, regel 35 1994 regel 36 regel 37 regel 38 regel 39 49 Chapter 2

regel 1 36. Graham JM, Sagar HJ: A data-driven approach to the study of heterogeneity in idiopathic regel 2 Parkinson’s disease: identification of three distinct subtypes. Mov Disord 14:10-20, regel 3 1999 regel 4 37. Hely MA, Morris JG, Traficante R, et al: The sydney multicentre study of Parkinson’s regel 5 disease: progression and mortality at 10 years. J Neurol Neurosurg Psychiatry regel 6 67:300-307, 1999 regel 7 38. Hoehn MM, Yahr MD: Parkinsonism: onset, progression and mortality. Neurology regel 8 17:427-442, 1967 regel 9 39. Hughes AJ, Daniel SE, Blankson S, et al: A Clinicopathological Study of 100 Cases of regel 10 Parkinsons-Disease. Archives of Neurology 50:140-148, 1993 regel 11 40. Imms FJ, Edholm OG: Studies of gait and mobility in the elderly. Age Ageing 10:147- regel 12 156, 1981 regel 13 41. Jankovic J, McDermott M, Carter J, et al: Variable expression of Parkinson’s disease: regel 14 a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology regel 15 40:1529-1534, 1990 regel 16 42. Jansson B, Jankovic J: Low cancer rates among patients with Parkinson’s disease. Ann regel 17 Neurol 17:505-509, 1985 regel 18 43. Kessler II: Epidemiologic studies of Parkinson’s disease. 3. A community-based survey. regel 19 Am J Epidemiol 96:242-254, 1972 regel 20 44. Kessler II: Epidemiologic studies of Parkinson’s disease. II. A hospital-based survey. Am regel 21 J Epidemiol 95:308-318, 1972 regel 22 45. Kompoliti K, Goetz CG, Boeve BF, et al: Clinical presentation and pharmacological regel 23 therapy in corticobasal degeneration. Arch Neurol 55:957-961, 1998 regel 24 46. Koponen H, Stenback U, Mattila E, et al: Delirium among elderly persons admitted to a regel 25 psychiatric hospital: clinical course during the acute stage and one-year follow-up. Acta regel 26 Psychiatr Scand 79:579-585, 1989 regel 27 47. Kostic V, Przedborski S, Flaster E, et al: Early development of levodopa-induced regel 28 dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology regel 29 41:202-205, 1991 regel 30 48. Kovacs CS, Howse DC, Yendt ER: Reversible parkinsonism induced by hypercalcemia regel 31 and primary hyperparathyroidism. Arch Intern Med 153:1134-1136, 1993 regel 32 49. Kurtzke JF, Goldberg ID: Parkinsonism Death Rates by Race, Sex, and Geography. regel 33 Neurology 38:1558-1561, 1988 regel 34 50. Lang AE, Lozano AM: Parkinson’s disease. First of two parts. N Engl J Med 339:1044- regel 35 1053, 1998 regel 36 51. Leonard BE: Evidence for a biochemical lesion in depression. J Clin Psychiatry 61 regel 37 Suppl 6:12-17, 2000 regel 38 regel 39 50 Parkinson’s disease: symptoms and age dependency

52. Litvan I, Agid Y, Calne D, et al: Clinical research criteria for the diagnosis of progressive regel 1 supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP regel 2 international workshop. Neurology 47:1-9, 1996 regel 3 53. Louis ED, Marder K, Cote L, et al: Differences in the prevalence of essential tremor regel 4 among elderly African Americans, whites, and Hispanics in northern Manhattan, NY. regel 5 Arch Neurol 52:1201-1205, 1995 regel 6 Chapter 2 54. Louis ED, Marder K, Cote L, et al: Mortality from Parkinson disease. Arch Neurol regel 7 54:260-264, 1997 regel 8 55. Lundgren-Lindquist B, Aniansson A, Rundgren A: Functional studies in 79-year-olds. III. regel 9 Walking performance and climbing capacity. Scand J Rehabil Med 15:125-131, regel 10 1983 regel 11 56. Marder K, Flood P, Cote L, et al: A pilot study of risk factors for dementia in Parkinson’s regel 12 disease. Mov Disord 5:156-161, 1990 regel 13 57. Marder K, Leung D, Tang M, et al: Are demented patients with Parkinson’s disease regel 14 accurately reflected in prevalence surveys? A survival analysis. Neurology 41:1240- regel 15 1243, 1991 regel 16 58. Marttila RJ, Rinne UK: Epidemiology of Parkinson’s disease in Finland. Acta Neurol regel 17 Scand 53:81-102, 1976 regel 18 59. Mayeux R, Denaro J, Hemenegildo N, et al: A Population-Based Investigation of regel 19 Parkinsons-Disease with and Without Dementia - Relationship to Age and Gender. regel 20 Archives of Neurology 49:492-497, 1992 regel 21 60. Mayeux R, Marder K, Cote LJ, et al: The frequency of idiopathic Parkinson’s disease regel 22 by age, ethnic group, and sex in northern Manhattan, 1988-1993. Am J Epidemiol regel 23 142:820-827, 1995 regel 24 61. Mayeux R, Stern Y, Rosenstein R, et al: An estimate of the prevalence of dementia in regel 25 idiopathic Parkinson’s disease. Arch Neurol 45:260-262, 1988 regel 26 62. McKeith I, O’Brien J: Dementia with Lewy bodies. Aust N Z J Psychiatry 33:800- regel 27 808, 1999 regel 28 63. Mielke R, Kessler J, Szelies B, et al: Normal and pathological aging--findings of positron- regel 29 emission-tomography. J Neural Transm 105:821-837, 1998 regel 30 64. Mitchell IJ, Boyce S, Sambrook MA, et al: A 2-deoxyglucose study of the effects of regel 31 dopamine agonists on the parkinsonian primate brain. Implications for the neural regel 32 mechanisms that mediate dopamine agonist-induced dyskinesia. Brain 115 ( Pt regel 33 3):809-824, 1992 regel 34 65. Moeller JR, Ishikawa T, Dhawan V, et al: The metabolic topography of normal aging. J regel 35 Cereb Blood Flow Metab 16:385-398, 1996 regel 36 regel 37 regel 38 regel 39 51 Chapter 2

regel 1 66. Moeller JR, Nakamura T, Mentis MJ, et al: Reproducibility of regional metabolic regel 2 covariance patterns: comparison of four populations. J Nucl Med 40:1264-1269, regel 3 1999 regel 4 67. Morens DM, Davis JW, Grandinetti A, et al: Epidemiologic observations on Parkinson’s regel 5 disease: incidence and mortality in a prospective study of middle-aged men. Neurology regel 6 46:1044-1050, 1996 regel 7 68. Palombo E, Porrino LJ, Bankiewicz KS, et al: Local cerebral glucose utilization in regel 8 monkeys with hemiparkinsonism induced by intracarotid infusion of the neurotoxin MPTP. regel 9 J Neurosci 10:860-869, 1990 regel 10 69. Pearce RK, Hawkes CH, Daniel SE: The anterior olfactory nucleus in Parkinson’s disease. regel 11 Mov Disord 10:283-287, 1995 regel 12 70. Potagas C, Dellatolas G, Ziegler M, et al: Clinical assessment of olfactory dysfunction in regel 13 Parkinson’s disease. Mov Disord 13:394-399, 1998 regel 14 71. Quinn N: Multiple system atrophy--the nature of the beast. J Neurol Neurosurg regel 15 Psychiatry Suppl:78-89, 1989 regel 16 72. Quinn N: Parkinsonism--recognition and differential diagnosis. BMJ 310:447-452, regel 17 1995 regel 18 73. Quinn N, Critchley P, Marsden CD: Young onset Parkinson’s disease. Mov Disord regel 19 2:73-91, 1987 regel 20 74. Quinn NP, Wenning GK: Multiple system atrophy. Adv Neurol 69:413-419, 1996 regel 21 75. Rajput AH, Rozdilsky B: Dysautonomia in Parkinsonism: a clinicopathological study. J regel 22 Neurol Neurosurg Psychiatry 39:1092-1100, 1976 regel 23 76. Rautakorpi I, Takala J, Marttila RJ, et al: Essential tremor in a Finnish population. Acta regel 24 Neurol Scand 66:58-67, 1982 regel 25 77. Rogers JD, Brogan D, Mirra SS: The nucleus basalis of Meynert in neurological disease: regel 26 a quantitative morphological study. Ann Neurol 17:163-170, 1985 regel 27 78. Schapira AHV: Science, medicine, and the future - Parkinson’s disease. British Medical regel 28 Journal 318:311-314, 1999 regel 29 79. Schoenberg BS, Anderson DW, Haerer AF: Prevalence of Parkinsons-Disease in the regel 30 Biracial Population of Copiah County, Mississippi. Neurology 35:841-845, 1985 regel 31 80. Schoenberg BS, Osuntokun BO, Adeuja AOG, et al: Comparison of the Prevalence of regel 32 Parkinsons-Disease in Black Populations in the Rural United-States and in Rural Nigeria - regel 33 Door-To-Door Community Studies. Neurology 38:645-646, 1988 regel 34 81. Stacy M, Jankovic J: Differential diagnosis of Parkinson’s disease and the parkinsonism regel 35 plus syndromes. Neurol Clin 10:341-359, 1992 regel 36 82. Stern M, Dulaney E, Gruber SB, et al: The epidemiology of Parkinson’s disease. A case- regel 37 control study of young-onset and old-onset patients. Arch Neurol 48:903-907, 1991 regel 38 regel 39 52 Parkinson’s disease: symptoms and age dependency

83. Sudarsky L: Geriatrics: gait disorders in the elderly. N Engl J Med 322:1441-1446, regel 1 1990 regel 2 84. Sudarsky L, Ronthal M: Gait disorders among elderly patients. A survey study of 50 regel 3 patients. Arch Neurol 40:740-743, 1983 regel 4 85. Sudarsky L, Simon S: Gait disorder in late-life hydrocephalus. Arch Neurol 44:263- regel 5 267, 1987 regel 6 Chapter 2 86. Taniwaki T, Nakagawa M, Yamada T, et al: Cerebral metabolic changes in early multiple regel 7 system atrophy: a PET study. J Neurol Sci 200:79-84, 2002 regel 8 87. Tanner CM: Epidemiology of Parkinson’s disease. Neurol Clin 10:317-329, 1992 regel 9 88. Tanner CM, Ben Shlomo Y: Epidemiology of Parkinson’s disease. Adv Neurol 80:153- regel 10 159, 1999 regel 11 89. Tinetti ME, Williams TF, Mayewski R: Fall risk index for elderly patients based on number regel 12 of chronic disabilities. Am J Med 80:429-434, 1986 regel 13 90. Wenning GK, Ben Shlomo Y, Magalhaes M, et al: Clinical features and natural history of regel 14 multiple system atrophy. An analysis of 100 cases. Brain 117 ( Pt 4):835-845, 1994 regel 15 91. Wermuth L, Stenager EN, Stenager E, et al: Mortality in patients with Parkinson’s disease. regel 16 Acta Neurol Scand 92:55-58, 1995 regel 17 regel 18 regel 19 regel 20 regel 21 regel 22 regel 23 regel 24 regel 25 regel 26 regel 27 regel 28 regel 29 regel 30 regel 31 regel 32 regel 33 regel 34 regel 35 regel 36 regel 37 regel 38 regel 39 53 Chapter 2

regel 1 regel 2 regel 3 regel 4 regel 5 regel 6 regel 7 regel 8 regel 9 regel 10 regel 11 regel 12 regel 13 regel 14 regel 15 regel 16 regel 17 regel 18 regel 19 regel 20 regel 21 regel 22 regel 23 regel 24 regel 25 regel 26 regel 27 regel 28 regel 29 regel 30 regel 31 regel 32 regel 33 regel 34 regel 35 regel 36 regel 37 regel 38 regel 39 54