Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression

OBJECTIVE: To compare verbal fluency among Alzheimer's disease, Parkinson's disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity. METHODS: Patients from an outpatient university center with a clinical diagnosis of Alzheimer's disease, Parkinson's disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson's disease, major depression, and Alzheimer's disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals). We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model. RESULTS: The mean digit span and verbal fluency scores were lower in patients with Alzheimer's disease (n = 34) than in patients with major depression (n = 52) or Parkinson's disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer's disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson's disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson's disease groups listed 44% (ROM = 1.44) and 48% (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer's disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26% (ROM = 0.74) reduction in the number of words listed when compared to mild cases. CONCLUSIONS: Verbal fluency provides a better characterization of Alzheimer's disease, major depression, and Parkinson's disease, even at later stages

Cognitive and neuroanatomical correlates of neuropsychiatric symptoms in Parkinson's disease: A systematic review

Introduction Neuropsychiatric symptoms are one of the most common non-motor symptoms in Parkinson's disease (PD). These symptoms have a negative impact on daily living activities and cognitive abilities. This review will be centred on published articles which focused on clarifying the cognitive and neuroanatomical features associated with the appearance of specific neuropsychiatric symptoms in this disease. Methods All articles indexed in the Web of Science and PubMed databases were reviewed for potential inclusion in October 2014. In the first stage of the review, we identified 41 articles that investigated neuropsychiatric symptoms and cognitive impairments in PD. In the second stage, there were 26 published articles on the neural bases of neuropsychiatric symptoms in PD. Results The main findings revealed that executive dysfunctions were common in patients with depression, apathy, visual hallucinations (VH), impulse control disorders (ICDs) and anxiety, whereas, memory deficits were associated mainly with depression and VH. Imaging studies have shown that frontal lobe atrophy was frequently observed in patients with depression, apathy, VH and ICDs. Conclusion This review gives a snapshot of those cognitive and neural correlates of neuropsychiatric symptoms in PD. Methodological shortcoming in the available studies were identified, however, of which the most critical appeared neglecting the presence of multiple neuropsychiatric symptoms in some of the patients included in studies of specific individual symptoms. Additionally, in most studies only patients in the moderate to severe stages were included which limits possible inferences to the early stage of the disease

Apathy in Mild Parkinson's Disease: Neuropsychological and Neuroimaging Evidence.

BACKGROUND: Apathy is one of the most common neuropsychiatric symptoms in Parkinson's disease (PD). Few studies have investigated the cognitive and neuroanatomical correlates of apathy in PD, and those which have done so have not controlled for the presence of other neuropsychiatric comorbidities. OBJECTIVE: To explore the cognitive and neuroanatomical correlates of apathy in PD at a mild disease stage. METHODS: Sixty-five PD patients and 24 healthy controls participated in this study. Patients underwent extensive neuropsychological screening, neuropsychiatric assessment using the Neuropsychiatric Inventory, structural MRI scanning, and neurological examination. A voxel-based multiple regression analysis was used to assess the relationship between grey matter volumes and apathy scores. RESULTS: Higher apathy scores correlated with lower grey matter volume in several brain areas including the left insula, left inferior/middle/medial frontal gyrus, right anterior cingulate, and the left superior temporal gyrus. Significant impairments were found in tests assessing executive functions, and a trend-level significant difference was observed in long term memory tests in patients with apathy, when compared with patients without apathy. CONCLUSIONS: Apathy was associated with greater levels of atrophy in the frontal and temporal cortex, and anterior cingulate, as well as overall lower level of cognitive performance, particularly in executive function and memory skills. Apathy appears to be associated with cognitive impairments in PD, therefore, treatment of this symptom might mitigate its effects on cognitive performance in this clinical population

Predicting cognitive impairment in Parkinson's disease using neurophysiology and biochemical parameters as biomarkers

PhD ThesisParkinson’s disease (PD) is a common neurodegenerative condition with multiple associated non-motor symptoms. Of these, dementia is a frequent debilitating complication of the disorder, with significant morbidity and mortality. Some forms of mild cognitive impairment in PD (PD-MCI) may represent a pre-dementia state and certain clinical, laboratory and neurophysiological parameters may increase the accuracy of prediction of cognitive decline. If validated, these markers would offer the opportunity for disease modification and therapeutic intervention at a critical early stage of the illness, when the viable neuronal population is greater. The key aim of this thesis was to characterise cognitive impairment in PD in a cohort of newly diagnosed cases, and evaluate how a panel of biomarkers correlated with cognitive phenotypes to predict risk of future cognitive decline. The main findings were that PD-MCI was common, and was associated with a distinct clinical phenotype. Memory impairment was the most common single domain affected, although the majority of those with PD-MCI were classified as nonamnestic single domain subtype. A significant correlation was found between pattern recognition memory, sensitive to temporal lobe impairments, and cerebrospinal amyloid-β 1-42 levels, thought to represent amyloid-β metabolism and deposition Both amyloid-β 1-42 and 1-40 levels were significantly lower in those with impaired cognition. In addition, short latency afferent inhibition, a neurophysiological in vivo non-invasive measurement of cholinergic function, was also reduced in participants with mild cognitive impairment. These findings suggest that cholinergic dysfunction and amyloid deposition may contribute to the underlying pathophysiology of early PD- MCI. The major conclusion from this thesis is that PD-MCI is heterogeneous and more frequent than previously reported in early disease. This is associated with abnormalities of amyloid processing and cholinergic dysfunction, and may highlight those at risk of developing dementia. Longitudinal assessment of these individuals will enable us to determine and better model those measures predictive of cognitive decline at an early disease stage.Parkinson’s UK, The Michael J Fox Foundation, Newcastle University Lockhart Fun

The comparative neuropsychology of dementia

PhD ThesisOn the basis of neuropathological, neurochemical, genetic, and clinical profile studies on patients, distinct forms of dementia, such as dementia with Lewy bodies (DLB), have been distinguished which were originally thought to be Alzheimer's disease (AD). Dementia with Lewy bodies is probably the second most common form of dementia in the elderly. In this thesis, a well characterised and investigated cohort of DLB and AD patients were compared to non-demented elderly controls in order to establish profiles of cognitive decline in these groups. Initially, comprehensively matched experimental groups were compared using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The DLB group was less impaired than the AD group on a test of visual pattern recognition memory. However, the DLB group performed worse on a number of cognitive tests. Comparison of larger, carefully matched, experimental groups using the Cognitive Drug Research Computerised Assessment Battery (CDR) also revealed differences in the profile of cognitive impairment in DLB and AD. The DLB group showed more marked deficits in attentional abilities than the AD group. In particular, the DLB group were unable to sustain attention. Conversely, the DLB group were less impaired on a test of visual secondary recognition memory than the AD group. Further division of the DLB group into cases with and without persistent visual hallucinations revealed distinct patterns of cognitive impairment in these two groups. Generally, DLB cases with persistent visual hallucinations showed greater attentional and spatial working memory deficits than the DLB cases without persistent visual hallucinations. A final study compared decline in cognitive function over 1 year in DLB, AD and control groups. Similar rates of cognitive decline were identified in a number of cognitive domains in AD and DLB groups. In addition, disproportionate decline in the ability to sustain attention was identified in the DLB group. A comparative model relating known neuropsychological, neurochemical, and neuropathological features of DLB and AD was proposed

Neuropsychiatric and cognitive symptoms in Parkinson’s disease: the contribution to subtype classification, to differential diagnosis, their clinical and instrumental correlations

Il piano di ricerca è volto ad approfondire il contributo dei sintomi neuropsichiatrici e cognitivi nelle diverse fasi della Malattia di Parkinson (MP). In particolare, l’argomento di studio è focalizzato sull’analisi dei sintomi cognitivi e neuropsichiatrici nella MP, affrontando queste tematiche anche mediante l’utilizzo di tecniche di neuroimaging, in pazienti drug-naïve, in fase precoce di malattia ed in fase avanzata. Nei pazienti drug-naïve, la ricerca è stata finalizzata alla caratterizzazione dei sintomi neuropsichiatrici e cognitivi nei sottotipi motori (i.e., tremorigeni vs acinetico-rigidi) e rispetto alla lateralità di esordio degli stessi (i.e., lateralità destra vs lateralità sinistra). Nei pazienti in fase precoce di malattia, è stato indagato il contributo dei sintomi neuropsichiatrici e cognitivi nella diagnosi differenziale tra MP e Paralisi Sopranucleare Progressiva (PSP) in pazienti valutati entro i 24 mesi dall’esordio motorio, finestra temporale in cui spesso si assiste ad un overlapping dei sintomi motori. Nei pazienti in fase avanzata di malattia, la ricerca è stata finalizzata alla caratterizzazione, mediante i sintomi neuropsichiatrici e cognitivi, del Gioco D’Azzardo Patologico (gambling) rispetto agli altri tipi di Disturbi del controllo degli Impulsi (ICDs). Ancora nell’ambito dell’ICDs, è stato sviluppato uno studio di neuroimaging, volto ad identificare i correlati morfostrutturali (spessori corticali e volumi dei nuclei sottocorticali) di tali disturbi. Infine, si sono identificati i sintomi neuropsichiatrici e cognitivi che possono impedire l’esecuzione di un esame di Risonanza Magnetica (RM), al fine, in ambito clinico, di preparare adeguatamente all’esame i pazienti più a rischio di mancato svolgimento e con l’intento di indagare, in ambito di ricerca, la reale rappresentatività campionaria dei pazienti inseriti in studi di RM

Goal-orientated cognitive rehabilitation for dementias associated with Parkinson's disease―A pilot randomised controlled trial

OBJECTIVE: To examine the appropriateness and feasibility of cognitive rehabilitation for people with dementias associated with Parkinson's in a pilot randomised controlled study. METHODS: This was a single-blind pilot randomised controlled trial of goal-oriented cognitive rehabilitation for dementias associated with Parkinson's. After goal setting, participants were randomised to cognitive rehabilitation (n = 10), relaxation therapy (n = 10), or treatment-as-usual (n = 9). Primary outcomes were ratings of goal attainment and satisfaction with goal attainment. Secondary outcomes included quality of life, mood, cognition, health status, everyday functioning, and carers' ratings of goal attainment and their own quality of life and stress levels. Assessments were at 2 and 6 months following randomisation. RESULTS: At 2 months, cognitive rehabilitation was superior to treatment-as-usual and relaxation therapy for the primary outcomes of self-rated goal attainment (d = 1.63 and d = 1.82, respectively) and self-rated satisfaction with goal attainment (d = 2.04 and d = 1.84). At 6 months, cognitive rehabilitation remained superior to treatment-as-usual (d = 1.36) and relaxation therapy (d = 1.77) for self-rated goal attainment. Cognitive rehabilitation was superior to treatment as usual and/or relaxation therapy in a number of secondary outcomes at 2 months (mood, self-efficacy, social domain of quality of life, carers' ratings of participants' goal attainment) and at 6 months (delayed recall, health status, quality of life, carer ratings of participants' goal attainment). Carers receiving cognitive rehabilitation reported better quality of life, health status, and lower stress than those allocated to treatment-as-usual. CONCLUSIONS: Cognitive rehabilitation is feasible and potentially effective for dementias associated with Parkinson's disease

Mild Cognitive Impairment in Presurgical Deep Brain Stimulation for Parkinson\u27s Disease

Although clinically characterized by motor impairments, Parkinson\u27s disease (PD) often affects cognition early in the disease course. Cognitive changes common in PD include visuospatial abnormalities and prominent executive function (EF) deficits, with 30% of individuals eventually developing Parkinson’s disease dementia (PDD). Mild cognitive impairment (MCI) has been identified as a transitional state between normal cognition and PDD. A large cohort of individuals with PD at the Kentucky Neuroscience Institute have undergone pre-surgical evaluations for deep brain stimulation, although cognitive performance in this cohort has never been probed. Baseline cognitive performance of this cohort from 2017-2020 was examined to characterize the pattern of cognitive functioning in these individuals. Data from 136 patients were available for inclusion, and 110 were available for MCI analyses. Prevalence of MCI was approximately 20%, with highest agreement between MCI criteria and clinician diagnostic impressions using a cut point of 1.5 standard deviations (SD) below normative values. The memory domain was most often impaired for those with MCI (65.5%), whereas the language domain was least often impaired (20.9%). Areas under the curve (AUC) were accordingly weaker for language domain measures (e.g., Boston Naming Test, AUC=.695) relative to domains such as visual memory (e.g., BVMT-R Delay, AUC=.883) and EF (e.g., D-KEFS Trails Switching, AUC=.829). Results support the use of 1.5 SD below normative values as a cut point for identifying MCI in PD and highlight the need for visual memory measures in PD cognitive evaluations. Results also align with the extant findings of impairment in key domains such as EF in PD-MCI. Further longitudinal investigation is needed to elucidate the impact of pre-DBS PD-MCI on post-surgical cognitive outcomes

Biomarker and pathology studies in neurodegenerative cognitive impairment

Background: Dementia is a major cause of functional impairment and early death in older age groups. Neurodegenerative disorders are the most common cause of dementia. The most frequent neuropathological lesions include neurofibrillary tangles and senile plaques, hallmark lesions for Alzheimer´s disease (AD), and Lewy body pathology, which characterize Lewy body disease (LBD). Clinically, the neuropathological entity LBD can present as either Parkinson´s disease (PD) or dementia with Lewy bodies (DLB), differentiated on the basis of the presenting symptoms being either motor or cognitive. While the majority of LBD patients develop both motor symptoms and cognitive impairment, some patients with clinical PD will never experience cognitive impairment and likewise some patients with DLB will never develop motor symptoms. Similarly the clinical presentation of AD is also heterogeneous, for instance, the highly variable occurrence of neuropsychiatric symptoms and rate of progression. These differences have a major impact on quality of life for patients and carers, as well as health care costs, but their mechanisms and neuropathological underpinnings are poorly understood. Furthermore the correlation between clinical diagnosis and neuropathological findings is relatively low, and LBD patients presenting with cognitive impairment particularly risk being misclassified as AD. This highlight the need for more precise biomarkers for these clinical syndromes that can be implemented at the start of and during the course of the disease. Biomarkers may inform about disease pathology, thus paving the way for new treatment, they increase diagnostic accuracy and aid in setting a prognosis. Biomarkers are needed in the selection of patients for treatment studies and to identify which patients should benefit from new treatment when available. The cerebrospinal fluid (CSF) biomarkers beta-amyloid 42 (abeta42), total tau (t-tau) and tau protein phosphorylated at amino acid 181 (p-tau181) reflect key AD pathologies. The Lewy bodies found in LBD are composed mainly of the protein !-synuclein. !-synuclein is reduced in CSF in LBD, but with considerable overlap between LBD, controls and other disease groups. Aim: The main aim of this thesis was to increase understanding of pathological mechanisms underlying important clinical features in neurodegenerative cognitive impairment, by exploring the associations between clinical presentation and biomarkers and pathology. The first objective was to explore the association between AD pathology CSF markers and neuropsychiatric symptoms in newly diagnosed AD patients; secondly to assess the association between CSF markers of AD and LBD pathology and early cognitive impairment in PD; thirdly to examine the correlation between clinical diagnosis of DLB and Lewy body pathology at autopsy. Methods: This is a clinical translational neuroscience project based on two clinical cohort studies. The dementia Study of Western Norway (Demvest) included newly diagnosed dementia patients from specialist clinics in geriatric medicine and old age psychiatry in Western Norway. The Parkinson´s Progression Markers Initiative (PPMI) is an international multicentre study, including newly diagnosed PD patients and healthy controls. A comprehensive battery of neuropsychological tests, a structured neuropsychiatric evaluation, clinical examination, and imaging were part of both studies. CSF sampling was done according to standardized protocols and CSF was analysed using commercially available immunoassays. In the Demvest study, participants were recruited for brain donation, and autopsy results were obtained applying commonly used neuropathological protocols and diagnostic criteria. Results: We undertook three specific studies to investigate objective I, II and III. In study I, apathy in patients with early Alzheimer´s disease correlated with t-tau and ptau181 concentrations in CSF, higher values being associated with more severe apathy. There were no associations between depression or psychosis and agitation and CSF markers. In study II, decreased CSF !-synuclein in newly diagnosed PD-patients without dementia correlated with impaired global cognition and impairment of executive functions and attention. CSF abeta42 was decreased in PD with mild cognitive impairment compared with controls after adjusting for covariates. No correlations were found between memory or visuospatial functions and CSF markers. Study III examined autopsy results of 56 patients followed from dementia diagnosis to death. 20 patients received a pathological diagnosis of LBD; the corresponding clinical diagnosis were probable DLB (n=11), Parkinson´s disease with dementia (PDD) (n=5) and probable or possible AD (n=4). Of the 56, 14 patients received a clinical diagnosis of probable DLB, 11 of these had pathological LBD and three AD. Sensitivity, specificity, positive and negative predictive values of a clinical DLB diagnosis were 73%, 93%, 70%, and 90% respectively. Conclusions and implications: We have reported a novel association between neuropsychiatric symptoms and CSF biomarkers reflecting core AD pathology. The relationship between t-tau and p-tau181 and apathy may reflect an association between neurofibrillary tangle pathology and apathy in early AD. Cognitive impairment in early PD was associated with biomarkers of both Lewy body and AD pathology. 18 of 20 LBD patients in the Demvest study had Braak neurofibrillary tangle stage IV or higher, representing severe AD pathology at autopsy. Thus our findings suggest a role for AD pathology in both early and established LBD. Accurate diagnosis is crucial for clinical practice and research. With a sensitivity of 73%, the clinical 2005 DLB criteria are not sensitive enough. More than one in four DLB patients were not identified even when structured rating scales for core DLB symptoms were applied. We regard a specificity of 93% as satisfactory. Our results illustrate that not all DLB patients fulfil the 2005 DLB criteria at disease presentation, highlighting the need for re-evaluation of the diagnosis if new symptoms appear. Studies applying the most recent 2017 DLB criteria will show if this revision has increased sensitivity without decreasing specificity

Cognitive impairment in Parkinson’s disease: Impact and identification of comorbid disease mechanisms

Cognitive impairment is a common and debilitating feature of Parkinson's disease (PD). While it is primarily caused by cerebral propagation of α-synuclein protein, evidence of comorbid diseases is frequently found in autopsy samples. This includes tau and amyloid-β pathologies – the hallmarks of Alzheimer's disease (AD) – and cerebrovascular damage. Comorbid diseases may influence cognition in PD over and above the effects of α-synuclein alone, and this influence may interfere with the results of clinical trials of next-generation medical treatments that target α-synuclein. The primary aims of this thesis were to define the extent and the effects of comorbid disease mechanisms in PD, and to identify viable clinical strategies for detecting coexistent disorders in vivo. Methods included a systematic review of autopsy studies; a factor analysis of the Montreal Cognitive Assessment (MoCA); a regression analysis of two genes; and a cross-sectional neuropsychological study of 45 patients. The systematic review found significant tau pathology in around one-third of PD patients at death. Significant amyloid-β pathology affected over half, and conferred a worse prognosis. Other pathologies (e.g. cerebrovascular disease) were less common, and did not contribute to dementia in PD. The factor analysis showed that the MoCA has limited value for distinguishing cognitive profiles in PD, suggesting that it should be used only for screening. The genetic project found that variation in the APOE gene influenced cognitive decline in early PD; the effect varied between men and women. Variation in MAPT did not affect cognitive decline. Finally, the neuropsychological study found that over half of cognitively impaired PD patients could be clinically diagnosed with a coexistent cognitive disorder, with AD being the most common. Collectively, the results of this thesis show that comorbid diseases, particularly AD, are common in PD, and these contribute to the cognitive phenotype. Consequently, a clinical assessment incorporating selected neuropsychological tests can be used to identify comorbid diseases in PD patients. It is important to consider the potentially confounding impact of multimorbidity in the design and analysis of clinical trials that aim to modulate neurodegeneration in PD by targeting α-synuclein