Decline In PD Research Articles

Prediction of cognitive decline in PD.

Prediction of cognitive decline in PD.

Initial cognitive changes in Parkinson's disease.

The focus on cognitive impairment in neurodegenerative diseases, including PD, is shifting from the dementia stage to earlier stages of impairment, including mild cognitive impairment. This shift is driven primarily by the desire to improve long-term outcomes by delivering therapeutic interventions earlier in the clinical course, even presymptomatically in those at highest risk, and at the initial stage in the pathophysiological cascade that underpins common dementia syndromes. This article focuses on key findings and challenges in studying earliest stages of cognitive decline in PD, including a detailed examination of neuropsychological testing, cognitive performance in early and prodromal PD, epidemiological research for PD mild cognitive impairment to date, and expert recommendations for assessment. © 2018 International Parkinson and Movement Disorder Society.

Regional volumetric change in Parkinson's disease with cognitive decline

BackgroundParkinson's disease (PD), characterized by motor dysfunction and cognitive decline, may demonstrate specific patterns of brain atrophy. Although cross-sectional magnetic resonance imaging (MRI) studies show correlation between regional brain volume loss and cognitive impairment, there is only scarce evidence from longitudinal studies validating the link between cognition and brain anatomy in PD. ObjectiveTo test the relationship between magnitude and spatial extent of atrophy in PD patients with progressive, significant cognitive decline and dementia (PDD). MethodsWe followed thirty-three initially non-demented patients with prevalent PD for three years while monitoring cognitive function and brain atrophy. Longitudinally acquired T1-weighted magnetic resonance images were analyzed in the voxel-based morphometry framework of SPM. ResultsGroups did not differ significantly with respect to age or gender. More males developed PDD (7 males, 3 females) compared to those remaining intact (12 males, 11 females). Clusters of lower grey matter volume were found in PDD compared to PD in left uncus at baseline and an expanded region that included the left hippocampus and parahippocampal gyrus at 36months. The cognitive status by scan interaction showed differential changes between groups in the right insula. At a more liberal statistical threshold we observed changes in the right insula and bilateral hippocampi as well as the right cuneus additional to the lower brain stem. ConclusionsRegion specific atrophy, consistent with the pattern of cortical Lewy body deposition seen in autopsy studies, can be detected with MRI in PD patients with significant cognitive decline. MRI may be useful for tracking cognitive decline in PD.

Increase of EEG Spectral Theta Power Indicates Higher Risk of the Development of Severe Cognitive Decline in Parkinson's Disease after 3 Years.

Objective: We investigated quantitative electroencephalography (qEEG) and clinical parameters as potential risk factors of severe cognitive decline in Parkinson’s disease.Methods: We prospectively investigated 37 patients with Parkinson’s disease at baseline and follow-up (after 3 years). Patients had no severe cognitive impairment at baseline. We used a summary score of cognitive tests as the outcome at follow-up. At baseline we assessed motor, cognitive, and psychiatric factors; qEEG variables [global relative median power (GRMP) spectra] were obtained by a fully automated processing of high-resolution EEG (256-channels). We used linear regression models with calculation of the explained variance to evaluate the relation of baseline parameters with cognitive deterioration.Results: The following baseline parameters significantly predicted severe cognitive decline: GRMP theta (4–8 Hz), cognitive task performance in executive functions and working memory.Conclusions: Combination of neurocognitive tests and qEEG improves identification of patients with higher risk of cognitive decline in PD.

Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer's Pathology in Parkinson's Disease Dementia.

Neuronal loss and α-synuclein (α-syn) pathology are diagnostic of PD in the appropriate clinical context. However, some PD patients have co-morbid Alzheimer's disease (AD) pathology on autopsy, including amyloid-β (Aβ) plaques and neurofibrillary tangles. Florbetapir(18F) is a PET ligand that detects Aβ pathology. We hypothesized that florbetapir(18F) imaging could detect Aβ pathology in Parkinson disease dementia (PDD) patients prior to death. To determine the utility of florbetapir(18F) PET imaging in detecting Aβ pathology in patients with autopsy-confirmed PDD. Five participants with PDD had florbetapir(18F) PET imaging prior to death as a part of a longitudinal research study of cognitive decline in PD. PET scans were evaluated by expert raters blinded to clinical and neuropathological information. At autopsy, all five participants underwent semi-quantitative assessments of regional Aβ and tau immunohistochemistry. All participants met neuropathological criteria for PD. Two had both positive florbetapir(18F) scans and Aβ-positive plaques in multiple brain regions. Regional florbetapir(18F) binding correlated with regional semi-quantitative Aβ pathology in these cases. Three cases had negative florbetapir(18F) scans. Two of these had significant tau pathology without Aβ pathology, consistent with progressive supranuclear palsy (PSP) in one case and argyrophilic grain disease (AGD) in the other. The last case had a low level of AD neuropathological change. Florbetapir(18F) Aβ imaging can detect the presence of Aβ neuropathology in patients with PDD. This imaging technique may aid the clinical evaluation of PDD patients to determine if cognitive decline is occurring in the setting of Aβ accumulation.

Changes in anatomical and functional connectivity of Parkinson's disease patients according to cognitive status

PurposeThis study assesses the patterns of structural and functional connectivity damage in patients with Parkinson's disease dementia (PDD) compared with cognitively unimpaired Parkinson's disease patients (PD-Cu) and healthy controls (HC). Materials and methodsResting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor magnetic resonance imaging (DTI) scans were obtained from 30 PD and 21 sex- and age-matched HC. The between-group difference in posterior cingulate (PCC) functional connectivity (FC) was performed to assess FC dysfunction. Atlas-based spatial statistics of DTI was applied to compare White matter (WM) fibers impairment between groups. Results(1) Functional connectivity: (1) PD-Cu compared with HC showed a decreased PCC functional connectivity of the right medial temporal lobe (MTL). In addition, PCC-right MTL connectivity strength of PD was significantly correlated with Montreal Cognitive Assessment (MoCA) score. (2) PDD group shows a decreased FC of PCC-right parahippocampa compared with PD-Cu group; while show a widespread decreased PCC FC compared with HC group. (2) Anatomical connectivity: (1) Relative to PD-Cu, significant lower FA values were found in the left hippocampus in PDD. (2) PDD showed higher MD values in a widespread WM regions compared with PD-Cu and HC. (3) Positive correlation was observed between MoCA score and FA value of left inferior longitudinal and hippocampus, and bilateral superior longitudinal fasciculus in PD. ConclusionsCognitive decline in PD is associated with FC damage of PCC-right MTL and microstructural damage of left hippocampus. Nevertheless, combining fMRI and DTI method may provide markers able to contribute to the prediction of PDD.

Predicting cognitive decline in Parkinson's disease: can we ask the genes?

Parkinson’s disease dementia (PDD) is characterized by progressive cognitive decline, mainly affecting executive functions, which occurs in PD patients at least 1 year after the onset of motor symptoms, when no other causes of dementia can be detected. Such temporal cut-off allows to discriminate between PDD and Lewy body disease (LBD) in which dementia is present since the disease onset, along with parkinsonism, visual hallucinations, and fluctuations in the level of consciousness. The prevalence of dementia in patients with PD is 25%, increasing up to 80% in patients with late onset after 20 years of follow-up. In contrast, PDD has been detected in only 20% of young onset PD patients after a follow-up of more than 18 years (1). Clinical criteria for probable PDD require a diagnosis of PD (2) and a slowly progressive dementia syndrome. Typical cognitive deficits in two of four domains (attention, executive function, visuospatial function, and free recall) and at least one behavioral symptom (apathy, depression/anxious mood, hallucinations, delusions, or excessive daytime sleepiness) must be present. Exclusion criteria include unknown time interval between motor and cognitive symptoms, acute confusion, resulting from systemic diseases or drug intoxication and features compatible with vascular dementia (3). In recent years, several studies have focused on predictive markers of cognitive decline in PD. Clinical, neuroimaging, and molecular markers have been identified. Nonetheless, which markers are most reliable and applicable to clinical practice to predict the long-term prognosis of these patients still needs to be clarified.

Montreal Cognitive Assessment for the screening and prediction of cognitive decline in early Parkinson's disease.

Early diagnosis of cognitive impairment in PD would allow appropriate monitoring and timely intervention to reduce the progression to dementia (PDD). To study the usefulness of the Montreal Cognitive Assessment (MoCA) in the screening for mild cognitive impairment (PD-MCI) and its predictive utility in determining longitudinal cognitive decline in PD. Prospective longitudinal study of patients with mild PD. PD-MCI and PDD was diagnosed based on the Movement Disorder taskforce (MDS) criteria. Receiver Operating Characteristic analyses and Cox regression analyses were performed. 95 patients; mean age 66.37 (SD 7.86); mean H&Y score of 1.99 (SD 0.45) were studied. At baseline, 34 patients fulfilled the MDS criteria for PD-MCI. MoCA, compared to the MMSE had a high discriminatory power in detecting PD-MCI [Area Under Curve (AUC) of 0.912, p<0.001]. A MoCA score of ≤26 provided a sensitivity of 93.1% for the diagnosis of PD-MCI. In the longitudinal cohort over 2 years, baseline MOCA was useful in predicting cognitive decline (AUC of 0.707, p=0.05). With Cox regression analyses, a 1-point lower score on baseline MoCA was associated with a 34% increased risk of cognitive decline [Hazard ratio (HR) 1.34; 95% CI: 1.03-1.74: p=0.029]. A baseline MoCA ≤26 was highly predictive of progressive cognitive decline (HR 3.47, 95% CI: 2.38-5.07; p<0.01). MoCA is a reliable tool in predicting cognitive decline in early PD. A MoCA score of ≤26 significantly increases the risk for progressive cognitive decline.

Should post-mortem brain dissection be performed in Parkinson's disease with atypical dementia?

We describe a patient affected by PD with a rapid progression of cognitive decline. This case could suggest the coexistence of many neurodegenerative diseases, which is a common condition in older patients. We propose an hypothetical trajectory of the cognitive impairment usually associated with motor symptoms in the later phase of Parkinsonian patients. The trajectory is almost linear in classical Parkinson's disease dementia (PDD), while a constant acceleration of the cognitive decline with a subsequent change of the slope of the direction could suggest the coexistence of PD with other neurodegenerative disease. Finally, if the cognitive decline in PD is comparable to a "stepped" decline, vascular lesions could be the cause of the change of the slope. This case could suggest to request an autopsy in all cases of unexplained PDD, for better understanding the mixture of non-motor symptoms in PD.

Mild cognitive impairment in Parkinson's disease is associated with a distributed pattern of brain white matter damage

This study assesses the patterns of gray matter (GM) and white matter (WM) damage in patients with Parkinson's disease and mild cognitive impairment (PD-MCI) compared with healthy controls and cognitively unimpaired PD patients (PD-Cu). Three-dimensional T1-weighted and diffusion tensor (DT) magnetic resonance imaging (MRI) scans were obtained from 43 PD patients and 33 healthy controls. Cognition was assessed using a neuropsychological battery. Tract-based spatial statistics was applied to compare DT MRI indices between groups on a voxel-by-voxel basis. Voxel-based morphometry was performed to assess GM atrophy. Thirty PD patients were classified as MCI. Compared with healthy controls, PD-Cu and PD-MCI patients did not have GM atrophy. No region of WM damage was found in PD-Cu patients when compared with healthy controls. Relative to healthy controls and PD-Cu patients, PD-MCI patients showed a distributed pattern of WM abnormalities in the anterior and superior corona radiata, genu, and body of the corpus callosum, and anterior inferior fronto-occipital, uncinate, and superior longitudinal fasciculi, bilaterally. Subtle cognitive decline in PD is associated with abnormalities of frontal and interhemispheric WM connections, and not with GM atrophy. DT MRI might contribute to the identification of structural changes in PD-MCI patients prior to the development of dementia.

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.

Higher urate means less clinical decline in PD

Higher urate means less clinical decline in PD

Mild cognitive impairment in Parkinson's disease

Cognitive decline in PD results in significant impairment and the development of dementia is a major predictor of nursing home placement and death. The estimates of dementia in PD range from 31% to 84% [1–3]. There has been widespread use of the term mild cognitive impairment (MCI) to describe an intermediate stage between normal cognitive function and dementia [4,5]. While the majority of research published on MCI has been in the field of Alzheimer's disease, our group and others have reported patients with PD and MCI who have cognitive dysfunction but do not yet meet criteria for dementia [6–10].

Cerebral amyloid angiopathy in Lewy body disease

While Alzheimer and Lewy body pathologies are discussed as major substrates of dementia in Parkinson's disease (PD/Lewy body disease of brainstem type), the incidence and impact of cerebral amyloid angiopathy (CAA) and its association with cognitive decline in PD and dementia with Lewy bodies (DLB) are unknown. The severity of CAA and other Alzheimer lesions were assessed in 68 cases of autopsy-confirmed PD, 32 of them with dementia (PDD), and in 20 cases of DLB. PDD patients were significantly older than those without dementia (mean age 84.5 vs 77.6 years; p < 0.01), the age of DLB patients was in between both groups (mean 80.0 years), while duration of disease was DLB < PDD < PD (mean 6.5 vs 8.5 and 14.3 years). PDD patients had a significantly higher neuritic Braak stage (mean 4.2 vs 2.4, p < 0.01), significantly higher cortical amyloid beta (Abeta) load, capillary cerebral amyloid angiopathy (CapCAA) and generalized CAA than those without dementia (mild CapCAA in 22% vs moderate to severe CapCAA in 87%; mild generalized CAA in 5.5% vs moderate to severe generalized CAA in 82%). Mean PD stage was higher in both DLB and PDD than in PD (mean 5.2 vs 4.5 and 4.0, respectively): Mean neuritic Braak stage in DLB was 3.4, severe Abeta plaque load was seen in 95%, moderate to severe CapCAA in 90% and mild to severe generalized CAA in 70%. This and other recent studies imply an association of CAA with cognitive decline in both PD/PDD and DLB, particularly in cases with concomitant AD-type pathology.

Beta-Amlyoid 1–42 and Tau-Protein in Cerebrospinal Fluid of Patients with Parkinson’s Disease Dementia

Measurement of τ-protein and β-amyloid_1–42(Aβ42) in cerebrospinal fluid (CSF) has gained increasing acceptance in the differential diagnosis of Alzheimer’s disease. We investigated CSF τ-protein and Aβ42 concentrations in 73 patients with advanced idiopathic Parkinson’s disease with dementia (PDD) and 23 patients with idiopathic Parkinson’s disease without dementia (PD) and in a comparison group of 41 non-demented neurological patients (CG) using commercially available enzyme-linked-immunoabsorbant-assay (ELISA). τ-Protein levels were statistically significantly higher and Aβ42 lower in the PDD patients compared to PD patients and the CG. This observation was most marked (p < 0.05) in a subgroup of patients with PDD carrying the apolipoprotein genotype Ε3/Ε3. The distribution of the apolipoprotein genotypes in PDD and PD patients was similar to that of the CG. Although a significant difference in τ-protein values was observed between PDD and CG, no diagnostic cut-off value was established. These findings suggest that such protein CSF changes may help to support the clinical diagnosis of cognitive decline in PD and that there may be apolipoprotein-E-isoform-specific differences in CSF protein regulation in advanced PDD.

Orthostatic hypotension in Parkinson's disease: association with cognitive decline?

Orthostatic hypotension is common in Lewy body disorders and may be related to disease progression and the spread of Lewy body pathology. We therefore hypothesize that PD patients with orthostatic hypotension (OH) have a different cognitive profile compared to PD patients without OH. This cross-sectional study included 175 PD patients. Blood pressure (BP) was measured with a validated digital blood pressure monitor and patients with a systolic BP drop of > or =20 mmHg or a systolic pressure of <90 mm Hg after standing were considered to have OH. Cognition was assessed using MMSE extended by a selection of computerized cognitive tests focusing on reaction time, sustained attention, working memory and episodic verbal and visual memory. Eighty-seven (49.7%) of the PD patients had OH. These patients were significantly more impaired in sustained attention and visual episodic memory compared to PD patients without OH. We conclude that there are differences in the neuropsychological performance of patients with PD and OH, supporting the hypothesis that OH might be a marker for disease progression and cognitive decline in PD.

The 24-h whole body leucine and urea kinetics at normal and high protein intakes with exercise in healthy adults.

In healthy adult men adapted to a diet/exercise regimen for 6 days, the effects of small, frequent meals supplying daily protein intakes of 1 (n = 8) or 2.5 g . kg-1 . day-1 (n = 6) on leucine oxidation, urea production, and whole body protein synthesis (PS) and degradation (PD) have been compared with the use of a 24-h continuous intravenous [13C]leucine and [15N,15N]urea infusion protocol. Two 90-min periods of exercise (approximately 50% maximal O2 consumption) were included during the fasting and the fed periods of the 24-h day. Subjects were determined to be at approximate energy, nitrogen, and leucine balances on both diets. Increased protein intake raised the urea production rate; the absolute rate of urea hydrolysis was the same on both diets. When the first-pass splanchnic uptake of leucine was taken to be 25% of intake, PS was stimulated by feeding (after an overnight fast) at both protein intake levels (P < 0.05 and P < 0.01), whereas PD declined significantly (P < 0.01) at both protein levels. Protein gain at a high protein intake appears to be the result of both a stimulation of PS and a marked decline in PD, whereas at a less generous intake, the gain appears to be a result of a fall in PD with a less evident change in PS. Exercise moderately decreased PS during and/or immediately after exercise at each protein level, and there was a postexercise-induced increase (P < 0.01) in PD, which was more dramatic when feeding was at the higher protein intake level.

Electrical activity and sodium transfer across in vitro pig placenta.

Electrical activity generated by pieces of pig placenta, taken from anesthetized animals and mounted in Ussing chambers, has been investigated. Ten minutes after the start of voltage clamping, potential difference (PD; fetal side positive, open circuit), short circuit current (SCC), and resistance were 5.9 +/- 0.4 (SE) mV, 8.6 +/- 0.5 microA X cm-2, and 720 +/- 45 omega X cm2, respectively (n = 50). Ouabain (10(-4) M) added to the fetal side caused a maximum decline in PD and SCC from the time of addition of -3.7 +/- 0.98 mV and -3.9 +/- 1.4 microA X cm-2 (n = 6); epinephrine (10(-5) M) added to the fetal side caused increases of +1.0 +/- 0.2 mV and +4.0 +/- 1.4 microA X cm-2, respectively (n = 14). Drug concentrations for 50% maximum response for the effect of a series of adrenergic agonists on SCC were (in M) isoproterenol 1.2 +/- 0.05 X 10(-8), norepinephrine 6.1 +/- 0.3 X 10(-8), epinephrine 2.4 +/- 0.1 X 10(-7), and phenylephrine 4.7 +/- 0.2 X 10(-5), suggesting the involvement of fetally oriented beta-adrenergic receptors. Fetal epinephrine (10(-5) M) also stimulated net Na+ flux (Jnet) toward the fetal side to an extent equal to its effect on SCC. In control experiments Jnet was small but was inhibited by fetal side ouabain (10(-4) M) to produce a maternally directed Jnet, significantly different to the SCC. Replacement of Na+ by choline reduced SCC markedly but did not abolish it. In the absence of Na+, epinephrine had no effect on SCC. These results suggest that active Na+ transfer is not completely responsible for the control electrical activity of pig placenta. Epinephrine, however, modulates SCC entirely by stimulating net Na+ transfer toward the fetal side.