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Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson’s Disease?

Baumeister, Alan A. PhD

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Harvard Review of Psychiatry: 3/4 2021 - Volume 29 - Issue 2 - p 142-158
doi: 10.1097/HRP.0000000000000283
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Abstract

The possible association between Parkinson’s disease (PD) and attention-deficit/hyperactivity disorder (ADHD) is an important, newly emerging topic of inquiry. The possibility that PD and ADHD are related clinical entities has been suspected for at least 20 years. Until recently, the reasons for this suspicion were conjectural, resting primarily on putative common abnormalities of dopamine (DA) function. In what appears to be the first direct test of this hypothesis, Walitza and colleagues1 sought to determine retrospectively whether patients with Parkinson’s disease were more likely than controls to have had childhood onset ADHD. Although total scores on measures used to diagnose ADHD retrospectively were insufficient for such diagnosis, subjects with PD had significantly more core symptoms of ADHD in childhood.

A recent large-scale, retrospective, population-based cohort study of persons born in Utah between 1950 and 1992 provides additional evidence for a link between PD and ADHD.2 In that study, to enhance diagnostic sensitivity, investigators used an outcome measure that included PD and related disorders (secondary PD, other degenerative diseases of the basal ganglia, and essential tremor), which they referred to collectively as diseases of the basal ganglia and cerebellum (BG&C). Risk for BG&C in a cohort of ~32,000 patients who had been diagnosed with ADHD was significantly increased 2.4-fold compared to ~159,000 matched non-ADHD controls. A comparable significant 2.6-fold increase in risk was also observed in ADHD patients when the outcome diagnosis was restricted to PD per se. Of particular note, the risk for BG&C was dramatically increased (6- to 8-fold) in persons with ADHD who were known to have been prescribed stimulant medication. By way of comparison, the risk for lung cancer among former heavy smokers with five or fewer years since quitting is increased 12-fold.3 Thus, the magnitude of the reported association between BG&C and stimulant-treated ADHD is substantial.

These findings and others discussed below suggest that an important association exists between PD and ADHD. ADHD precedes PD by definition, if not in fact.4 Thus, ADHD or factors associated with ADHD may be antecedents that increase the likelihood for subsequent development of PD. The delineation of such antecedents could have important implications for understanding the etiology and pathogenesis of both disorders. In the review that follows, evidence pertaining to the possible nature of the relationship between PD and ADHD is explored. First, an overview of PD is given to provide background for subsequent discussion.

OVERVIEW OF PARKINSON’S DISEASE

After Alzheimer’s disease, PD is the next most common degenerative neurological disorder of senescence.5–11 The incidence and prevalence of Parkinson’s disease increase almost exponentially with age, affecting approximately 1% of persons over 60. PD occurs slightly more often in men than women, in a ratio of about 3 to 2. PD is the fastest-growing neurological disorder globally. The number of persons worldwide with PD doubled between 1990 and 2015. This increase is largely, but not wholly, explained by increased life expectancy and the consequent increased number of persons aged 60 and over.

The pathogenic mechanisms responsible for PD are manifold, interactive, complex, and elusive. Traditionally, PD has been divided into familial (inherited) and nonfamilial (sporadic) forms. The familial form accounts for a small subset (5%–10%) of total PD cases, most having early onset.12 The sporadic form comprises the majority of senescent cases and has a strong environmental component.13 It has recently become clear, however, that sporadic PD also has a heritable component.14,15 Generally speaking, the clinical presentation and underlying pathology of familial and sporadic forms are similar.16,17 These findings indicate that PD has multiple genetic and environmental causal pathways that converge on a common neurobiological substrate.17,18

The discovery in the 1980s of a neurotoxin called MPTP, which produces rapid and permanent parkinsonism in humans and animals, spurred intense interest in the role of environmental toxins.19,20 Numerous potential environmental risk factors are associated with PD, including exposure to pesticides, herbicides, industrial solvents, and heavy metals, as well as rural living and farming/agriculture.21,22 Such factors, however, individually account for only a small amount of the variance in PD. By contrast, smoking is associated with a 40% decrease in the risk for PD. It is not known whether the association between smoking and PD is causal. If so, reduced tobacco use resulting from public health initiatives may contribute to increasing rates of PD.9

Diagnosis of Parkinson’s disease is usually based on clinical presentation of motor signs. Widely used diagnostic criteria require the occurrence of two or more of the following: resting tremor, bradykinesia, rigidity, and postural/gait instability. Clinical diagnosis can be confirmed only by postmortem neuropathologic analysis (see below). Clinical-pathological studies indicate that the accuracy of clinical diagnosis is ~50% and ~80% in patients with a disease duration of <5 years and >5 years, respectively.23,24 Although motor signs are the principal clinical criteria for diagnosis of PD, a variety of nonmotor signs and symptoms also occur. These include REM sleep behavior disorder (e.g., dream enacting behavior), altered olfaction (e.g., hyposmia), gastrointestinal disorders (e.g., constipation), excessive daytime sleepiness, cognitive impairment, and depression.25–27

An important recent development in the diagnosis of PD is the recognition of a prodromal syndrome. The underlying pathology in PD develops slowly over many years, probably decades. A problem with using classic motor signs to diagnose PD is that these signs do not manifest until extensive neurodegeneration has occurred. Early identification of persons at risk for PD has potential therapeutic implications.27 Prodromal PD syndrome is a heterogenous collection of subtle motor and nonmotor signs and symptoms. Subtle motor deficits are detectable on neuropsychological tests (e.g., Purdue Pegboard Test) several years before diagnosis of PD.28 The nonmotor features of prodromal PD include constipation, hyposmia, and REM sleep behavior disorder. This sleep disorder is an especially powerful predictor of subsequent development of neurodegenerative disease, including PD, and precedes onset of PD by an average of 28 years.29,30 Constipation is a risk factor for PD, and it may precede the onset of motor symptoms by as much as 20 years.31–33 Olfactory dysfunction occurs in ~90% of patients with PD and is associated with increased risk for PD for up to 4 years before the motor signs emerge.34 Other risk factors for PD include cognitive impairments, anxiety, and depression.26,35,36

The relationship between the premotor features of PD and its pathogenesis is of considerable interest. Neuronal inclusions, called Lewy bodies and Lewy neurites—consisting mostly of misfolded α-synuclein protein—are a pathologic hallmark of idiopathic PD.37–40 According to Braak’s hypothesis, PD is initiated by an unknown pathogen (e.g., a virus) that enters the body by way of the nasal cavity and gut, initiating Lewy pathology and producing the prodromal gastrointestinal and olfactory defects.41–45 The pathology then spreads toward the central nervous system by way of olfactory and vagus nerves and enters the brain at the olfactory bulb and the dorsal motor nucleus of the vagus nerve. The rostral progression of pathology from the dorsal motor nucleus through the midbrain and forebrain eventually damages neural structures that control movement. Braak’s hypothesis has considerable support.46–49 Not all patients with PD, however, evidence the proposed pathologic changes in the proposed sequence, and the role of Lewy pathology in neurodegeneration is uncertain. It is not clear whether Lewy pathology is the cause of neurodegeneration or whether it is a neuroprotective response to neurodegeneration.50–52 Either way, Lewy pathology is a biomarker for PD.

The pathognomonic feature of PD is selective degeneration of mesencephalic DA neurons.53 For unknown reasons, DA neurons in the substantia nigra (SN) are more vulnerable than other DA pathways, including those in the adjacent ventral tegmental area (VTA). Postmortem histologic studies show that ~80% of SN and ~50% of VTA cell bodies are lost in advanced disease.54,55 The heightened vulnerability of SN DA neurons may be related to differential cellular response to α-synuclein. Overexpression of a mutant α-synuclein gene in mice induces in vivo increases in firing rates of SN DA but not VTA DA neurons.56 Moreover, mutant α-synuclein–induced activation of DA neurons occurred in middle-aged but not young adult mice. It was suggested that acquired sensitivity to this effect of α-synuclein may be an early pathophysiological marker of SN DA neuronal vulnerability that precedes neurodegeneration.

ADHD AND PD: A COMMON PATHWAY LINKAGE

Multiple lines of evidence suggest that PD and ADHD share structural, chemical, and functional alterations of mesencephalic DA neurons. Transcranial sonography (TCS) of the SN shows increased echogenicity, relative to control subjects, in patients with PD57–60 and in children and adolescents with ADHD.61,62 In PD, hyperechogenicity of the SN, defined as greater than the 90th percentile of controls, is associated with a 17-fold increased risk for subsequent development of PD.58 SN echogenicity is also increased in patients with neuroleptic-induced parkinsonism, and the size of the echogenic signal correlates with severity of parkinsonian symptoms.63 In ADHD, SN hyperechogenicity has been reported in 48% of children and adolescents with ADHD, and size of the echogenic signal correlated positively with the severity of core symptoms of ADHD.61 The methodologic quality of studies that have employed transcranial sonography in the diagnosis of PD is good. A meta-analysis of these studies59 found that 26 of the 31 studies examined had a score of 10 or greater (out of a maximum of 14) on the Quality Assessment of Diagnostic Accuracy Studies.64,65 In the two studies that found hyperechogenicity in persons with ADHD, one62 employed a blinded design, the other61 did not, and in both studies ADHD subjects received stimulant medication. Additional studies are needed to replicate transcranial sonography findings in children and adolescents with ADHD to determine whether SN hyperechogenicity occurs in adults with ADHD and to determine the role of stimulant medications on observed effects. Studies are also needed to determine the pathologic changes responsible for hyperechogenicity of the SN. Increased SN echogenicity in PD is associated with several pathologic changes, including gliosis and increased iron concentration.59 Interestingly, a recent study found increased iron concentration in the striatum of adults with ADHD.66 Additional studies are needed to determine whether iron is increased in the SN in ADHD, and whether SN hyperechogenicity is associated with alterations of nigrostriatal DA neurons.

PD and ADHD also have similar structural changes in projection regions of mesencephalic DA neurons. DA neurons of the SN project to the dorsal striatum (putamen and caudate). The DA pathway from the SN to the putamen is the first to lose neurons in PD, and it is thought to be primarily responsible for bradykinesia and rigidity.67–69 Atrophy of the putamen is a common finding in structural MRI imaging of PD.70 Scores of structural MRI studies of children and adults with ADHD have been conducted in the last 20 years, and multiple meta-analyses of these studies have been published.71–74 A robust finding from these studies is reduced volume of the caudate and lentiform nuclei (i.e., the putamen and globus pallidus) in children with ADHD.

A caveat is warranted regarding structural changes in the striatum in ADHD. Several studies have found that reduced striatal volume detected by MRI in ADHD patients diminishes with age, to the extent that it is no longer detectable in adults.72,73,75 This suggests that striatal development is delayed in ADHD but eventually normalizes in early adulthood. However, not all studies are in agreement in this regard. Using a relatively large sample and conventional T1-weighted imaging, Proal and colleagues76 found significantly reduced caudate volume in adults with ADHD. Moreover, a recent study by Sethi and colleagues66 indicates that conventional MRI has reduced sensitivity to detect striatal abnormalities in adults with ADHD. In this study, magnetization transfer imaging (MTI), which provides improved contrast between white and gray matter, detected reduced volume of the ventral striatum in adults with ADHD that was not demonstrable using conventional MRI. The authors postulated that differences in striatal iron content may explain differential sensitivity of children and adults with ADHD to conventional MRI. Indeed, the same study found evidence for increased iron content in the striatum of adults with ADHD compared to children with ADHD.

Molecular imaging studies also suggest commonalities between PD and ADHD. Loss of nigrostriatal DA neurons in PD is associated with decreases in the dorsal striatum of multiple markers of DA function, including DA, DA metabolites, and membrane and vesicular DA transporters (DAT and VMAT, respectively).77,78 The most studied marker of striatal DA function in ADHD is DAT. Both increases and decreases in striatal DAT have been reported in ADHD. A meta-analysis of these studies found that much of this variation across studies is accounted for by variation in the stimulant exposure history of subjects.79 Striatal DAT levels tend to be lower in drug-naive ADHD patients than in those who received long-term stimulant therapy.

Deficits in mesolimbic DA are also demonstrable in both PD and ADHD. Mesolimbic DA neurons project from the VTA to the ventral striatum (nucleus accumbens and olfactory tubercle).80 Structural pathology, including decreased volume, and decreased DA concentration are demonstrable in the nucleus accumbens of patients with PD.81–84 Using conventional MRI technology, children with ADHD have decreased volume of the nucleus accumbens and other limbic structures.75 As noted above, adults with ADHD have decreased volume of the ventral striatum when studied using MTI.66

The mesolimbic DA pathway to the nucleus accumbens plays a central role in mediating natural and drug-induced reward.85,86 Deficits in reward processing occur in both PD and ADHD. Mesolimbic-associated clinical presentations in PD include apathy, anhedonia, and deficits in reward-based learning.87,88 The latter appears to result from an impaired response to reward anticipation rather than processing related to reward receipt.88–90 The most consistent and frequently reported manifestation of deficit reward processing in ADHD is an aversion to delay of gratification. Children and adults with ADHD tend to choose smaller immediate rewards over larger delayed rewards.91–93 This characteristic in ADHD, like the impairment in PD, appears to result from diminished striatal DA signaling related to reward anticipation.92,94–97

NEUROPSYCHOLOGICAL FEATURES OF EARLY-STAGE PD AND ADULT ADHD, AND THEIR NEURAL CORRELATES

It has been suggested that ADHD symptoms may precede the motor symptoms of PD.1 This raises the possibility that adult ADHD may be part of the PD prodrome. In this section the neuropsychological profile of early-stage PD (PD-ES) is compared to that of adult ADHD. For the purpose of the following discussion, PD-ES is defined as either newly diagnosed PD, PD with disease duration of two or fewer years, or PD that has not advanced beyond Hoehn and Yahr stage 2.98 Adult ADHD is defined as ADHD present in persons aged 18 or older. A comprehensive review of the neuropsychology of PD-ES and adult ADHD is beyond the scope of this article. Accordingly, the following discussion focuses on neuropsychological features that have been assessed in both conditions.

Comparative Neuropsychology of PD-ES and Adult ADHD

Comparison of the results of neuropsychological testing in PD-ES and adult ADHD is fraught with conceptual and methodological difficulty. To varying degrees, neuropsychological tests assess multiple cognitive, perceptual, affective, and behavioral domains. Which domains particular tests assess is a frequent topic of discussion and debate.99–104 Different investigators may characterize the domains assessed by particular tests differently. For example, the cognitive domain assessed by the Trail Making Test Part B is variously characterized as attention105,106 or as motor control and cognitive flexibility.107–110 In addition, many neuropsychological tests have multiple subtests that are designed to tap different processes. Different studies using a given test may report or combine results of subtests differently, leading to apparent inconsistencies. Adding to the difficulty, there are often multiple ways to score particular tests, which do not necessarily have common psychometric properties or tap common domains and neural processes.111–113 Finally, samples of persons with PD-ES and adult ADHD used in the studies discussed below are often clinically heterogenous, which, no doubt, accounts for much of the inconsistency across studies.107,114–118 For all of these reasons, it is important to be as precise as possible about subject characteristics and the particular tests and measures used when comparing results across studies and clinical populations.

Notwithstanding these caveats, some tentative conclusions about the comparative neuropsychology of PD-ES and adult ADHD can be offered. Table 1 shows the neuropsychological tests that have been employed in both groups and whether individual studies report impairment or not. Studies that have employed standard neuropsychological tests of executive function137—including Stoop interference tests, trail making tests, backward digit span tests, semantic fluency tests, card sorting tests, and tower tests—report impairments in both PD-ES patients105,106,119–122,132,133,135,136 and adults with ADHD.107–110,123–127,129,131,134 In terms of cognitive domains, these studies suggest that both groups have impairments in core domains of executive function, including working memory, cognitive flexibility, inhibitory control, and planning.102–104,113,138 Diverse memory impairments have also been reported in PD-ES patients105,122,132,133,135 and adults with ADHD,108,109,130,139 including deficits in immediate and delayed recall and recognition, which are classic measures of episodic memory.140,141 Short-term memory—assessed by the digit span forward test—does not appear to be impaired in PD-ES.105,106,122 The digit span forward test has produced mixed results in adults with ADHD.107,109,110,128 A wide range of attentional deficits have been reported in adult ADHD, including impaired selective, divided, and sustained attention.108,142–144 Although many of the neuropsychological tests that have been employed in PD-ES tap attentional processes, there is a paucity of research on attention per se in this group, though impairment on the Brief Test of Attention, a measure of auditory divided attention,145 in PD-ES has been reported.132 A large body of evidence exists regarding cognitive function in persons at risk for subsequent development of PD. These studies show, with considerable consistency (although see Marchand et al.146 and Weintraub et al.147), that such persons have impairments in executive functions, attention, and memory.35,148–154 The studies on the neuropsychological deficits that precede PD are particularly important because they are consistent with the idea that the cognitive deficits of adult ADHD may be part of the PD prodrome.

Table 1 - Studies Reporting Results of Neuropsychological Tests in Persons with Early-Stage Parkinson’s Disease or Adult ADHD
Test Early-stage Parkinson’s disease Adult ADHD
Impaired Not impaired Impaired Not impaired
Stroop interference test Henik et al. (1993)119
Dujardin et al. (1999)120
Aarsland et al. (2009)121
Broeders et al. (2013)122
Muslimović et al. (2005)106 King et al. (2007)123
Antshel et al. (2010)124
Boonstra et al. (2010)125
Fuermaier et al. (2013)109
Fuermaier et al. (2015)108
Kakuszi et al. (2016)126
Johnson et al. (2001)127
Saboya et al. (2009)128
Pazvantoğlu et al. (2012)129
Butzbach et al. (2019)130
Trail Making Test Part A Muslimović et al. (2005)106
Elgh et al. (2009)105
Broeders et al. (2013)122
Murphy (2002)131
Mostert et al. (2015)107
Johnson et al. (2001)127
Saboya et al. (2009)128
Rohlf et al. (2012)110
Pazvantoğlu et al. (2012)129
Trail Making Test Part B Muslimović et al. (2005)106
Elgh et al. (2009)105
Broeders et al. (2013)122
Johnson et al. (2001)127
Murphy (2002)131
Rohlf et al. (2012)110
Pazvantoğlu et al. (2012)129
Fuermaieret al. (2013)109
Mostert et al. (2015)107
Fuermaieret al. (2015)108
Saboya et al. (2009)128
Butzbach et al. (2019)130
Digit Span Forward Muslimović et al. (2005)106
Elgh et al. (2009)105
Broeders et al. (2013)122
Fuermaier (2013)109
Mostert et al. (2015)107
Saboya et al. (2009)128
Rohlf et al. (2012)110
Digit Span Backward Muslimović et al. (2005)106
Broeders et al. (2013)122
Kalbe et al. (2016)132
Elgh et al. (2009)105 Boonstra et al. (2010)125
Rohlf et al. (2012)110
Mostert et al. (2015)107
Saboya et al. (2009)128
Fuermaier et al. (2013)109
Butzbach et al. (2019)130
Category (semantic) fluency Muslimović et al. (2005)106
Elgh et al. (2009)105
Aarsland et al. (2009)121
Broeders et al. (2013)122
Pereira et al. (2014)133
Kalbe et al. (2016)132
Tucha et al. (2005)134
Mostert et al. (2015)107
Boonstra et al. (2010)125
Letter (phenomic) fluency Broeders et al. (2013)122
Pereira et al. (2014)133
Elgh et al. (2009)105 Tucha et al. (2005)134
Fueramier et al. (2013)109
Mostert et al. (2015)107
Johnson et al. (2001)127
Boonstra et al. (2010)125
Fuermaier et al. (2015)108
Card sorting tests Levin et al (1988)135
Elgh et al. (2009)105
Broeders et al. (2013)122
Kalbe et al. (2016)132
Antshel et al. (2010)124
Rohlf et al. (2012)110
Johnson et al. (2001)127
Saboya et al. (2009)128
Boonstra et al (2010)125
Tower tests Foltynie et al. (2004)136
Broeders et al. (2013)122
Murphy (2002)131 Saboya et al. (2009)128
Boonstra et al. (2010)125
ADHD, attention-deficit/hyperactivity disorder.

PD-ES, Adult ADHD, and Mild Cognitive Impairment

Another possible area of clinical overlap between PD-ES and adult ADHD is mild cognitive impairment (MCI). MCI—along with its corollary, mild neurocognitive disorder, from the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders—are diagnostic categories for cognitive decline, indicated by subjective complaints and neuropsychological test evidence, that does not substantially impair adaptive functioning.4,115 The concept of MCI evolved from efforts to define and diagnose a transition stage between normal cognition and dementia in Alzheimer’s disease.155–157 Diagnosis of MCI is also associated with increased risk for developing dementia in Parkinson’s disease.118,158 Approximately 20% to 40% of PD-ES patients meet Movement Disorder Society criteria for MCI.133,159–162 Depending on the extent of neuropsychological testing performed, those criteria for Parkinson’s disease with MCI (PD-MCI) allow for classification into four PD-MCI subtypes.115 Amnestic and non-amnestic subtypes are based on presence or absence of memory impairment. These two categories can be further divided based on whether the impairment is in a single domain or multiple domains. Among drug-naive PD-ES patients, the amnestic multidomain MCI subtype is the most common.159 Impairments in executive function, memory, attention, and visuospatial function have been reported in PD-ES with MCI.133,159 A recent study found that multi-domain MCI may be a part of the PD prodrome.148

The relationship between MCI and adult ADHD is unclear. The cognitive features of MCI overlap substantially with the cognitive impairments in adult ADHD.163 This overlap can make it difficult to distinguish between these syndromes.164 Nevertheless, a recent study found that adults with ADHD were no more likely to score in the MCI range on the Montreal Cognitive Assessment than persons without ADHD.165

A related issue is whether ADHD is associated with dementia. Indeed, there has been speculation that adult ADHD and dementia may be different points along a pathophysiological continuum.163,166 The results of research on this topic are mixed. Ivanchak and colleagues167 did not find an association between retrospectively diagnosed ADHD and dementia in geriatric subjects. By contrast, a recent large-scale, population-based cohort study in Taiwan found that the risk for developing dementia is increased 3.4-fold in adults with ADHD compared to matched non-ADHD controls.168 A case-control study found that Lewy body dementia and Alzheimer’s disease are associated with adult symptoms of ADHD.169 Another cohort study in the United States found that a severe ADHD phenotype is associated with increased hospitalization for Lewy body dementia and Alzheimer’s disease.170 All of these studies have methodological limitations. Nevertheless, the weight of the extant evidence, albeit sparse, suggests an association between adult ADHD and subsequent development of dementia.

Neural Correlates of Cognitive Impairments in PD-ES and Adult ADHD

Numerous studies have been conducted to elucidate the neural mechanisms that underlie cognitive impairment in PD-ES and PD-MCI patients. Cortical thinning or morphometric changes in PD-ES or PD-MCI patients have been reported in prefrontal, temporal, parietal, occipital, and insular cortices, and in numerous subcortical structures, including the caudate, amygdala, nucleus accumbens, thalamus, putamen, and hippocampus.171–176 Some of these structural changes have been correlated with deficits in cognitive function. The hippocampus and associated structures have been specifically implicated in memory impairment in PD-ES and PD-MCI. Compared to PD patients with normal cognition (PD-NC), PD-MCI patients have decreased hippocampal volume, which in non-demented PD patients is correlated with memory impairment on the memory subscale of the Dementia Rating Scale.176 Compared to healthy controls, drug-naive PD-ES patients have hippocampal atrophy, which is correlated with performance on the Wechsler Memory Scale–Revised.172 In addition, compared to PD-NC patients, drug-naive PD-ES patients with MCI display atrophy of the entorhinal cortex;174 which serves as the major relay between cortico-hippocampal circuits involved in memory;177,178 in PD-MCI patients, decreased volume of the entorhinal cortex is correlated with memory impairment, assessed by the Hopkins Verbal Learning Test.174 Impaired sustained attention has been associated with atrophy of the prefrontal cortex in PD-ES patients.172

Functional imaging studies have also found neural correlates of cognitive impairments in PD-ES and PD-MCI. Drug-naive PD-ES patients with MCI compared to PD-NC patients had increased activity in the right inferior frontal and left fusiform gyri, and activity in the right inferior frontal gyrus was negatively correlated with the Montreal Cognitive Assessment score, category fluency, and the Symbol Digit Modalities Test,179 the last being a measure of speed and efficiency of neural processing.180 PD-MCI, compared to PD-NC, patients have prolonged arterial transfer time in the right thalamus, which is negatively correlated with semantic fluency,181 a commonly used measure of executive function.104

Structural and functional imaging studies have implicated the cerebellum in neuropsychological deficits in PD, including PD-ES. Although historically controversial, a role for the cerebellum in cognition and affect is now generally accepted.182,183 Atrophy of the cerebellum is associated with cognitive and affective impairments in PD.184–187 In PD-ES, altered connectivity between the cerebellum and a variety of cortical and subcortical regions has been reported.188,189

Numerous functional imaging studies have been conducted to evaluate neural correlates of neuropsychological impairment in adult ADHD. Functional imaging has been conducted during tasks designed to assess working memory,190–194 more complex mixtures of executive functions (e.g., set shifting/inhibition/executive attention/working memory),195–199 various aspects of reward processing,200–205 and attention/inhibition.200,204,206 Studies employing working-memory tasks have found activation differences between persons with adult ADHD and non-ADHD controls in multiple forebrain, midbrain, and hindbrain regions. The brain regions that have been most frequently reported to exhibit altered activity during working-memory tasks in adults with ADHD are various regions of the cerebellum and prefrontal cortex.190,192–194 The most frequently reported brain region to exhibit altered activity in adults with ADHD during tasks that tap multiple executive functions is the cingulate cortex.195–199 Other areas that exhibited altered activity in adults with ADHD during tasks that tap multiple executive functions include areas of the prefrontal cortex, such as the dorsolateral prefrontal cortex and orbitofrontal cortex,195,197 dorsal striatum,197,199 and insula.195,197 During tasks involving reward processing, adults with ADHD have been reported to have altered activity in prefrontal cortical areas, including the ventromedial prefrontal and orbitofrontal cortices,200,201,204,205 dorsal and ventral striatum,201,202,204,205 and anterior cingulate.201,203,204 Functional imaging during tests of attention/inhibition revealed altered activity in prefrontal and parietal areas, dorsal striatum, thalamus, anterior cingulate, and cerebellum.200,204,206 Perhaps the safest generalization that can be drawn from these disparate findings is that cognitive impairments in adults with ADHD are associated with altered activity in fronto-striato-cerebellar networks, which is consistent with the conclusions of others.190,200,207,208

Cognitive deficits in PD-ES and PD-MCI are associated with DA dysfunction in cortico-striatal circuits that are implicated in executive function. Christopher and colleagues,209 using PET imaging, reported that PD-MCI patients, compared to PD-NC patients and healthy controls, had significantly decreased indices of DA function in the associative striatum and reduced D2 receptors in the insula, the latter effect being correlated with a composite measure of executive function. PD-MCI patients in this study were not early stage. Decreased striatal DA function was present in PD-MCI patients, however, after controlling for disease severity. Schragg and colleagues210 found that results of SPECT imaging for caudate DAT contributed to prediction of cognitive decline (Montreal Cognitive Assessment score) in drug-abstinent PD-ES patients. Siepel and colleagues,211 also using SPECT imaging, found that DAT binding in the caudate and putamen in drug-naive PD-ES patients is associated with impairment in executive function and attention. Another PET study revealed area-specific increases and decreases in floro-L-dopa uptake in the frontal cortex and striatum, respectively, in drug-naive PD-ES patients compared to healthy controls; performance on a test of vigilance was positively correlated with uptake in the dorsolateral prefrontal cortex, and performance on the Stroop test was negatively correlated with uptake in the medial frontal and anterior cingulate cortices.212 Williams-Gray and colleagues213 reported that a particular variant of the COMT gene, which codes for an enzyme involved in DA metabolism, is correlated with executive function assessed by the Tower of London Test in PD-ES patients. Finally, decreased striatal DA function has also been linked to cognitive impairment in prodromal PD.147,149

A relative paucity of studies have examined the association of DA function with cognitive impairment in adults with ADHD. There is evidence for correlations between DA receptor and DAT binding in the dorsal and ventral striatum on measures of interference/inhibition, inattention, and motivation in this group.93,214–218

Comorbid Psychiatric Disorders in PD-ES and Adult ADHD

Comorbid psychiatric disorders are another area of overlap between PD-ES and adult ADHD. PD-ES and PD-MCI patients have increased occurrence of depressive and anxiety disorders.219–221 In PD-MCI, symptoms of depression and anxiety are more strongly associated with the amnestic than non-amnestic MCI subtype.222 Depression in PD-MCI is positively correlated with apathy,220 though depression and apathy are separable disorders.223 A large body of evidence indicates that depressive and anxiety disorders are part of the PD prodrome.224–228 Indeed, depression, in particular, is among the diagnostic criteria for prodromal PD.229 Although research is mixed on how early it is that depressive and anxiety disorders emerge before the motor symptoms of PD, some studies have indicated that it may be as much as 15 to 20 years,224,226 indicating that these disorders are not necessarily secondary to the disabling symptoms of PD. Moreover, patients with PD have higher rates of depression than those with other chronic disabling diseases.230 Depression in advanced PD has been linked to pathological changes in raphe nuclei,231 the site of ascending serotonin neurons. A paucity of research is available on the pathophysiology of depression and anxiety in PD-ES and prodromal PD.

Adults with ADHD have increased risk for depression.232–235 The mechanisms that mediate this association are unknown. Based largely on results of family and twin studies, Faraone and Larsson236 proposed that ADHD and depression are associated because they share common genetic etiologies. An alternative hypothesis that has received considerable attention posits that depression is caused by the adverse consequences of ADHD, such as impaired peer and family relationships and low academic achievement. Research designed to test this hypothesis indicates that such variables account for a substantial amount of the variance in depression in adolescents with ADHD.237–239 Systematic investigation into the variables that mediate the association between adult ADHD and depression is lacking. Nevertheless, on the assumption that ADHD is a developmental disorder, an important feature of the association between adult ADHD and depression is that the former precedes the latter. This is borne out by empirical research.240 As noted above, the opposite temporal relationship exists between the onset of PD and depression. This could suggest that the mechanisms that underlie the association with depression are different in these disorders or that ADHD and depression are part of the PD prodrome.

STIMULANTS AND PARKINSON’S DISEASE

Two clinical conditions can be associated because the treatment for one directly causes the other. Amphetamines and methylphenidate are the principal medications used to treat ADHD. It has been suggested that the association between PD and ADHD may be explained, in part, by toxic effects of these drugs on DA neurons.241 Amphetamine, methamphetamine, and methylphenidate are distinct chemicals, and, where it is important, they are discussed separately below. However, due to the considerable overlap of pharmacological profiles of amphetamine and methamphetamine, in certain contexts it is convenient to discuss these drugs together.

Much of the research on stimulant neurotoxicity has focused on methamphetamine because of its widespread abuse. The research on animals and human methamphetamine abusers is clear—methamphetamine and other amphetamines are toxic to mesencephalic DA neurons. Indeed, methamphetamine-induced neurotoxicity is used to model PD in animals.242 In mice, rats, and monkeys, prolonged exposure to methamphetamine/amphetamine (meth/amph) causes cell loss in the SN,243–245 degeneration of striatal DA axon terminals,243,246–248 decreases in striatal DA and DAT, and decreased DAT function.249–256 The pattern of neurotoxic changes induced by methamphetamine parallels the DA deficits seen in PD. In monkeys, the methamphetamine-induced decrease in DA concentration is greatest in the putamen, followed by the caudate and then the nucleus accumbens, and toxic change in SN DA neurons is greater than in VTA neurons.250 It has been reported that, in monkeys, methamphetamine-induced decreases in striatal DA markers occur without decreases in cell numbers in the ventral midbrain, suggesting that the terminals of DA neurons are more affected than cell bodies.244 In the same study, substantial recovery of striatal DAT occurred after 1.5 years. However, another study, also in monkeys, found that neurotoxic effects of methamphetamine lasted for up to four years after exposure.257

Numerous diverse findings point to pathologic changes in DA systems in human chronic meth/amph abusers. Echogenicity of the substantia nigra is increased in abstinent adult meth/amph abusers,258–260 and the degree of this increase is positively correlated with the duration of meth/amph abuse and the estimated amount of lifetime methamphetamine intake.258 Persons with a history of meth/amph abuse have increased Parkinson motor symptoms.258,260 Postmortem studies of striatal tissue of meth/amph abusers show significant reductions in several indices of DA function, including DA, DAT, VMAT, and tyrosine hydroxylase, in numerous DA terminal regions, including the caudate, putamen, and nucleus accumbens.261–263 PET studies show reduced DAT density in abstinent meth/amph abusers.264–266 DAT levels begin to recover after a year of abstinence267 but remain decreased for up to three years.265 Finally, several epidemiological and case-control studies have shown an association between history of meth/amph abuse and increased risk for subsequent or early development of PD or increased parkinsonism.260,268–273

An important question is whether amphetamines, as they are used clinically to treat ADHD, are toxic to DA neurons. In most of the animal and human studies cited above, stimulant exposure levels are high relative to clinical doses, and dosing regimens (as stimulants) rarely mimic the manner in which these drugs are used clinically. The study by Ricaurte and colleagues248 is an exception. In that study, baboons orally self-administered a racemic (3:1 d/l) amphetamine mixture twice daily in increasing doses ranging from 2.5 to 20 mg/day for four weeks. Plasma amphetamine concentrations, measured at one-week intervals, were comparable to those observed in children taking amphetamine for ADHD. Two to four weeks after cessation of amphetamine treatment, multiple markers of striatal DA function were decreased, including DA and DAT. In another group of animals (squirrel monkeys), d/l amphetamine blood concentration was titrated to clinically comparable levels for four weeks by administering varying doses of amphetamine by orogastric gavage. These animals also had decreased markers of striatal DA function assessed two weeks after cessation of amphetamine.

Methylphenidate (MPH) appears to be substantially less neurotoxic than meth/amph. MPH had no effect on survival of embryonic DA cells in vitro but rather had a protective effect against the DA neurotoxin 1-methyl-4-phenylpyridinium.274 Repeated administration of MPH to adult rats (50 mg/kg for 30 days,254 100 mg/kg for 4 days275) or to adult rhesus monkeys (1–96 mg/kg for 6 months)254 had no effect on striatal DA. By contrast, repeated doses (10–40 mg/kg, every 2 hours × 4) of MPH in adult mice caused a short-term decrease in striatal DA.255 These doses and higher doses (80–100 mg/kg every 2 hours × 4) had no long-term effect on striatal DA.255 Some evidence suggests that MPH may be more toxic during early brain development. Prolonged exposure (once daily for 5 days/week for 12 weeks) of young mice to a relatively low dose (10 mg/kg) of MPH produced gliosis and a ~20% decline in DA neurons in the substantia nigra.276 Similarly, administration of MPH (2 mg/kg/day for 2 weeks) in prepubertal, but not post-pubertal, rats produced a prolonged decrease in striatal DAT.277 By contrast, two studies designed to mimic prolonged developmental exposure in children using dosing regimens that produced MPH blood levels in the clinical therapeutic range (15–25 ng/ml) in rhesus monkeys found no effect of MPH treatment on DAT or DA receptors.278,279

The mechanisms responsible for differential meth/amph and MPH neurotoxicity are unclear. Oxidative stress, excitotoxicity, and mitochondrial dysfunction have all been implicated in the neurotoxic actions of both meth/amph and MPH.280–282 Recent evidence suggests that stimulant neurotoxicity is mediated by effects on protein folding. As noted above, misfolding of α-synuclein is associated with neurodegeneration in PD. Amphetamine binds preferentially to the N-terminus of α-synuclein and enhances misfolding, whereas MPH binds to both the N- and C-termini, resulting in a loop structure that inhibits misfolding.283

The unambiguous neurotoxicity of meth/amph is worrisome. Use of prescription meth/amph formulations in the United States doubled between 2006 and 2016, and exceeded that of MPH in 2016.284,285 By contrast, in other developed regions of the world, MPH is still the most widely used stimulant.286,287 The National Survey on Drug Use and Health 2015–2016 found that 16 million adults in the United States used prescription stimulants.288 The prevalence of 30-day prior use of prescription meth/amph among U.S. children and adolescents was 1.3% between 2011 and 2014. Among children aged 6 to 11, the prevalence of meth/amph use in this period was 2.1%.284 If meth/amph, as it is used clinically, is toxic to DA neurons, the rising clinical use of amphetamines in the United States may portend increases in PD in the coming years.

POSSIBLE LINKAGE MECHANISMS

If PD and ADHD are associated clinical entities, then understanding the mechanisms responsible for this association could provide insights into the etiology and pathogenesis of both disorders. One possible explanation for an association between PD and ADHD is that both are causally related to a common exposure. The study that provides the principle epidemiological evidence for a link between PD and ADHD2 controlled for some potential confounding exposures (e.g., antipsychotic and tobacco use) but not for others. Potentially relevant variables that were not controlled include traumatic brain injury and exposure to environmental toxins. Antecedent traumatic brain injury increases risk for both PD and ADHD,289,290 and both disorders are associated with lead, mercury, and pesticide exposure.291–296 Additional epidemiological studies are needed to assess the contribution of such variables to the association between PD and ADHD.

Genetic factors may also mediate an association between PD and ADHD. ADHD has a strong familial component (h2 = ~0.75).236 As noted above, although environmental factors play a major role in sporadic PD, genetic factors are important.15 A possible genetic linkage between PD and ADHD has been investigated. Analysis of nine ADHD candidate genes, chosen for their involvement in the regulation of monoamine neurotransmitters, showed no association with PD.297 By contrast, ADHD is associated with copy-number variations in PARK2.298 Mutations in PARK2 occur in ~10% to ~20% of cases with early-onset, sporadic PD.12,299 If PD and ADHD are associated by virtue of an association with PARK2, it might be expected that ADHD would be more strongly associated with early- than late-onset PD. The study by Curtin and colleagues2 did not find an association between ADHD and age at onset of BG&C.

There is intriguing evidence that ADHD, like PD, may be associated with Lewy pathology. Golimstok and colleagues169 reported that ten-year antecedent ADHD symptoms are significantly increased in patients with Lewy body dementia compared to both controls and patients with Alzheimer’s disease. Fluegge and Fluegge170 reported that antecedent severe ADHD was associated with an increase in hospitalization for both Lewy body dementia and Alzheimer’s disease. Between ~30% and ~50% of patients with AD also have Lewy pathology.300 Thus, ADHD has been associated with three neurodegenerative disorders, all of which are also associated with Lewy pathology. Another intriguing finding is that α-synuclein expression is increased in experimental models of traumatic brain injury301–303 and by environmental neurotoxins that are associated with both PD and ADHD.291,303 Although, as noted above, the nature of the relationship between Lewy pathology and neurodegeneration is unclear, these findings raise the possibility that α-synuclein may be a biomarker for both ADHD and PD. Clinical-pathological studies necessary to evaluate this hypothesis do not appear to have been undertaken.

Another possible explanation for an association between PD and ADHD is that stimulant medication damages DA neurons and either causes parkinsonism or exacerbates the damage to DA neurons caused by other factors. The study by Curtin and colleagues2 found that medical use of stimulant medication in ADHD is associated with a 6- to 8-fold increase in the risk for BG&C. One possible explanation for this finding—in fact, the one preferred by the authors—is that stimulant treatment is a marker for severe ADHD and that severe ADHD is an independent risk factor for BG&C. In support of this hypothesis, Curtin and colleagues2 reported that the risks for both BG&C and PD are significantly increased 1.8- and 2.3-fold, respectively, in ADHD patients with no known history of prescription stimulant use or stimulant abuse. By contrast, it is possible that ADHD patients in this study had stimulant exposure that was not recorded in the medical records. A particularly puzzling finding by Curtin and colleagues2 is that the risk for BG&C is increased 8-fold among persons with ADHD who had a known history of medical use of MPH alone. This finding is difficult to reconcile with the substantial evidence (discussed above) that MPH is less toxic than meth/amph. Another curiosity in the Curtin and colleagues2 data is that the stimulant effect was significant for the composite outcome BG&C—which included PD, secondary PD, other diseases of the basal ganglia, and essential tremor—but not for PD alone. Although the composite outcome was used to increase diagnostic sensitivity, it may have also decreased specificity.304 Thus, disorders distinct from PD may have contributed to the stimulant effect. The nature of the relationship between stimulant exposure in ADHD and risk for subsequent development of PD obviously needs further investigation.

CONCLUSION

Epidemiological evidence indicates that persons with a diagnosis of ADHD have increased risk for the subsequent development of Parkinson’s disease. The central question raised by this observation is: what is the nature of this relationship? The structural, functional, and molecular neuroimaging studies reviewed here indicate that PD and ADHD share a common neurobiological substrate involving perturbations of mesostriatal DA neurons. Another relevant finding is that adults with ADHD and persons with prodromal PD or PD-ES have similar neuropsychological profiles. The comparative neuropsychology of these conditions reveals common deficits in executive function, memory, attention, and inhibition. Neuroimaging studies reveal complex differences in the brain structures and networks that mediate these deficits in PD-ES and adult ADHD. However, frontostriatal circuits are implicated in both. Collectively, these disparate lines of evidence are consistent with the possibility that ADHD, prodromal PD, PD-ES, and PD are sequential manifestations of a common pathophysiological continuum.

Nevertheless, much additional research is needed to assess this hypothesis. As noted previously, subject heterogeneity and methodological differences make it difficult to compare neuropsychological studies of adults with ADHD and persons who have prodromal features or are in the early stages of PD. Additional neuropsychological studies that employ a uniform set of measures and methodologies in more homogenous subject samples are needed, and future studies of adults with ADHD should be expanded beyond neuropsychological testing to include other markers for prodromal PD (e.g., REM sleep behavior disorder, anosmia, constipation) and also PD biomarkers (e.g., Lewy pathology). A related issue that has not been taken into consideration is whether adult ADHD is a unitary construct or one that subsumes distinct clinical entities. Notwithstanding the widely held view that ADHD is a developmental disorder, current evidence indicates that ADHD can occur in adults de novo.305 It is conceivable that developmental- and adult-onset forms of ADHD may be differentially associated with PD.

The mechanisms responsible for the association between PD and ADHD are not known. The evidence reviewed here does not support a strong genetic linkage. Thus, environmental exposures seem likely to mediate the association. Among the possible environmental exposures, stimulant treatment of ADHD is the most salient. Further research on the possible link between clinical use of stimulants and PD is urgently needed. Avenues for future research are suggested above. If an association between clinical use of stimulants and PD or related disorders is confirmed, it could have serious implications for therapeutics and public health.

Declaration of interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of the article.

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Keywords:

amphetamine; attention-deficit/hyperactivity disorder; methylphenidate; Parkinson’s disease; stimulants

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