28 March 2011. Parkinson’s disease not only freezes up movement. Scientists are becoming increasingly aware of what the disorder does to the mind as well. A symposium at the 10th International Conference on Alzheimer’s and Parkinson’s Diseases, held 9-13 March 2011 in Barcelona, Spain, showcased researchers’ efforts to get a handle on cognitive impairment in PD. What are its features, how does it progress, and how does it relate to the development of PD dementia (PDD)?
Data from varied speakers displayed a remarkable level of agreement, painting a picture of early brain and cognitive changes characteristic for Parkinson’s pathology. Scientists distinguished between PDD—which denotes the dementia that develops years after a person has been living with diagnosed PD and pathology has spread to the cortex—and early PD-associated cognitive decline. The latter was their prime focus. They largely agreed it selectively affects certain mental abilities, such as visuospatial skills, fluency, and attention. Unlike the cognitive decline that precedes Alzheimer’s disease, it usually spares memory. Intriguingly, the development of posterior-cortical deficits was shown to predict the conversion of cognitive impairment to dementia, and could be a fruitful focus for further research. Speakers noted that cognitive deficits in PD can precede motor symptoms, suggesting they could have prognostic value. Numerous imaging studies bolster neuropsychological test results and provide clues to the biology. As a group, the speakers called for more longitudinal studies to help characterize the factors that lead to dementia in PD, so they can target pathways for future interventions.
How Parkinson’s Progresses
Motor problems are actually an advanced symptom of Parkinson’s disease, said Yoshikuni Mizuno at Kitasato University, Sagamihara, Japan, in an overview talk. The common late-onset variety of PD attacks lower brain regions first, beginning in the medulla oblongata. As Lewy bodies accumulate in the dorsal motor nucleus, digestion slows down. Constipation is often the first sign of PD, appearing up to 15 years before motor symptoms develop, Mizuno said. Other autonomic nervous systems follow, with the second measurable symptom being the loss of sympathetic nerve fibers to the heart. As Lewy bodies spread into the olfactory bulb, a person’s sense of smell deteriorates, occurring about five years before motor symptoms, Mizuno said. The disorder moves into the pons, begetting sleep disorders and depression, and then into the midbrain, where degeneration of the substantia nigra eventually leads to the characteristic motor problems. Much later in the disease, the cortex succumbs, and hallucinations and dementia may develop. Dementia is seen in only about 25 to 30 percent of PD patients, however, Mizuno said.
Where Does Cognitive Impairment Fit In?
Despite the late onset of dementia, the first cognitive deficits can be detected even before motor symptoms manifest themselves, said Kenneth Marek at Yale University in New Haven, Connecticut. He described recent findings from the Parkinson Associated Risk Syndrome (PARS) longitudinal study, which identifies people at high risk of PD and looks for factors that predict who develops the disorder. The researchers screened around 5,000 healthy people over 50; about half were relatives of PD patients and the other half were randomly chosen. To qualify for the study, volunteers needed to score in the lowest 15 percentile on the University of Pennsylvania Smell Identification Test (UPSIT). In addition to a poor sense of smell, 28 percent of the roughly 300 participants also had diminished dopamine transport in the brain as evident by brain imaging. By contrast, only 8 percent of people whose sense of smell was intact had that second early warning sign of PD. The participants with low dopamine also had statistically significant cognitive deficits in trail-making tests (a visuospatial task), semantic fluency, and processing speed. The degree of impairment correlated with the level of both dopamine transport reduction and loss of olfaction, Marek said. This suggests that cognitive losses are an early feature of PD, he said, and that cognitive testing could be used in conjunction with other screens to help predict PD risk.
Scientists have known for some time that mild cognitive impairment (MCI) can be present in PD, with several studies showing a prevalence of around 25 percent (see, e.g., Aarsland et al., 2010). However, this figure may be an underestimate, suggested Roberto Monastero at the University of Palermo, Italy. In a study of some 500 healthy elderly Italians versus 300 with PD, Monastero’s team found that more than half of those with PD had cognitive decline in at least one area and met Petersen’s criteria for MCI (see Winblad et al., 2004). MCI can be classified as amnestic (involving memory problems) or non-amnestic. The researchers found there was no difference in the prevalence of amnestic MCI between people with and without PD, but Parkinson’s patients were twice as likely to have non-amnestic MCI as were controls.
Does Cognitive Decline in PD Lead to Dementia?
A major unanswered question is whether the cognitive impairment in PD inevitably leads to dementia. Perhaps not, suggested Jaime Kulisevsky at the Autonomous University of Barcelona, Spain, who co-hosted AD/PD 2011. Kulisevsky pointed out that the literature shows that cognitive impairment does not greatly worsen over periods of one to three years, and some patients remain non-demented for decades. This is in contrast to dementia with Lewy bodies (DLB), where patients also have both cognitive and motor symptoms, but deteriorate quickly.
To tease apart the factors that contribute to dementia, Kulisevsky’s team designed an assessment, the Parkinson’s Disease Cognitive Rating Scale, that separately scores frontostriatal and posterior-cortical functions (see Pagonabarraga et al., 2008). This scale has been adopted by The Movement Disorder Society for assessing cognition in PD, Kulisevsky wrote to ARF. Kulisevsky’s group validated the test on a prospective cohort of around 90 PD patients and 60 controls. They found that people with PD showed a gradual, steady decline on executive tasks that rely on the frontal cortex and striatum, such as visuospatial tasks and phonemic fluency (the ability to generate words that begin with particular letters). A very different pattern emerged for skills that require the posterior cortex, however. These include copying images (i.e., drawing a clock) and semantic fluency (the ability to generate words that belong to particular categories). On these tasks, Kulisevsky said, about 20 percent of patients exhibited rapidly plummeting abilities, a phenomenon that began roughly three years after PD diagnosis. Notably, semantic fluency and copying ability were the only two tasks where poor performance predicted progression to dementia. These findings have been replicated in a five-year longitudinal study of more than 120 people (see Williams-Gray et al., 2009).
The data suggest a model where, in some people, posterior cortical dysfunction rapidly develops over a background of progressive frontocortical impairment and leads to dementia, Kulisevsky said. He noted that poor posterior cortical function is the primary feature seen in imaging studies of people with PD-MCI. Other people with PD do not progress in this way, even though they also have a cognitive impairment. “Maybe we should not label all cognitive impairment in PD as ‘PD-MCI,’” Kulisevsky proposed. “MCI may be better defined in terms of the posterior-cortical deficit.” This might help distinguish the non-progressive cognitive impairment in PD from the rapidly progressing condition, Kulisevsky suggested. This parallels a prior shift in AD, where MCI was seen for some years as a precursor to AD, until biomarker and more specific cognitive tests enabled the definition within MCI of people who already had very early AD from other people who did not.
Genetics of PD Dementia
The Barcelona team has also unearthed a genetic contributor to dementia. First author Núria Setó-Salvia and colleagues published in Archives of Neurology this month that the H1 haplotype of the MAPT (tau) gene is overrepresented in PD patients, and particularly in PDD. The authors further refined the genetic association. They found a rare sub-haplotype, H1p, that was 20 times more common in people with PDD than in controls, as well as a protective sub-haplotype, H2a, that was twice as common in controls as in PDD. These data support previous findings that MAPT genotype affects the development of dementia, the authors note, seen, for example, in the study by Williams-Gray et al. The latter authors suggest that the dementing posterior-cortical deficits in PD involve tau, while fronto-executive defects have a more dopaminergic basis and evolve independently.
MAPT haplotype has been linked to other forms of Parkinson’s-associated dementia as well, such as frontotemporal dementia with parkinsonism and the atypical parkinsonian syndromes progressive supranuclear palsy and corticobasal degeneration (see ARF related news story). Significantly, MAPT haplotype showed no connection to AD or dementia with Lewy bodies in this study, perhaps suggesting that PDD and DLB involve distinct genetic factors. The tau haplotype had been identified by John Hardy and colleagues many years ago (see ARF St. Moritz story), but, puzzlingly to some, generated only weak signals in AD studies, where tau tangles are a defining pathology (see ARF related news story and Q&A). The gene for tau, MAPT, is not among the AlzGene Top 42, but ranks second place on PDGene Top Results.
Features of Cognitive Impairment in PD
Keith Wesnes at United BioSource Corporation, Gooring on Thames, U.K., took a different approach to dissecting the specific features of cognitive deficits in PD. His team used a computerized test system to measure several aspects of attention and memory. They found the main losses in people with PD were in powers of attention, in working memory capacity, and in pattern separation, which is the ability to discriminate similar pictures. Wesnes said the last suggests a deficit in the dentate gyrus. The loss in attention is dramatic, he said, about twice as much as that seen in a person who has consumed 0.7 g/kg of alcohol. Importantly, decreased power of attention predicted cognitive decline in this study. Wesnes noted that attention deficits can interfere with activities of daily living and could lower scores on standard cognitive tests such as the Mini-Mental State Exam. Attention deficit is a major component of cognitive impairment in PD, Wesnes concluded.
Imaging results reinforce many of these cognitive test findings. Irena Rektorova at Masaryk University, Brno, Czech Republic, reviewed a number of recent studies, both structural and functional. On the structural side, a small study showed that cognitive impairment in PD comes with a loss of gray matter in the left frontal lobe and both temporal lobes, a pattern midway between that of PDD and unimpaired PD (see Beyer et al., 2007). Another study showed that cognitive decline in PD was associated with anterior caudate atrophy and posterior ventricular enlargement (see Apostolova et al., 2010). In general, however, structural MRI has not been a useful tool for diagnosing cognitive decline in PD.
Poor cognitive performance also seems to correlate with changes seen by functional MRI, Rektorova said. This includes a decreased functional connectivity between the core regions engaged in the default-mode brain network, and cortical areas responsible for multisensory integration and reorienting of attention. This data dovetails with test findings of reduced attentive power and global cognitive performance. Cognitive problems also go along with weakened connections to occipital areas and disturbances in the resting state visual processing network, Rektorova said. This fits with observed visuospatial and posterior deficits, and with positron emission tomography (PET) markers of cholinergic deficits observed in these brain regions (see Hilker et al., 2005).
PD-MCI also involves metabolic changes. Using fluorodeoxyglucose PET (FDG-PET), one study showed higher activity in brainstem and cerebellum and lower activity in prefrontal and parietal regions in PD-MCI compared to PD alone (see Huang et al., 2008). This finding has been replicated (see Lyoo et al., 2010 and Nobili et al., 2009). Subclinical vascular pathology of brain vessels may be a factor in PD-MCI, Rektorova noted, as work from her group showed that ultrasound markers of both large and small vessel impairment correlated with poor cognitive scores (see Rektor et al., 2009). None of these findings have been broadly replicated and garnered robust consensus yet, however.
One point speakers made repeatedly is that MCI in PD looks different from MCI in AD. For example, Rektorova pointed out that the core default-mode network, which reflects resting activity of the brain and becomes dysfunctional in AD (see ARF related news story), appears normal in PDD. Monastero noted that MCI in PD involves a different pattern of brain atrophy than other forms of MCI (see, e.g., Lee et al., 2010). Non-amnestic MCI predominates in Parkinson’s, further distinguishing it from the memory impairments typical of AD.
What Lies Ahead
The speakers touched only briefly on how medication and treatment might affect cognitive deficits. Wesnes said that attention deficits in PD patients were the same whether the patients were on or off L-dopa, but he noted that treatment with rivastigmine, a cholinesterase inhibitor, gradually improved performance in these tests. Rektorova observed that reduced I-FP-CIT uptake in the caudate nucleus correlates with poor performance on the “Tower of London” task in people with PD (see Rektorova et al., 2008), but that PD patients on L-dopa perform this task normally. 123I-FP-CIT is a SPECT imaging tracer of the dopamine transporter, and reduced uptake denotes dopaminergic degeneration. Rektorova’s team has also shown that repetitive transcranial magnetic stimulation of the inferior frontal cortices can increase processing speed in slowed brain networks (see Baláz et al., 2010). In the future, Rektorova said, a better understanding of PD-associated cognitive impairment will help researchers develop more accurate prognoses and improve selection of people for prevention trials and surgical interventions. The latter, called deep-brain stimulation (DBS), tends to most help those patients who have primarily motor, not cognitive, symptoms (see ARF DBS series).—Madolyn Bowman Rogers.
Setó-Salvia N, Clarimón J, Pagonabarraga J, Pascual-Sedano B, Campolongo A, Combarros O, Mateo JI, Regaña D, Martínez-Corral M, Marquié M, Alcolea D, Suárez-Calvet M, Molina-Porcel L, Dols O, Gómez-Isla T, Blesa R, Lleó A, Kulisevsky J. Dementia risk in Parkinson disease: Disentangling the role of MAPT haplotypes. Arch Neurol. 2011 Mar;68(3):359-64. Abstract