P1-043: Low level of nuclear phosphorylated tau is associated with cognitive impairment at early stage of the disease whereas an increase in the amount of this protein associates with neuronal death

Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.

Download Full-text

CSF Biomarkers Reflecting Protein Pathology and Axonal Degeneration Are Associated with Memory, Attentional, and Executive Functioning in Early-Stage Parkinson′s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21228519 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8519

Author(s):

Linda P. Oosterveld ◽

Tessa I. Kuiper ◽

Nour K. Majbour ◽

Inge M. W. Verberk ◽

Karin D. van Dijk ◽

...

Keyword(s):

Cognitive Impairment ◽

Executive Functioning ◽

Light Chain ◽

Early Stage ◽

Csf Biomarkers ◽

Phosphorylated Tau ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cognitive Domains ◽

Csf Biomarker

In early-stage Parkinson′s disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament light chain, amyloid-β42, and tau are associated with cognitive performance in early-stage PD patients. CSF levels of total-α-synuclein and phosphorylated-α-synuclein, neurofilament light chain, amyloid-β42, and total-tau and phosphorylated-tau were measured in 26 PD patients (disease duration ≤5 years and Hoehn and Yahr stage 1–2.5). Multivariable linear regression models, adjusted for age, gender, and educational level, were used to assess the relationship between CSF biomarker levels and memory, attention, executive and visuospatial function, and language performance scores. In 26 early-stage PD patients, attention and memory were the most commonly affected domains. A higher CSF phosphorylated-α-synuclein/total-α-synuclein ratio was associated with better executive functioning (sβ = 0.40). Higher CSF neurofilament light was associated with worse memory (sβ = −0.59), attentional (sβ = −0.32), and executive functioning (sβ = −0.35). Reduced CSF amyloid-β42 levels were associated with poorer attentional functioning (sβ = 0.35). Higher CSF phosphorylated-tau was associated with worse language functioning (sβ = −0.33). Thus, CSF biomarker levels, in particular neurofilament light, were related to the most commonly affected cognitive domains in early-stage PD. This indicates that CSF biomarker levels may identify early-stage PD patients who are at an increased risk of developing cognitive impairment.

Download Full-text

Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia

Journal of Alzheimer s Disease ◽

10.3233/jad-201122 ◽

2020 ◽

pp. 1-10

Author(s):

Christopher Gonzalez ◽

Nicole S. Tommasi ◽

Danielle Briggs ◽

Michael J. Properzi ◽

Rebecca E. Amariglio ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Older Adults ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Early Stage ◽

Cognitively Normal ◽

Financial Capacity ◽

Posterior Cingulate ◽

Dorsolateral Prefrontal

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p < 0.001; inferior temporal: p < 0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p < 0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p < 0.001; and amyloid and supramarginal tau interaction: p = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

Download Full-text

Development of the Positive Photo Appreciation for Dementia program for people with mild cognitive impairment and early‐stage Alzheimer's disease: A feasibility study

Geriatrics and Gerontology International ◽

10.1111/ggi.13739 ◽

2019 ◽

Vol 19 (10) ◽

pp. 1064-1066

Author(s):

Masumi Ishihara ◽

Tami Saito ◽

Takashi Sakurai ◽

Aiko Osawa ◽

Ikue Ueda ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Feasibility Study ◽

Early Stage

Download Full-text

Anosognosia in People with Cognitive Impairment: Association with Cognitive Deficits and Behavioral Disturbances

Dementia and Geriatric Cognitive Disorders Extra ◽

10.1159/000367987 ◽

2015 ◽

Vol 5 (1) ◽

pp. 42-50 ◽

Cited By ~ 14

Author(s):

Antonella De Carolis ◽

Virginia Cipollini ◽

Valentina Corigliano ◽

Anna Comparelli ◽

Micaela Sepe-Monti ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Deficits ◽

Rating Scale ◽

Motor Behavior ◽

Psychiatric Symptoms ◽

Early Stage ◽

Functional Anatomy ◽

Night Time ◽

Behavioral Disturbances ◽

The Relationship

Aims: To investigate, in a group of subjects at an early stage of cognitive impairment, the relationship between anosognosia and both cognitive and behavioral symptoms by exploring the various domains of insight. Methods: One hundred and eight subjects affected by cognitive impairment were consecutively enrolled. The level of awareness was evaluated by means of the Clinical Insight Rating Scale (CIRS). Psychiatric symptoms were evaluated using the Italian version of the Neuropsychiatric Inventory (NPI), whereas memory (memory index, MI) and executive (executive index, EI) functions were explored using a battery of neuropsychological tests and qualified by means of a single composite cognitive index score for each function. Results: A significant positive correlation between the total NPI score and global anosognosia score was found. Furthermore, both the MI and EI scores were lower in subjects with anosognosia than in those without anosognosia (p < 0.001 and p < 0.007, respectively). When the single domains of the CIRS were considered, anosognosia of reason of visit correlated with the EI score (r = -0.327, p = 0.01) and night-time behavioral disturbances (r = 0.225; p = 0.021); anosognosia of cognitive deficit correlated with depression (r = -0.193; p = 0.049) and the MI score (r = -0.201; p = 0.040); anosognosia of functional deficit correlated with the MI score (r = -0.257; p = 0.008), delusions (r = 0.232; p = 0.015) and aberrant motor behavior (r = 0.289; p = 0.003); anosognosia of disease progression correlated with the MI score (r = -0.236; p = 0.015), agitation (r = 0.247; p = 0.011), aberrant motor behavior (r = 0.351; p = 0.001) and night-time behavioral disturbances (r = 0.216; p = 0.027). Conclusions: Our study suggests that, in the early stage of cognitive impairment, anosognosia is associated with both cognitive deficits and behavioral disorders according to the specific functional anatomy of the symptoms.

Download Full-text

Using Regional Homogeneity to Reveal Altered Spontaneous Activity in Patients with Mild Cognitive Impairment

BioMed Research International ◽

10.1155/2015/807093 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Yumei Wang ◽

Xiaochuan Zhao ◽

Shunjiang Xu ◽

Lulu Yu ◽

Lan Wang ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Spontaneous Activity ◽

Healthy Aging ◽

Early Stage ◽

Brain Activity ◽

Regional Homogeneity ◽

Whole Brain ◽

Spontaneous Brain Activity ◽

Regional Brain Activity

Most patients with mild cognitive impairment (MCI) are thought to be in an early stage of Alzheimer’s disease (AD). Resting-state functional magnetic resonance imaging reflects spontaneous brain activity and/or the endogenous/background neurophysiological process of the human brain. Regional homogeneity (ReHo) rapidly maps regional brain activity across the whole brain. In the present study, we used the ReHo index to explore whole brain spontaneous activity pattern in MCI. Our results showed that MCI subjects displayed an increased ReHo index in the paracentral lobe, precuneus, and postcentral and a decreased ReHo index in the medial temporal gyrus and hippocampus. Impairments in the medial temporal gyrus and hippocampus may serve as important markers distinguishing MCI from healthy aging. Moreover, the increased ReHo index observed in the postcentral and paracentral lobes might indicate compensation for the cognitive function losses in individuals with MCI.

Download Full-text

Olfactory Function and Diffusion Tensor Imaging as Markers of Mild Cognitive Impairment in Early Stages of Parkinson's Disease

Clinical EEG and Neuroscience ◽

10.1177/15500594211058263 ◽

2021 ◽

pp. 155005942110582

Author(s):

Sophie A. Stewart ◽

Laura Pimer ◽

John D. Fisk ◽

Benjamin Rusak ◽

Ron A. Leslie ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Diffusion Tensor Imaging ◽

Mild Cognitive Impairment ◽

White Matter ◽

Neurodegenerative Disorder ◽

Diffusion Tensor ◽

Early Stage ◽

White Matter Integrity

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to established groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

Download Full-text