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Cognitive decline in Parkinson's disease: A prospective longitudinal study
Abstract and Figures
This controlled prospective study examined the evolution and predictors of cognitive decline in Parkinson's disease (PD). Consecutive patients diagnosed at baseline with PD (n = 89), established PD (EPD) patients (n = 52) with a mean disease duration of 6.5 years, and healthy control subjects (n = 64) underwent extensive neuropsychological assessment twice, approximately 3 years apart. A standardized regression-based method, normative data, and multivariate normative comparisons were used to assess the cognitive course of PD. Cognitive performance of newly diagnosed patients decreased significantly over time, particularly on measures of psychomotor speed and attention and to a lesser extent on tests of memory, visuospatial skills, and executive functions. About 50% of the patients showed cognitive decline and 9% developed dementia. Similar results were observed in EPD patients. None of the baseline features predicted cognitive change in newly diagnosed patients, whereas age at disease onset and axial impairment (postural and gait disorders) contributed to decline in established patients. We conclude that within few years after diagnosis, PD patients show faster rate of cognitive decline than matched healthy subjects, particularly in domains of attention and psychomotor speed. Selection bias probably led to underestimation of the true extent of cognitive decline in established patients.
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... Standardized Z-scores were calculated for those tests without norm scores or in order to compare different test versions with each other (words memory learning test and Digit Span Task). In line with the method of Muslimović et al. (2009), we replaced a missing value by the worst value observed within that specific cohort, when a participant had attempted to perform a test, but was unable to do it (46 values in total over all time points) (Muslimović et al., 2009). ...
... Standardized Z-scores were calculated for those tests without norm scores or in order to compare different test versions with each other (words memory learning test and Digit Span Task). In line with the method of Muslimović et al. (2009), we replaced a missing value by the worst value observed within that specific cohort, when a participant had attempted to perform a test, but was unable to do it (46 values in total over all time points) (Muslimović et al., 2009). ...
... According to each item of UPDRS III, the scores were divided into four sub-scores: tremor sub-score (items 20 and 21), rigidity sub-score (item 22), bradykinesia sub-score (items [23][24][25][26], and axial sub-score (items 18, 19, and 27-31) [12]. The improvement rates at each timepoint were calculated. ...
... The PD group showed a statistically lower performance on both cognitive function scales than that in the HC group. This finding goes in line with previous studies which reported that drug-naïve patients with PD suffered from cognitive impairment [25,26]. However, the cognitive scale score of the participants in this study was lower than that in similar studies. ...
Background:
The symptoms of early Parkinson's disease (PD) are complex and hidden. The aim of this study is to explore and summarize the characteristics of the symptoms of drug naïve patients with PD.
Objectives:
and Methods Drug-naïve patients with PD and age-matched healthy controls were recruited from the outpatient clinic of Wuhan Union Hospital. The motor and non-motor symptoms were evaluated for further analysis using Unified Parkinson's Disease Rating Scale (UPDRS) I, II, and III; Sniffin' Sticks Screening 12 test; Mini-Mental State Exam (MMSE); Montreal Cognitive Assessment (MoCA); Hamilton Anxiety Scale (HAMA); and Hamilton Depression Scale (HAMD) scores. The acute levodopa challenge test (ALCT) was adopted to assess the reaction to dopaminergic treatment.
Results:
We recruited 80 drug-naïve patients with PD and 40 age-matched healthy controls (HCs). Approximately 53.7% of the patients were females. The mean onset age was 59.96 ± 10.40 years. The mean UPDRS I, II, and III were 2.01 ± 1.90, 6.18 ± 3.68, and 26.13 ± 12.09, respectively. Compared with HCs, PD patients had lower scores in MMSE and MoCA; and higher scores in HAMA and HAMD (p < 0.05). In ALCT, 54 patients showed good responses to levodopa while 26 patients did not. The mean improvement rate of UPDRS III was 34.09% at 120 min.
Conclusion:
The motor symptoms of patients with early PD were mild but virous. They also suffered from different non-motor symptoms. In ALCT, about two thirds of patients (54/80) with early PD showed good response to levodopa. Among four aspects of motor symptoms, bradykinesia reacted best to ALCT, while axial symptoms were the worst.
... Other behavioural symptoms can include difficulty initiating voluntary movement (akinesia), involuntary eye movements, and blinking [5][6][7][8]. In some cases, it may take up to 15 years before an accurate and reliable clinical diagnosis can be made [9][10][11], even though as many as 50% of PD patients [12] may have been experiencing other pathological changes associated with PD, such as autonomic nervous system dysfunctions [13], REM sleep behaviour disorder [14,15], Figure 1. Progression of clinical symptoms from early prodromal through to clinical diagnosis of Parkinson's disease. ...
... The loss of dopaminergic neurons in the SNpC has long been associated with impaired motor movement and cognitive impairment and is usually considered the core pathological characteristic of PD [12,[62][63][64]. However, more recent evidence from patients and clinical studies reveals that the pathology of PD follows a caudo-rostral pattern in which the loss of neurons in the locus coeruleus (LC) occurs earlier than the loss of neurons in the SNpC [10,[65][66][67]. ...
Parkinson's disease (PD) is a chronic and progressive age-related neurodegenerative disease affecting up to 3% of the global population over 65 years of age Currently, the underlying physiological aetiology of PD is unknown. However, the diagnosed disorder shares many common non-motor symptoms associated with ageing-related neurodegenerative disease progression, such as neuroinflammation, microglial activation, neuronal mitochondrial impairment, and chronic au-tonomic nervous system dysfunction. Clinical PD has been linked to many interrelated biological and molecular processes, such as escalating proinflammatory immune responses, mitochondrial impairment, lower adenosine triphosphate (ATP) availability, increasing release of neurotoxic reactive oxygen species (ROS), impaired blood brain barrier integrity, chronic activation of microglia, and damage to dopaminergic neurons consistently associated with motor and cognitive decline. Prodromal PD has also been associated with orthostatic hypotension and many other age-related impairments, such as sleep disruption, impaired gut microbiome, and constipation. Thus, this review aimed to present evidence linking mitochondrial dysfunction, including elevated oxidative stress, ROS, and impaired cellular energy production, with the overactivation and escalation of a microglial-mediated proinflammatory immune response as naturally occurring and damaging interlinked bidirectional and self-perpetuating cycles that share common pathological processes in ageing and PD. We propose that both chronic inflammation, microglial activation, and neuronal mitochondrial impairment should be considered as concurrently influencing each other along a continuum rather than as separate and isolated linear metabolic events that affect specific aspects of neural processing and brain function.
... Stroop interference scores have been developed to isolate the specific effect of incongruence of color-words from the Stroop color-word performance score to better account for the cognitive process of conflict monitoring, although this is not without controversy over its accuracy. 33 Classically, interference computed as the "difference" of the color naming score minus the color-word naming score 29,34 is thought to be confounded by slow information processing speed, such as seen in PD. [35][36][37][38] The ratio interference score calculation is thought to avoid some of the effects of slow processing speed and correlate well with executive function measures. 31 ...
Background
PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico‐striato‐pallido‐thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications.
Objective
To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD).
Methods
Participants with idiopathic PD were administered the oral Symbol Digit Modalities Test (SDMT; n = 181) and the Stroop test ( n = 172) in the off‐medication and “best on” medication states. ANCOVA was used to test for differences between off‐medication and on‐medication scores corrected for age and years of education.
Results
After administration of symptomatic medications, scores worsened on the SDMT ( F = 11.70, P < 0.001, d = −0.13), improved on the Stroop color ( F = 26.89, P < 0.001, d = 0.184), word ( F = 6.25, P = 0.013, d = 0.09), and color‐word ( F = 13.22, P < 0.001, d = 0.16) test components, and the Stroop difference and ratio‐based interference scores did not significantly change. Longer disease duration correlated with lower scores on the SDMT, Stroop color, word, and color‐word scores; however, longer disease duration and higher levodopa‐equivalents correlated with higher Stroop difference‐based interference scores.
Conclusions
Symptomatic medication differentially affects performance on two cognitive tests in PD. After acute treatment, core Stroop measures improved, Stroop interference was unchanged, and SDMT performance worsened, likely reflecting complex changes in processing speed and executive function related to acute treatment. When considering motor symptom therapies in PD, an individual's cognitive demands and expectations, especially regarding executive function, should be considered.
... A clinically relevant treatment effect is defined as a difference of ≥ 0.3 points in the mean change from baseline for the composite Z-scores for global cognitive functioning and/or one or more cognitive domains between the treatment and placebo group. As there are no published data on the natural course of neuropsychological functioning of patients with Fahr's disease, the 0.3 points difference of the composites was based on populations with similar neuropsychological profiles as we suspect in Fahr's disease: Parkinson's disease and Chronic Solvent induced Encephalopathy, and using a comparable neuropsychological assessment as this study [41][42][43]. ...
Background
Fahr’s disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr’s disease or syndrome.
Methods
The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr’s disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, the Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life.
Results
Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.
Conclusions
Fahr’s disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr’s disease or syndrome.
Trial registration
ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402 .
... As there are no published data on the natural course of neuropsychological functioning of patients with Fahr's disease, the 0.3 points difference of the composites was based on populations with similar neuropsychological pro les as we suspect in Fahr's disease: Parkinson's disease and Chronic Solvent induced Encephalopathy, and using a comparable neuropsychological assessment as this study. (41)(42)(43) For the secondary endpoints, the same strategy will be used as for the primary endpoint. Missing data will be handled by multiple imputation, where appropriate. ...
Background
Fahr’s disease and syndrome are rare disorders leading to calcification of the small arteries in the basal ganglia of the brain, resulting in a wide range of symptoms comprising cognitive decline, movement disorders and neuropsychiatric symptoms. No disease-modifying therapies are available. Studies have shown the potential of treatment of ectopic vascular calcifications with bisphosphonates. This paper describes the rationale and design of the CALCIFADE trial which evaluates the effects of etidronate in patients with Fahr’s disease or syndrome.
Methods
The CALCIFADE trial is a randomised, placebo-controlled, double-blind trial which evaluates the effects of etidronate 20 mg/kg during 12 months follow-up in patients aged ≥ 18 years with Fahr’s disease or syndrome. Etidronate and placebo will be administered in capsules daily for two weeks on followed by ten weeks off. The study will be conducted at the outpatient clinic of the University Medical Center Utrecht, The Netherlands. The primary endpoint is the change in cognitive functioning after 12 months of treatment. Secondary endpoints are the change in mobility, neuropsychiatric symptoms, volume of brain calcifications, dependence in activities of daily living, and quality of life.
Results
Patient recruitment started in April 2023. Results are expected in 2026 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.
Conclusions
Fahr’s disease and syndrome are slowly progressive disorders with a negative impact on a variety of health outcomes. Etidronate might be a new promising treatment for patients with Fahr’s disease or syndrome.
Trial registration
ClinicalTrials.gov, NCT05662111. Registered 22 December 2022, https://clinicaltrials.gov/ct2/show/NCT01585402.
... Despite the different interpretations of each test in terms of cognitive function, all tests share a strong processing speed or motor speed component, which might suggest a general slowness of iRBD-MCI. Several studies have already reported lower scores in processing/motor speed [7,11], and this also fits well with the observed gradual deterioration in psychomotor speed in PD [31]. Why a predominantly reported executive deficit was not observed may result, among other things, from differences in the constructs measured depending on disease progression. ...
Objective
To date, very few studies have focused on structural changes and their association with cognitive performance in isolated REM sleep behaviour disorder (iRBD). Moreover, the results of these studies are inconclusive. This study aims to evaluate differences in the associations between brain morphology and cognitive tests in iRBD and healthy controls.
Methods
Sixty-three patients with iRBD and thirty-six controls underwent MRI with a 3 T scanner. The cognitive performance was assessed by a comprehensive neuropsychological battery. Based on performance, the iRBD group was divided into two subgroups with (iRBD-MCI) and without mild cognitive impairment (iRBD-NC). The high-resolution T1-weighted images were analysed using an automated atlas segmentation tool, voxel-based (VBM) and deformation-based (DBM) morphometry to identify between-group differences and correlations with cognitive performance.
Results
VBM, DBM and the comparison of ROI volumes yielded no significant differences between iRBD and controls. In the iRBD group, significant correlations in VBM were found between several cortical and subcortical structures primarily located in the temporal, parietal, occipital lobe, cerebellum, and basal ganglia and three cognitive tests assessing psychomotor speed and one memory test. Between-group analysis of cognition revealed a significant difference between iRBD-MCI and iRBD-NC in tests including a processing speed component.
Conclusions
iRBD shows deficits in several cognitive tests that correlate with morphological changes, the most prominent of which is in psychomotor speed and visual attention as measured by the TMT-A and associated with the volume of striatum, insula, cerebellum, temporal lobe, pallidum and amygdala.
... Esto concuerda con las alteraciones cognitivas que se produce en la EP y que provocan un procesamiento más lento de la información y en la respuesta. De este modo, se observa una ralentización en las actividades de la vida diaria que requieren una atención mantenida (Nutt y Wooten, 2005;Micheli, 2006;Tedrus et al., 2009;Muslimović et al., 2009). ...
En este trabajo se exponen los resultados de una investigación realizada con softwares de realidad virtual para rehabilitar motora y verbalmente a enfermos de párkinson en actividades de la vida diaria. Objetivos: analizar la mejora verbal de pacientes de párkinson que se sometieron a un programa de realidad virtual y hacer una comparativa con un grupo de control de enfermos con semejantes características que no lo utilizaron. Metodología: seleccionamos pacientes de párkinson con una escala de motricidad (UPDRS) de bajo índice, es decir, que no fueran dependientes y que pudieran ejecutar los ejercicios propuestos por el software. Se les realizó una evaluación del lenguaje antes de someterse a la realidad virtual y otra después. Resultados y conclusiones: se observa una discreta mejora verbal en los contextos trabajados que se prevé mucho más notable si el uso de los softwares mencionados se alargara en el tiempo y si se amplía la muestra de participantes. Los datos cualitativos ofrecieron mayores conclusiones que los cuantitativos.
... Así y en suma, la literatura sobre la escritura en EP permite evidenciar aspectos de la mecánica visomotora y los procesos periféricos, de ejecución, que se alteran en esta patología, igual que algunos de los mecanismos compensatorios que utilizan los pacientes para reposicionar trazos, figuras, letras y palabras (Letanneux et al., 2014;Oliveira et al., 2020;Teulings et al., 2002). En este sentido, las características del deterioro cognitivo-comunicativo asociadas a EP, entre ellas el enlentecimiento del procesamiento de la información con dificultad para responder efectivamente ante una demanda (Hoogland et al., 2017;Ramani & Sivagami, 2011), la bradipsiquia y dificultades para el acceso a los sistemas semánticos y léxicos y la escasa flexibilidad mental y rigidez cognitiva, la perseveración de ideas y creatividad baja (Kalia & Lang, 2015;Muslimović et al., 2009;Riedel et al., 2010), podrían influir en los procesos motores, visoespaciales y cognitivos para la escritura de palabras. ...
Las personas con enfermedad de Parkinson (EP) muestran dificultades de escritura, que pueden indicar alteraciones en la planificación lingüístico-cognitiva o en la mecánica de la escritura. Este estudio busca establecer si hay alteración del procesamiento fonológico-silábico en la escritura en personas con EP en estadio leve y si la modalidad del input (auditivo o pictórico) influye en el acceso a la unidad silábica. Veinte participantes con EP y 20 controles escribieron palabras en español. Se presentó una palabra auditivamente o un dibujo para indicar la palabra a escribir. Se compararon palabras donde las mismas dos letras pertenecían a diferentes sílabas (a y r en ba.res, intersilábica) o a la misma sílaba (bar.ba, intrasilábico). Se midió la duración de la pausa entre estas dos letras (intervalo 2: I2). Las personas mayores del grupo control evidenciaron un I2 mayor en la condición intersilábica, independientemente de la modalidad del input, lo cual implica un papel funcional de la sílaba en el procesamiento de la escritura, como anteriormente se ha encontrado en adultos jóvenes. Las personas del grupo EP solo mostraron este efecto con input auditivo, no con input pictórico. Parece que la sílaba actúa como unidad fonológica de procesamiento en la escritura con el input auditivo, que también activa procesos fonológicos. Por el contrario, el procesamiento visual de los dibujos parece interferir con el proceso de escritura habitual.
Purpose
The purpose of this study was to determine the effect of a concurrent working memory task on acoustic measures of speech in individuals with Parkinson's disease (PD).
Method
Individuals with PD and age- and sex-matched controls performed a speaking task with and without a Stroop-like concurrent working memory task. Cepstral peak prominence, low-to-high spectral energy ratio, fundamental frequency ( f o ) standard deviation, articulation rate, pause duration, articulatory–acoustic vowel space, relative f o , mean voice onset time (VOT), and VOT variability were calculated for each condition. Mixed-model analyses of variance were performed to determine the effects of group, condition (presence of the concurrent working memory task), and their interaction on the acoustic measures.
Results
All measures except for VOT variability, mean pause duration, and relative f o offset differed between people with and without PD. Cepstral peak prominence, articulation rate, and relative f o offset differed as a function of condition. However, no measures indicated disparate effects of condition as a function of group.
Conclusion
Although differentially impactful on limb motor function in PD, here a concurrent working memory task was not found to be differentially disruptive to speech acoustics in PD.
Supplemental Material
https://doi.org/10.23641/asha.24759648
Test-retest reliabilities and practice effects of a broad range of neuropsychological measures were examined in 384 normal or neurologically stable adults. Median test-retest interval was 11 months (range 3-16 months). The reliability estimates for most of the measures are reasonably good, ranging from .70 to low .90s. en exception is the relatively poor reliabilities of most memory measures. For all test measures, the value on initial testing is a strong determinant of the value on the second examination. Practice effects are seen on most measures. The magnitude of the practice effects, however, varies as a function of type of measure, test-retest interval, age, and overall competency level, of the participant. This study provides several types of retest information that may be useful for future research and clinical work: comparative reliabilities of the various measures, estimate of error variability associated with each administration, standard deviation of the change, and comparative magnitude of practice effects on various tests.
Patients with Huntington's Disease (HD) were tested on 2 tasks, probabilistic classification learning and artificial grammar learning. Both tasks are performed normally by amnesic patients and are considered to be independent of declarative memory. Patients with HD were severely impaired in probabilistic learning but performed normally in artificial grammar learning. The probabilistic classification task may be akin to habit-learning tasks that depend on the neostriatum, whereas artificial grammar learning may depend on changes within the neocortex similar to what is thought to occur in perceptual priming. The deficit in the probabilistic classification task indicates that impaired nondeclarative learning in patients with HD occurs not only in motor tasks but also in nondeclarative learning tasks that have no motor component. (PsycINFO Database Record (c) 2012 APA, all rights reserved)