Effect of disease severity and dopaminergic medication on recollection and familiarity in patients with idiopathic nondementing Parkinson's
Introduction
This study investigated the effect of dopaminergic medication and disease severity on the assessment of familiarity and the recollection of episodic details during recognition in patients with nondementing idiopathic Parkinson's. These processes differ with respect to the type of information that they provide and the level of recognition confidence each typically produces. A widely held view holds that recollection is a high confidence threshold process that involves remembering specific details from episodic memory regarding a past event. By contrast, recognition based on feelings of familiarity varies continuously as a reflection of memory strength in the absence of retrieval of contextual detail (Yonelinas & Jacoby, 1995).
There is conflicting evidence regarding the status of recollection and familiarity at different stages of Parkinson's, with only one study to date examining recollection in patients in mild and moderate stages of disease severity (Hay, Moscovitch, & Levine, 2002). In this study, recollection was normal in the mild Parkinson's group (Hoehn & Yahr, 1967 rating severity ratings in the range of 1–2.5) but significantly declined in the moderate group (Hoehn and Yahr [HY] 3–4). Familiarity was not assessed. Three other studies have investigated the dual process view of recognition memory, sampling patients at a single disease stage. It is important to note that there was consistency between these studies in relation to their use of the remember–know paradigm and adoption of the formulae provided by Yonelinas and Jacoby (1995) to derive estimates of recollection and familiarity. Consistent with Hay et al.’s findings, recollection was spared in mild Parkinson's (mean illness duration = 5.79 years [HY not provided], Davidson, Anaki, Saint-Cyr, Chow, & Moscovitch, 2006) and deficient in moderate Parkinson's (HY 2–3, Edelstyn, Mayes, Condon, Tunnicliffe, & Ellis, 2007), although Barnes, Boubert, Harris, Lee, and David (2003) reported sparing of recollection in moderate Parkinson's (mean HY 2.86) unless the patients had a history of visual hallucinations (mean HY 3.39).
The effect of disease severity on familiarity is also uncertain. In the study by Davidson et al. (2006), familiarity was impaired in mild Parkinson's, whereas both Barnes et al. (2003) and Edelstyn et al. (2007) found it to be preserved in moderate Parkinson's. We have identified four reasons (there may be others) why evidence is not fully concordant. First, although each of these studies assessed medicated patients, not all may have been in an optimally medicated state (e.g., Hay et al., 2002). Second, there is considerable variation between studies in the mode of classifying disease stage. Third, neuropsychological characteristics of patients varied, with executive dysfunction present in some patients (Barnes et al., 2003, Edelstyn et al., 2007, Hay et al., 2002) but not others (Davidson et al., 2006). Fourth, a major problem of studies in this area is the accurate measurement of recollection and familiarity, and particularly of familiarity. This problem applies most strongly to the remember/know procedure where it is well established that procedural differences, inadequate training of participants and inadequate attempts to ensure participants understand the procedure, as may be the case when the remember–know procedure is used in a surprise memory test (e.g., Barnes et al., 2003).
An influential view in Parkinson's research, is that deficits in free recall (Daum et al., 1995, Gabrieli et al., 1996, Ivory et al., 1999, Johnson et al., 2005) and recollection (Hay et al., 2002, Barnes et al., 2003) are contingent on a breakdown in prefrontally mediated memory processes underlying long-term memory encoding and retrieval strategies (such as the use of semantic organisation). Strategic memory processes are likely to depend, at least in part, on executive functions such as planning, decision-making and working memory (Shimamura, Janowsky, & Squire, 1991), which therefore places the origin of the recollection deficits within the mesostriatal-frontal system. However, there is a growing body of evidence suggesting disruption of dopamine modulation of mesolimbic structures, includes the ventral tegmental area and the hippocampus, may also contribute to recall and recollection impairments in Parkinson's. Evidence in support of this proposal is reviewed below.
Firstly, animal studies demonstrate a critical role for dopamine in inducing hippocampal long-term potentiation, a form of synaptic plasticity thought to underlie memory storage (Lemon and Manahan-Vaughan, 2006, Mockett et al., 2004, Otmakhova and Lisman, 1996, Wood et al., 2006), mediated by D1, D3, D4 and D5 dopamine receptors in the CA1–3 fields of the hippocampus (Bentivoglio & Morelli, 2005, chap. 1; Li et al., 2003, Mockett et al., 2007, O’Carroll et al., 2006). Dopamine has also been shown to modulate synaptic plasticity in the perirhinal cortex (Bentivoglio & Morelli, 2005, chap. 1; Cummings et al., 2006, MacDonald et al., 2009), mediated by D2 receptor (Bentivoglio & Morelli, 2005, chap. 1). It should be noted at this point, that involvement of the hippocampus in recollection and the perirhinal cortex in familiarity has already been proposed in Aggleton and Brown, 1999, Aggleton and Brown, 2006 still controversial dual process model of episodic memory.
Secondly, anatomical evidence supporting a role of the mesolimbic circuit in memory comes from a series of functional magnetic imaging studies of healthy older adults. These investigations report a positive correlation between memory formation and integrity/activation of the ventral tegmental area (Bunzeck et al., 2007, Düzel et al., 2008, Kumaran and Düzel, 2008, Wittman et al., 2008). Whilst it appears that reward-related activation of the medial substantia nigra pars compacta is associated with improved hippocampus-dependent memory consolidation (Wittman et al., 2005), encoding-related midbrain activation also occurs independently of reward (Schott et al., 2004). Other evidence that genetic polymorphisms in the dopamine clearance pathways, such as the dopamine transporter (DAT1), affect encoding-related activation patterns in the midbrain and hippocampus (Schott et al., 2006) further supports the case that dopamine plays an important role in memory.
Thirdly, Braak et al. (2003) (see also Braak and Del Tredici, 2008, Braak et al., 2006) examined the brains of 41 patients obtained at autopsy, (clinical severity and cognitive function unknown at time of death). They proposed that α-synuclein pathology, the most abundant protein in Lewy bodies, spreads in a predictable caudo-rostral direction through the brain, beginning in the medulla oblongata and midbrain, before extending to the CA2 fields of the hippocampus and the transentorhinal region (i.e. the medial portion of the perirhinal cortex, BA 35/35a, Garey, 1999, Van Hoesen and Pandya, 1975, Taylor and Probst, 2008) and on to the primary sensory and association areas and prefrontal cortex (see Kalaitzakis, Graeber, Gentleman, & Pearce, 2008 for a critical discussion of this controversial model). Building on Braak et al.’s staging model, memory impairments are predicted based on medial temporal lobe pathology, and furthermore, hippocampal-dependent memory processes will decline prior to perirhinal-dependent processes, due to relative sparing of lateral perirhinal areas. However, the staging of these memory changes in relation to clinical severity is unclear.
Magnetic resonance (MR) imaging studies of Parkinson's patients using manual volumetric and voxel-based morphometry suggests recall impairments emerge, even in the mild–moderate stages (mean HY 2.5, Ibarretxe-Bilbao et al., 2008) once hippocampal pathology has reached a critical level (Brück et al., 2004, Camicoli et al., 2003, Camicioli et al., 1999, Duda et al., 2009, Laakso et al., 1996; but see Burton et al., 2004, Bouchard et al., 2008, Beyer et al., 2009, Dashtipour et al., 2009, Jokinen et al., 2009).
In sum, the findings from animal research and MR studies of healthy volunteers support a role for dopamine modulation of hippocampal and perirhinal memory processes, and furthermore, post-mortem studies of the brains of Parkinson's patients and MR studies of the hippocampus in nondementing Parkinson's patients indicate both structures are subject to the development of staged pathology.
Dopaminergic medication, and here we are primarily considering l-dopa, can also have a significant effect on cognitive function. Evidence indicates that the requisite dopaminergic state necessary to control motor symptoms has the potential to move the same patient away from their optimum for certain cognitive functions (see “l-dopa overdose hypothesis”, described by Gotham et al., 1988, Cools, 2006, Cools et al., 2001, Rowe et al., 2008), and may even lead to a dopamine dysregulation syndrome, marked by an increase in risk-taking behaviour such as pathological gambling and hypersexuality (Driver-Dunckley et al., 2003, Dodd et al., 2005). The relationship between the efficiency of neuronal activity and the state of dopaminergic modulation in the l-dopa overdose hypothesis is represented by a Yerkes-Dodson inverted U-shaped curve with cognitive functions declining with deviation away from optimum dopamine levels, indicated by the centre of the curve. Extrapolating this model to recollection and familiarity, implies that l-dopa has the capacity to both improve and impair these kinds of memory depending on baseline dopamine levels in the underlying neural circuitry.
The aim of our study was to investigate the impact of disease severity and dopaminergic medication on familiarity and recollection in nondementing idiopathic Parkinson's. The predictions for our study have been informed by the application of the l-dopa overdose hypothesis (Cools, 2006) on dopamine-dependent medial temporal lobe memory circuits, the staging model of α-synuclein pathology in Parkinson's (Braak et al., 2003) and the neural correlates of the dual process view of recognition memory (Aggleton and Brown, 1999, Yonelinas et al., 2002). Our central hypothesis was that the neural pathways on which recollection and familiarity separately depend, are differentially affected by disease progression, and consequently, the effects of dopaminergic medication on these memory measures will also differ.
The method used in this study to assess the effects of l-dopa on recognition memory, familiarity and recollection is the controlled l-dopa withdrawal procedure. This requires patients to abstain from their dopaminergic medication for a (“wash out”) period of 12–18 h prior to the memory assessment. Performance in this OFF state is compared with performance on a separate testing session, taking place at the same time of day as the OFF state, during which patients take their routine medication as usual. This procedure minimises, but does not eliminate, any effects that dopaminergic medication may have on recollection and familiarity. It is also less prone to the confounds of differences in disease severity compared to the alternative of comparing de novo, i.e. never medicated, patients with the same individuals at a later stage after l-dopa administration, or a different already-treated group.
Our first set of predictions applied to patients tested in an unmedicated state. In mild Parkinson's, we expected both recollection and familiarity to be preserved, contingent on the relative preservation of both the hippocampus, lateral and medial perirhinal cortical areas. By contrast, in moderate Parkinson's, a significant decline in recollection was predicted, contingent on developing pathology in the hippocampus. By contrast, relative sparing of familiarity performance was expected, due to preservation of lateral (if not medial) areas of the perirhinal cortex.
The second set of predictions pertained to the performance of the same patients assessed in a fully medicated state. We expected a l-dopa induced impairment of both recollection and familiarity in mild Parkinson's, as routine medication overdosed (close to) optimal dopamine levels in the hippocampus and perirhinal cortex. By contrast, in moderate Parkinson's, l-dopa should have a beneficial effect on recollection, as medication remediated depleted dopamine levels in the hippocampus. Familiarity performance was again expected to show relative sparing, as the same l-dopa which ‘overdosed’ optimal dopamine levels in the lateral perirhinal cortex also restored depleted levels in medial perirhinal cortex.
Section snippets
Participants
Twenty-three Parkinson's patients were recruited from the Parkinson's disease outpatient clinic in the Department of Neurology, University Hospital of North Staffordshire. During a clinical interview (SJE), patients were screened for adverse clinical events or issues (e.g., drastic medication changes, fatigue, distress) that might affect performance.
Medicated patients were subdivided into 2 subgroups based on HY score. Twelve patients rated as stage 1, 2 or 2.5 and classified as mild (mean HY =
Procedure
Two versions of a “yes/no” recognition memory test (RMT) were constructed from a pool of 320 4–6 letter words (mean word frequency = 229.2 per million, range 83–1789; mean concreteness = 462.7 and mean imageability = 491.2) using the norms provided by Coltheart (1981) and Baayen, Piepenbrock, and van Rijn (1993). The pool comprised 160 high frequency words (word frequency 229.2 per million, range 83–1789, concreteness = 462.7, imageability = 491.2) and 160 low frequency words (mean word frequency = 1.9 per
Results
Recognition memory, know and remember false alarm and hit rates for the Parkinson's and healthy volunteer groups are presented in Table 2. A trend for higher false alarms by patients in the medicated compared to the unmedicated condition is evident but not significant (t(22) = −0.42, p = 0.68).
A correction has been made to the data to eliminate extreme scores in accordance with Snodgrass and Corwin's (1988) recommendation. It is assumed that recollection and familiarity are stochastically
Discussion
Our study was designed to investigate the impact of disease severity and dopaminergic medication on the assessment of familiarity and the recollection of episodic details during recognition in patients with idiopathic, nondementing Parkinson's. Our predictions were derived from the convergence of three theories: the staging of α-synuclein pathology in Parkinson's (Braak et al., 2003); a dual process view of recognition memory (Aggleton & Brown, 1999, 2006; Yonelinas, 1994; see Yonelinas et al.,
Acknowledgements
This study was supported by an innovations grant from the Parkinson's Disease Society (K-0811). We thank the patients who agreed to delay their medication and their carers who had to support the patients at this time and the healthy volunteers. We also thank our peer-reviewers whose comments have greatly improved our manuscript.
References (82)
- et al.
Interleaving brain systems for episodic and recognition memory
Trends in Cognitive Science
(2006) - et al.
Sparing of the familiarity component of recognition memory in a patient with hippocampal pathology
Neuropsychologia
(2005) - et al.
Reality monitoring and visual hallucinations in Parkinson's disease
Neuropsychologia
(2003) - et al.
Age and dementia-associated atrophy predominates in the hippocampal head and amygdale in Parkinson's disease
Neurobiology of Aging
(2008) - et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiology of Aging
(2003) - et al.
Cognitive decline correlates with neuropathological stage in Parkinson's disease
Journal of Neurological Sciences
(2006) Dopaminergic modulation of cognitive function implications for L-DOPA treatment in Parkinson's disease
Neuroscience and Biobehavioral Reviews
(2006)- et al.
Reversal learning in Parkinson's disease depends on medication status and outcome valence
Neuropsychologia
(2006) - et al.
Dopamine and cognitive functioning in de novo subjects with Parkinson's disease: Effects of pramipexole and pergolide on working memory
Neuropsychologia
(2009) - et al.
Memory and skill acquisition in Parkinson's disease and frontal lobe dysfunction
Cortex
(1995)
A close relationship between verbal memory and SN/VTA integrity in young and older adults
Neuropsychologia
Mini-mental state: A practical method for grading the cognitive state of patients for the clinician
Journal of Psychiatry Research
Dissociating habit and recollection: Evidence from Parkinson's disease, amnesia and focal lesion patients
Neuropsychologia
Verbal memory in nondemented patients with idiopathic Parkinson's disease
Neuropsychologia
Impaired cognitive performance in Parkinson's disease is related to caudate dopaminergic hypofunction and hippocampal atrophy
Parkinsonism Related Disorders
The hippocampus and dopaminergic midbrain: Old couple, new insights
Neuron
Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats
Behavioral Brain Research
Extrastriatal dopamine D2 receptor binding modulates intraindividual variability in episodic recognition and executive functioning
Neuropsychologia
Associative memory and the medial temporal lobes
Trends in Cognitive Sciences
Dopamine D1/D5 receptor activation fails to initiate an activity-independent late-phase LTP in rat hippocampus
Brain Research
Anatomic localization of the transentorhinal region of the perirhinal cortex
Neurobiology of Aging
Some connections of the entorhinal (area 28) and perirhinal (area 35) cortices of the rhesus monkey. III. Efferent connections
Brain Research
The relation between remembering and knowing as bases for recognition: Effects of size congruency
Journal of Memory and Language
Episodic memory, amnesia, and the hippocampal-anterior thalamic axis
Behavioural and Brain Sciences
The CELEX lexical database (CD-ROM)
Dissociation between recall and recognition memory performance in an amnesic patient with hippocampal damage following carbon monoxide poisoning
Neurocase
Dopamine circuits and receptors
Automated 3D mapping of hippocampal and caudate atrophy and ventricular enlargement in Parkinson's disease with and without dementia
Movement Disorders
Impaired familiarity with preserved recollection after anterior temporal-lobe resection that spares the hippocampus
Proceedings of the National Academy of Sciences
Reply to “Controversies over the staging of α-synuclein pathology in Parkinson's disease”
Acta Neuropathology
Hippocampal and prefrontal atrophy in patients with early non-demented Parkinson's disease is related to cognitive impairment
Journal of Neurology, Neurosurgery and Psychiatry
Mesolimbic novelty processing in older adults
Cerebral Cortex
Cerebral atrophy in Parkinson's disease with and without dementia: A comparison with Alzheimer's disease, dementia with Lewy bodies and conreols
Brain
Parkinson's disease is associated with hippocampal atrophy
Movement Disorders
Dementia in Parkinson's disease is associated with hippocampal atrophy
Neurology
The MRC Psycholinguistic Database
Quarterly Journal of Experimental Psychology
Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands
Cerebral Cortex
Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of Huntingdon's disease
Human Molecular Genetics
Hippocampal volumes in patients with Parkinson's disease
Movement Disorders
Exploring the recognition memory deficit in Parkinson's disease: Estimates of recollection versus familiarity
Brain
Pathological gambling caused by drugs used to treat Parkinson's disease
Archives of Neurology
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