The Psychological Factors and Neural Substrates Associated with Metacognition among Community-Dwelling and Neurologic Cohorts of Older Adults

This project consists of three distinct, but sequential studies that explore the psychological factors and neuropathological substrates of metacognition or self-awareness among older adults. Study 1 examines the premorbid, psychological characteristics associated with metamemory—the mainstay of metacognitive research—in a healthy, community-dwelling cohort of older adults. Study 2 builds on these analyses, and examines the psychological characteristics associated with metacognition, more broadly, in a neurologic cohort of older adults with Essential Tremor (ET). Study 3, which utilizes post-mortem evaluations of participants from Study 2, goes beyond premorbid characteristics and examines whether distortions in metacognition are in part attributable to an underlying disease process. Findings demonstrated that psychological characteristics were associated with metacognitive accuracy in a healthy, community-dwelling cohort of older adults, but not among individuals with ET; further, distortions in metacognition among individuals with ET were better attributable to non-ET specific pathologies, such as amyloid β, neurofibrillary tangles, and regional-specific atrophy. This project underscores the importance of employing a biopsychosocial approach to understanding the factors that influence metacognition. Ultimately, by understanding and working effectively with awareness phenomena, there is a strong potential to reduce disability and enhance well-being

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

The Characterization of Alzheimer’s Disease and the Development of Early Detection Paradigms: Insights from Nosology, Biomarkers and Machine Learning

Alzheimer’s Disease (AD) is the only condition in the top ten leading causes of death for which we do not have an effective treatment that prevents, slows, or stops its progression. Our ability to design useful interventions relies on (a) increasing our understanding of the pathological process of AD and (b) improving our ability for its early detection. These goals are impeded by our current reliance on the clinical symptoms of AD for its diagnosis. This characterizations of AD often falsely assumes a unified, underlying AD-specific pathology for similar presentations of dementia that leads to inconsistent diagnoses. It also hinges on postmortem verification, and so is not a helpful method for identifying patients and research subjects in the beginning phases of the pathophysiological process. Instead, a new biomarker-based approach provides a more biological understanding of the disease and can detect pathological changes up to 20 years before the clinical symptoms emerge. Subjects are assigned a profile according to their biomarker measures of amyloidosis (A), tauopathy (T) and neurodegeneration (N) that reflects their underlying pathology in vivo. AD is confirmed as the underlying pathology when subjects have abnormal values of both amyloid and tauopathy biomarkers, and so have a biomarker profile of A+T+(N)- or A+T+(N)+. This new biomarker based characterization of AD can be combined with machine learning techniques in multimodal classification studies to shed light on the elements of the AD pathological process and develop early detection paradigms. A guiding research framework is proposed for the development of reliable, biologically-valid and interpretable multimodal classification models

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease

BACKGROUND Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI). METHODS Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD. RESULTS Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD. CONCLUSIONS This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia

Clinical diagnosis and risk factors for chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a pathognomonic distribution of hyperphosphorylated tau accumulations in neurons, astrocytes, and cell processes, situated around vessels at the depths of cortical sulci. Case reports of CTE pathology exhibit a common exposure to repetitive head impacts (RHI), suggesting that RHI are a necessary factor in the disease’s etiology. Currently, it is only possible to definitively diagnose CTE after death using histopathological techniques and consensus-based neuropathological diagnostic criteria recently established by the National Institute of Health and National Institute of Neurological Disorders and Stroke. Though considerable progress has been made in characterizing the neuropathology of CTE, less is known about the clinical aspects of the disease. Specifically, additional research is needed to identify disease-specific clinical manifestations, clinicopathological correlations, and a means of diagnosis during life, all of which are critical to developing future epidemiological studies, preventative measures, and treatment trials. Moreover, it is not yet known which specific aspects of RHI exposure (type, frequency, duration) are causally linked to developing clinically meaningful neurological impairments or CTE neuropathology, nor have studies identified risk-modifying factors, such as genotype (e.g. APOE). The objective of this dissertation’s published works was to systematically address these gaps in knowledge. First, to define a common clinical presentation of CTE, we conducted a retrospective analysis of medical records and semi-structured next-of-kin reports of 36 former athletes with autopsy-confirmed CTE without comorbid neurodegenerative disease. We then published clinical diagnostic criteria for CTE based on a systematic review of clinical features exhibited in 202 former athlete cases and a pooled analysis of 83 neuropathologically confirmed CTE cases. In subsequent analyses, we operationalized clinical criteria to investigate specific clinicopathological associations between tau, amyloid beta, age, APOE genotype, and clinical outcomes and utilized the clinical criteria to explore potential risk-factors related to RHI from boxing and football. Lastly, we developed a metric to quantify cumulative RHI exposure in retired, living, football players. Using this metric, our study was the first to indicate a causal relationship between cumulative RHI exposure and risk of later life cognitive, mood, and behavioral impairment. These studies are preliminary, and our results require replication and validation in larger, longitudinal prospective studies

Frontotemporal Dementia: A Clinical Review.

Frontotemporal dementias are a clinically, neuroanatomically, and pathologically diverse group of diseases that collectively constitute an important cause of young-onset dementia. Clinically, frontotemporal dementias characteristically strike capacities that define us as individuals, presenting broadly as disorders of social behavior or language. Neurobiologically, these diseases can be regarded as "molecular nexopathies," a paradigm for selective targeting and destruction of brain networks by pathogenic proteins. Mutations in three major genes collectively account for a substantial proportion of behavioral presentations, with far-reaching implications for the lives of families but also potential opportunities for presymptomatic diagnosis and intervention. Predicting molecular pathology from clinical and radiological phenotypes remains challenging; however, certain patterns have been identified, and genetically mediated forms of frontotemporal dementia have spearheaded this enterprise. Here we present a clinical roadmap for diagnosis and assessment of the frontotemporal dementias, motivated by our emerging understanding of the mechanisms by which pathogenic protein effects at the cellular level translate to abnormal neural network physiology and ultimately, complex clinical symptoms. We conclude by outlining principles of management and prospects for disease modification

Additive effect of cerebral atrophy on cognition in dementia-free elderly with cerebrovascular disease

Objective: To explore the additive effect of neurodegenerative diseases, measured by atrophy, on neurocognitive function in Asian dementia-free elderly with cerebrovascular disease (CeVD). Methods: The present study employed a cross-sectional design and was conducted between 2010 and 2015 among community-dwelling elderly participants recruited into the study. Eligible participants were evaluated with an extensive neuropsychological battery and neuroimaging. The weighted CeVD burden scale comprising markers of both small- and large-vessel diseases was applied, with a score of ≥2, indicating significant CeVD burden. Cortical atrophy (CA) and medial temporal atrophy (MTA) were graded using the global cortical atrophy scale and Schelten's scale, respectively. Global and domain-specific (attention, executive function, language, visuomotor speed, visuoconstruction, visual memory, and verbal memory) neurocognitive performance was measured using a locally validated neuropsychological battery (Vascular Dementia Battery, VDB). Results: A total of 819 dementia-free participants were included in the analysis. Among none-mild CeVD subjects, there was no significant difference in the global cognitive performance across atrophy groups (no atrophy, CA, and CA+MTA). However, in moderate-severe CeVD subjects, CA+MTA showed significantly worse global cognitive performance compared with those with CA alone (mean difference=-0.35, 95% CI -0.60 to -0.11, p=0.002) and those without atrophy (mean difference=-0.46, 95% CI -0.74 to -0.19, p<0.001, p<0.001). In domain-specific cognitive performance, subjects with CA+MTA performed worse than other groups in visual memory (p=0.005), executive function (p=0.001) and visuomotor speed (p<0.001) in moderate-severe CeVD but not in none-mild CeVD. Conclusions and relevance: Atrophy and moderate-severe CeVD burden showed an additive effect on global and domain-specific cognitive performance. This study highlights the importance of investigating the mechanisms of clinico-pathological interactions between neurodegenerative processes and vascular damage, particularly in the pre-dementia stage

The Genetic Analysis and Clinical Features of Early Onset Familial Alzheimer's Disease

Imperial Users onl

Cognitive and clinical phenotype in dementia with Lewy bodies

This dissertation describes the research studies I have most occupied during my Ph. D course. Due to the limited number of studies addressing which clinical and cognitive features are most useful in diagnosing early dementia with Lewy bodies (DLB) (Jicha et al. 2010; Boeve et al. 2012) I initially focused on the visuo-constructional impairments in prodromal DLB (study 1); afterwards on visual-spatial and visual-perceptual deficits (study 2) in a different sample of prodromal DLB. Later I investigated which cognitive impairments could be predictive of DLB in regards to the memory domain (Study 3 and 4). Here below the abstract for each study. Study 1. Assessment of visual-constructional deficits in MCI-DLB. Introduction: Visual-constructional deficits are a prominent feature of dementia with Lewy bodies (DLB) that may contribute to the differential diagnosis with Alzheimer's Disease (AD). The analysis of the pentagon copy included in the MMSE could be a promising tool for the diagnosis of DLB since its early stages (Ala et al. 2001). Aim: To assess the pentagon copy performance in prodromal stage of DLB with the Qualitative Scoring MMSE Pentagon Test (QSPT) (Caffarra et al., 2013). Methods: 30 patients with non amnestic-Mild Cognitive Impairment diagnosed as prodromal DLB (MCI-DLB) and 23 patients with amnestic-MCI diagnosed as prodromal AD (MCI-AD) were enrolled. All patients obtained a MMSE score ≥ 26/30. The diagnosis of DLB and AD was confirmed at 3-year follow-up visit according to established criteria. Each MMSE test was examined with the QSPT which is based on the assessment of different parameters of the pentagon drawing. A broad standard neuropsychological assessment was also performed. Results: The percentage of subjects who were unable to determine the correct number of angles in the pentagon copy test was 45.1% of MCI-DLB and 8.3% of MCI-AD patients (sensitivity 41.1%; specificity 91%). Attentive/executive functions and visual-spatial abilities were worse in the MCI-DLB group, while episodic memory impairment was greater in MCI-AD. Subtle extrapyramidal signs (63%) and RBD symptoms (56%) were the most frequent clinical features supporting the diagnosis of MCI-DLB. Conclusions: We suggest that a poor performance in determining the number of angles when performing the pentagon copying test, together with the presence of subtle extrapyramidal signs and symptoms of RBD may serve as a predictive tool for early DLB. Output of the study: This study has been published in parkinsonism and Related Disorders, 21(3), 303–305. (2015). High specificity of MMSE pentagon scoring for diagnosis of prodromal dementia with Lewy bodies. Cagnin, A., Bussè, C., Jelcic, N., Gnoato, F., Mitolo, M., & Caffarra, P. Study 2. Assessment of visual attention, visual-spatial and visual-constructional deficits in MCI-DLB. Background: Patients with prodromal dementia with Lewy bodies (DLB) may display a different cognitive pattern from Alzheimer's disease (AD) with more severe impairment of attentive and visuo-spatial abilities (Mc Keith, 2005). Objective: to investigate which cognitive functions could be predictive of the diagnosis of DLB and AD in patients with mild cognitive impairment (MCI). Methods: Fifty-three patients with MCI were followed over 3-years until a diagnosis of DLB (MCI-DLB: n=25) and AD (MCI-AD: n=28) were made according to standard criteria. At the first assessment patients underwent a thorough cognitive assessment, including MMSE-QSPT (Caffarra, 2013;), attention, memory, executive functions, constructive apraxia, visuo-perceptual abilities (VOSP battery). Results: The best clinical predictor of DLB was the presence of soft extrapyramidal signs (mean UPDRS score: 4.04 ± 5.9) detected in 72% of patients, followed by REM sleep behavior disorder (60%) and fluctuations (60%). Wrong performances in the pentagon’s number of angles were obtained in 44% of DLB and 3.7% of AD patients and correlated with speed of visual attention. Executive functions, visual attention and visuospatial abilities were worse in DLB, while verbal episodic memory impairment was greater in AD. Deficits in the visual-perceptual domain were present in both MCI-DLB and AD. Conclusions: Poor performance in the pentagon’s number of angles is specific of DLB and correlates with speed of visual attention. The dorsal visual stream seems specifically more impaired in MCI-DLB with respect to the ventral visual stream, the latter being involved in both DLB and AD. These cognitive features, associated with subtle extrapyramidal signs, should alert clinicians to a diagnostic hypothesis of DLB. Output of the study: This study has been published in Dementia and Geriatric Cognitive Disorders Extra 2015. Clinical and Cognitive Phenotype of Mild Cognitive Impairment Evolving to Dementia with Lewy Bodies. Cagnin, A., Bussè, C., Gardini, S., Jelcic, N., Guzzo, C., Gnoato, F., et al. 5 (3), 442–9. Study 3. Analysis of memory domain: specific verbal memory indices of the Rey’s Auditory Verbal Learning Test. Introduction: Several neuropsychological tests exploring episodic memory can’t always give a careful contribution to the differential diagnosis of degenerative diseases. The serial position effects, rather than the traditional scores, along with some important learning characteristic measures, could contribute to address towards a specific type of dementia. Objective: To comprehend if any of the specific measures of verbal memory obtained with the RAVLT, as the verbal learning (VL), verbal forgetting (VF) and the serial position effects, could be of value in distinguishing DLB from AD. Method: thirty-two AD and twenty-nine DLB patients were enrolled in the study and followed longitudinally for 3 years until the diagnosis was made according standard criteria. Twenty-eight normal elderly subjects served as controls. All subjects underwent baseline neuropsychological assessment including RAVLT. Specific verbal memory measures were evaluated: verbal learning (VL) [immediate recall test: trial 5 minus trial 1], verbal forgetting (VF) [trial 6 of delayed recall minus trial 5 of immediate recall], percentage of verbal forgetting (VF%) [% verbal forgetting/trial 5] and the serial position effects of immediate recall (trial 1). Results: The performances of DLB and AD were comparable in the immediate and delayed recall of the RAVLT (IC=95%). However, VL was higher in DLB than AD (DLB=0.25±0.1, AD=0.19±0.1; p<0.05) while VF% was greater in AD (AD=65.85%±41.3, DLB=42.97±33.0%; p=0.001). Logistic regression analysis showed that VF% may be considered a predictive marker of disease group allocation (T=-0.02, Wald (1)=4.85, p=0.03). With a VF% cut-off ≥75%, AD and DLB patients were differently distributed (Choerish=5.1), being 58% of AD versus 21% of DLB above this cut-off. Considering the serial position effects, recency effect was significant higher in AD than DLB (AD=2.09±1.1, DLB=1.34±1.2; p<0.05). Number of recalled words in the recency domain correlated positively with scores of the digit span backward test (r=0.54, p=0.005) and digit span forward (r=0.25, p=0.02) only in DLB (digit span backward: AD: r=0.88, p=0.88; NC: r=-0.02, p=0.94; digit span forward: AD: r=0.12, p=0.52; NC: r=0.24; p=0.22). Discussion: DLB patients showed different memory performances from AD at the RAVLT. In details, DLB had better performances of verbal learning and worse verbal forgetting and recency effect. These specific measures of verbal memory could be used as diagnostic marker in the differential diagnosis between DLB and AD. Output of the study: This study is in submission. Study 4. Analysis of memory domain in mild cognitive impairment: investigating the efficacy of the Free and Cued Selective Reminding Test (FCSRT). Objective: The main goal was to comprehend the efficacy of the Free and Cued Selective and Reminding Test (FCSRT) in differentiating patients with mild cognitive impairment converting to dementia with Lewy bodies (MCI-DLB) from patients with MCI due to Alzheimer’s disease (MCI-AD). Materials and methods: Thirty-five participants with MMSE≥26 were included in the study. Fifth-teen were diagnosed as probable DLB (MCI-DLB: n=15) and twenty as probable AD (MCI-AD: n=20) according to current criteria (Ferman et al. 2013; Albert et al. 2011). Patients underwent a comprehensive cognitive evaluation including the FCSRT for the episodic memory assessment. Results: At the FCSRT, MCI-DLB were significantly more spared than MCI-AD regarding the total memory recall (ITR) and the index of sensitivity of cueing (ISC) (ITR: DLB=35.13±1.26, AD=29.95±1.08, p=0.01; ISC: DLB=0.94±0.04, AD=0.76±0.04, p=0.00). Moreover, MCI-DLB performed worse than MCI-AD in digit cancellation task (DLB=45.49±1.43; AD=49.83±1.22; p=0.03), number of angles of Mini Mental (MMSE) pentagons copy (DLB=3.11±0.17; AD=3.72±0.15; p=0.01) and Rey figure copy (DLB=23.77±1.47; AD= 27.90±1.26; p= 0.05). Discussion: At early stage DLB showed to benefit more than AD from the controlled learning through category cues, exhibiting a greater ISC. MCI-DLB showed poorer performances in attentive and visuo-constructional tasks respect to AD. Conclusions: The FCSRT has shown its utility in the distinction between DLB and AD at early stage increasing the diagnostic accuracy. Moreover, since the main characteristic of the FCSRT is to assess verbal episodic memory isolating the storage capacities of the patients, we exclude a storage memory impairment in MCI-DLB patients. Output of the study: This study is in preparation.