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Author(s): Weintraub, Daniel; Caspell-Garcia, Chelsea; Simuni, Tanya; Cho, Hyunkeun R; Coffey, Christopher S; Aarsland, Dag; Alcalay, Roy N; Barrett, Matthew J; Chahine, Lana M; Eberling, Jamie; Espay, Alberto J; Hamilton, Jamie; Hawkins, Keith A; Leverenz, James; Litvan, Irene; Richard, Irene; Rosenthal, Liana S; Siderowf, Andrew; York, Michele; Parkinson’s Progression Markers Initiative | Abstract: ObjectiveTo determine the evolution of numerous neuropsychiatric symptoms and cognitive abilities in Parkinson disease from disease onset.MethodsProspectively collected, longitudinal (untreated, disease onset to year 5), observational data from Parkinson's Progression Markers Initiative annual visits was used to evaluate prevalence, correlates, and treatment of 10 neuropsychiatric symptoms and cognitive impairment in Parkinson disease participants and matched healthy controls.ResultsOf 423 Parkinson disease participants evaluated at baseline, 315 (74.5%) were assessed at year 5. Eight neuropsychiatric symptoms studied increased in absolute prevalence by 6.2-20.9% at year 5 relative to baseline, and cognitive impairment increased by 2.7-6.2%. In comparison, the frequency of neuropsychiatric symptoms in healthy controls remained stable or declined over time. Antidepressant and anxiolytic/hypnotic use in Parkinson disease were common at baseline and increased over time (18% to 27% for the former; 13% to 24% for the latter); antipsychotic and cognitive-enhancing medication use was uncommon throughout (2% and 5% of patients at year 5); and potentially harmful anticholinergic medication use was common and increased over time. At year 5 the cross-sectional prevalence for having three or more neuropsychiatric disorders/cognitive impairment was 56% for Parkinson disease participants versus 13% for healthy controls, and by then seven of the examined disorders had either occurred or been treated at some time point in the majority of Parkinson disease patients. Principal component analysis suggested an affective disorder subtype only.InterpretationNeuropsychiatric features in Parkinson disease are common from the onset, increase over time, are frequently comorbid, and fluctuate in severity.

This study was undertaken to determine the prevalence and correlates of cognitive impairment (CI) and neuropsychiatric symptoms (NPS) in early, untreated patients with Parkinson’s disease (PD). Background Both CI and NPS are common in PD and impact disease course and quality of life. However, limited knowledge is available about cognitive abilities and NPS.

It is well recognized that patients with Alzheimer’s disease (AD) suffer from early and profound memory failure and that this is probably related to severe pathological involvement of the medial temporal lobe structures involved in episodic memory function. This mechanism of memory failure is supported in part by data from neuroimaging showing atrophy of medial temporal structures in AD,1,2 which is related to memory function.3-6 In addition to AD, however, patients with memory loss may suffer from cerebrovascular disease. These patients are sometimes diagnosed as having ischemic vascular dementia (IVD). Although the precise nature and frequency of cerebrovascular disease as a cause of dementia are contentious,7-9 there is little doubt that it frequently coexists with AD at the time of postmortem examination10,11 and may occur as the sole cause of dementia.12,13 The contributions of cere-brovascular pathological characteristics to cognitive loss are particularly uncertain when the pathological characteristics are manifested only in subcortical structures. Severe persistent failure of long-term memory, as is common in IVD and AD, is classically related to lim-bic or diencephalic lesions. IVD patients frequently have no apparent strokes in these regions but are nonetheless amnestic.10,14-16 Studies suggest that the application of current diagnostic criteria for IVD17,18 generally excludes patients with AD alone and results in groups of patients with disease consisting of pure IVD and mixed AD/IVD. Thus, AD clearly contributes to the memory loss in many cases but may not be the only cause of memory loss in this population. There are currently several competing models of how subcortical vascular pathological changes might lead to dementia, all of which emphasize diffuse cortical dysfunction as a general basis for cognitive loss.7,19-21 The strategic lesion model proposes that even a single stroke may cause dementia by destroying critical subcortical nuclei, with consequent widespread cortical dysfunction,22 although cumulative effect models propose that an aggregation of strokes may subtract a critical volume of brain parenchyma or may synergistically disrupt functional circuits.23 The exact mechanism of memory loss in subcortical IVD is unclear, however. One explanation for memory loss in IVD patients with primarily subcortical cerebrovascular disease (“subcortical IVD”) invokes impairment of functional systems involving the frontal lobes. Recent studies, especially those that have comprised reasonably homoge-Association neous groups of vascular dementia patients, have generally found a consistent pattern of cognitive impairment in IVD that has been labeled “subcortical-frontal” and differs from the characteristic pattern of cognitive impairments in AD. Several studies have compared clinically diagnosed groups of patients with these two dementias and have found evidence of greater impairment of executive function24 and verbal fluency25,26 in IVD patients. Studies examining memory function in IVD patients have found overall better function than in comparably demented AD patients but have also found that retrieval, an aspect of memory performance with a large executive function component, is more impaired in IVD patients.26 Although the functional imaging literature shows that component processes of the episodic memory system are frequently widely distributed,27,28 it is also clear that lesions of prefrontal cortex and medial temporal structures result in significantly different types of memory deficits. Although the classic amnestic disorder associated with medial temporal lesions is not seen in patients with focal frontal lesions, these patients have impairments in organizing to-be-remembered material, in temporal ordering of memories, and in contextual memory.29-34 Frontal structures play a critical role in the regulation of working memory as well,35 the failure of which can contribute to episodic memory impairment. Because IVD and AD patients differ in the degree of dysfunction in frontal and temporal structures, one might predict that they would also differ in the degree to which memory impairment is related to the functioning of these different structures. If frontal dysfunction predominates in IVD, one might predict that memory failure would primarily correlate with the extent of physiological dysfunction in prefrontal cortex. Conversely, one might predict that in AD patients, in whom temporal lobe dysfunction predominates, memory failure would correlate primarily with temporal lobe dysfunction. A secondary prediction is that the pattern of memory failure would differ between patients in these 2 groups. This hypothesis does not necessitate entirely distinct neuropathological substrates for AD and IVD, because it is clear that AD pathological changes may occur in patients labeled as having “IVD.” Rather, the presence of substantial subcortical cerebrovascular disease may modify the expression of AD pathological changes so that the behavioral features more closely resemble those seen in subcortical frontal syndromes. The purpose of this study was to test this model of memory failure in IVD by attempting to show a specific link between subcortical stroke, cortical glucose metabolism, and memory function. We performed high-resolution [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) studies using a verbal memory task during the period of tracer uptake and then looked for relations between metabolic activity and memory task performance. Our hypothesis was that different brain regions would be related to memory ability in the two conditions—prefrontal cortex in subcortical vascular disease and temporal lobes in AD.

[18F]Fluorodeoxyglucose positron emission tomography (PET) is widely used to measure the cerebral metabolic rate of glucose consumption (CMRglc) in the study of normal and diseased brain (1–3). Because glucose is the sole substrate for normal brain metabolism, values of CM-Rglc likely reflect overall levels of brain metabolic activity. But whether CMRglc directly represents the metabolic activity of neurons, and not of other cells, has yet to be established. It is difficult to address this question, particularly in vivo in humans, with PET alone. PET data are acquired as averages over macroscopic volumes of tissue. Thus, the CMRglc values acquired by PET would be influenced by both neuronal metabolic rate and neuronal density in the tissue volume. Further, realistic tissue volumes contain not only neurons, but also other cells, in particular neuroglia, that consume glucose. There is growing evidence that glia actually consume glucose at a higher rate than neurons do (4). The issue is important because both aging and disease may reduce neuron populations and so affect the measurement of metabolic rates. Atrophy correction is only a partial solution because atrophy correction expresses cellular depletion in terms of gross tissue loss without regard to the type or density of cells present in the lost or in the remaining tissue. A method of indexing neuron density in vivo might permit more accurate assessment of these structural contributions to metabolic measurements, and therefore would improve the calculation of functional effects. The extent to which disease affects true metabolism could then be better understood. Proton magnetic resonance spectroscopic imaging of the brain (1H MRSI) detects the amino acid N-acetyl aspartate (NAA), which is found in high concentrations only in neurons and is virtually undetectable in other cells, including glia (5,6). NAA resonance intensity in the 1H MRSI spectrum is therefore related to neuron density and/or to NAA content per neuron. Thus, how CMRglc varies as a function of NAA concentration ([NAA]) should reflect the way in which brain glucose metabolism is affected by neuron density and/or by NAA content per neuron. The CMRglc-to-[NAA] relationship could be derived for an individual subject by plotting local CMRglc against local [NAA] across that subject’s brain. The CMGglc-to-[NAA] relationship might be expected to vary from subject to subject depending on factors such as subject cognitive status. However, there are limitations to this approach. First, although cortical gray matter is the tissue of primary interest in evaluating brain metabolic activity, PET and 1H MRSI data are often expressed in terms of whole, unsegmented brain tissue, rather than as values for cortical gray matter alone. Second, even if regional data are compared, the spatial resolution of MRSI is lower than that of PET, a source of possible signal infidelity. Therefore, the aims in this study were 1) to establish a method for the assessment of CMRglc and [NAA] in cortical gray matter, accounting for differences between PET and 1H MRSI image resolution; 2) to look for the quantitative relationship between gray matter CMRglc and [NAA] in individual cognitively normal, cognitively impaired, and demented subjects; and 3) to explore whether this CMRglc-to-[NAA] relation varies with cognitive status across subjects.

Studies of Alzheimer's disease using single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have found reductions in blood flow and glucose metabolism in temporal and parietal cortex. In 50 AD patients who underwent neuropsychological testing and SPECT perfusion imaging, we found significant correlations between perfusion and performance on the Mini-Mental Status Examination in the frontal and parietal lobes. In addition. specific correlations between perfusion in the frontal lobes and performance on tests of frontal lobe ability were noted. These findings, while suggesting the importance of perfusion measures in determining clinical features of the disease, do not clearly define perfusion changes as primary, since similar findings have been seen when metabolism is studied. In a separate group of 5 AD patients and 16 controls, we used PET with the perfusion tracer HIPDM and examined cerebrovascular reactivity to carbon dioxide inhalation. We found that in multiple brain regions, including the temporal lobes, AD patients showed robust and significant increases in perfusion in response to carbon dioxide that did not differ from the response seen in the controls. Taken together, these results show that while perfusion changes are important in AD, they are not clearly either primary or limiting.