Physical Activity and Mild Cognitive Impairment and Alzheimer’s Disease

Regular physical activity undoubtedly has many health benefits for all age groups. In the past decade, researchers and clinicians have begun to focus their attention on whether physical activity also can improve health outcomes of older adults who experience mild cognitive impairment (MCI) or dementia. This ongoing question is gaining relevance in light of the aging of the world population and with it the rise of age-related conditions, such as cognitive impairment. Not surprisingly, physical activity is among the potential protective lifestyle factors mentioned when strategies to delay or prevent dementia are discussed. The first large-scale multidomain intervention trials are under way to put this to the test. This review aims to give an overview of recent trials of physical activity in patients with MCI or dementia.     

Mild Cognitive Impairment in Parkinson’s Disease

Prospective studies conducted during the last decade have shown that the majority of patients with Parkinson’s disease (PD) develop dementia. In addition, using a variety of definitions and methods, more recent research suggests that approximately a quarter of PD patients without dementia have mild cognitive impairment (PD-MCI). Furthermore, several studies have shown that approximately 20% have MCI even at time of diagnosis of PD. The typical cognitive deficits include visuospatial, attentional, and executive deficits, but memory deficits have also been shown. The etiology of PD-MCI is not known, but it is likely that mechanisms known to contribute to dementia in PD (ie, limbic and cortical Lewy bodies, amyloid plaques, and cholinergic deficits) play a role, in addition to dysfunction of dopaminergic frontostriatal circuits. PD-MCI predicts a shorter time to dementia, and preliminary evidence suggests that this is particularly true for posterior cognitive deficits. There are currently no systematic clinical trials in PD-MCI.     

Common Variant in TREM1 Influencing Brain Amyloid Deposition in Mild Cognitive Impairment and Alzheimer’s Disease

Neurotoxicity Research - Triggering receptor expressed on myeloid cells-1 (TREM1) has been reported to associate with Alzheimer’s disease (AD) pathology. Recently, TREM1 variant rs2234246A...     

Mild Cognitive Impairment in Parkinson’s Disease—What Is It?

Purpose of Review

Mild cognitive impairment is a common feature of Parkinson’s disease, even at the earliest disease stages, but there is variation in the nature and severity of cognitive involvement and in the risk of conversion to Parkinson’s disease dementia. This review aims to summarise current understanding of mild cognitive impairment in Parkinson’s disease. We consider the presentation, rate of conversion to dementia, underlying pathophysiology and potential biomarkers of mild cognitive impairment in Parkinson’s disease. Finally, we discuss challenges and controversies of mild cognitive impairment in Parkinson’s disease.

Recent Findings

Large-scale longitudinal studies have shown that cognitive involvement is important and common in Parkinson’s disease and can present early in the disease course. Recent criteria for mild cognitive impairment in Parkinson’s provide the basis for further study of cognitive decline and for the progression of different cognitive phenotypes and risk of conversion to dementia.

Summary

Improved understanding of the underlying pathology and progression of cognitive change are likely to lead to opportunities for early intervention for this important aspect of Parkinson’s disease.

     

Plasma neurofilament light chain as a biomarker of Alzheimer’s disease in Subjective Cognitive Decline and Mild Cognitive Impairment

Journal of Neurology - Neurofilament light chain (NfL) is becoming increasingly notable in neurological diseases including AD, and it has been suggested as a new peripherical biomarker of...     

Discriminative capacity and construct validity of the Clock Drawing Test in Mild Cognitive Impairment and Alzheimer’s disease

Abstract

Objectives: The aim of this study was to analyze the psychometric and diagnostic properties of the Clock Drawing Test (CDT), scored according to the Babins, Rouleau, and Cahn scoring systems, for Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) screening, and develop corresponding cutoff scores. Additionally, we assessed the construct validity of the CDT through exploratory and confirmatory factor analysis.

Methods: We developed a cross-sectional study of ambulatory MCI and AD patients, divided in two clinical groups (450?MCI and 250 mild AD patients) and a normal control group (N?=?400). All participants were assessed with the CDT, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) for convergent validity.

Results: The selected scoring systems presented adequate validity and reliability values. The proposed cutoff scores showed 60 to 65% sensitivity and 58 to 62% specificity to identify MCI patients. The corresponding values for AD were 84 to 90% sensitivity and 76 to 78% specificity. Exploratory and confirmatory factor analysis revealed that the Babins scoring system had good construct validity and allowed us to propose a three-factor model for this system.

Conclusions: Our results confirmed the complexity of the CDT and support it as a cognitive screening instrument particularly sensitive to AD. The use of the CDT with MCI patients should be interpreted with more caution due to the lower sensitivity and specificity for milder forms of cognitive impairment.     

Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals With Mild Cognitive Impairment

Background

Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer’s disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects.

Can I Smell Gas (or Is It Lilac)? Olfactory Semantic Deficits in Mild Cognitive Impairment and Alzheimer’s Disease

Olfactory decline represents one of the earliest signs of Alzheimer’s disease (AD), and deficits in olfactory identification have now been identified in persons with amnestic mild cognitive impairment (aMCI). Whether the olfactory identification deficit in AD reflects underlying degraded semantic knowledge or lower-order olfactory deficits is uncertain. To address this question, we focused on the kinds of errors committed when participants were given a unirhinal olfactory identification task at baseline and after 1 year. The aim was to assess whether more errors were committed when the target smell is either semantically related or unrelated to the distracters. Fourteen AD, 13 aMCI, and 10 control participants were tested using a modified version of the University of Pennsylvania Smell Identification Test. Examination of error types showed that the control group predominantly selected distracters which were related to the target; in contrast, distracters that were unrelated to the target odor were selected as frequently as related odors by the AD and aMCI groups, for both nostrils. This pattern was maintained 1 year later, and previously designated aMCI patients who then met criteria for AD were more inclined to choose the unrelated distracters than were aMCI patients who did not meet AD criteria. Olfactory identification deficits in AD and aMCI plausibly reflect deterioration in ability to access olfactory-mediated semantic knowledge. This pattern of errors may help distinguish the olfactory identification deficits observed in AD from olfactory identification deficits observed in other conditions not associated with semantic loss.     

Combined Plasma Biomarkers for Diagnosing Mild Cognition Impairment and Alzheimer’s Disease

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Circulating plasmalogen levels and Alzheimer Disease Assessment Scale–Cognitive scores in Alzheimer patients

Background

Plasmalogens, which are key structural phospholipids in brain membranes, are decreased in the brain and serum of patients with Alzheimer disease (AD). We performed this pilot study to evaluate the relation between the levels of circulating plasmalogens and Alzheimer Disease Assessment Scale–Cognitive (ADAS-Cog) scores in patients with AD.

Methods

We evaluated participants’ ADAS-Cog scores and serum plasmalogen levels. For the 40 included AD patients with an ADAS-Cog score between 20 and 46, we retested their ADAS-Cog score 1 year later. The levels of docosahexaenoic acid plasmalogen were measured by use of liquid chromatography–tandem mass spectrometry.

Results

We found that the ADAS-Cog score increased significantly in AD patients with circulating plasmalogen levels that were ≤ 75% of that of age-matched controls at entry into the study. There was no change in score among participants with normal serum plasmalogen levels at baseline (> 75%).

Limitations

This was a pilot study with 40 patients, and the results require validation in a larger population.

Conclusion

Our study demonstrates that decreased levels of plasmalogen precursors in the central nervous system correlate with functional decline (as measured by ADAS-Cog scores) in AD patients. The use of both ADAS-Cog and serum plasmalogen data may be a more accurate way of predicting cognitive decline in AD patients, and may be used to decrease the risk of including patients with no cognitive decline in the placebo arm of a drug trial.     

L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer’s Disease

The urea cycle is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). Arginase-I (ARGI) accumulation at sites of amyloid-beta (Aβ) deposition is associated with L-arginine deprivation and neurodegeneration. An interaction between the arginase II (ARGII) and mTOR-ribosomal protein S6 kinase β-1 (S6K1) pathways promotes inflammation and oxidative stress. In this study, we treated triple-transgenic (3×Tg) mice exhibiting increased S6K1 activity and wild-type (WT) mice with L-norvaline, which inhibits both arginase and S6K1. The acquisition of spatial memory was significantly improved in the treated 3×Tg mice, and the improvement was associated with a substantial reduction in microgliosis. In these mice, increases in the density of dendritic spines and expression levels of neuroplasticity-related proteins were followed by a decline in the levels of Aβ toxic oligomeric and fibrillar species in the hippocampus. The findings point to an association of local Aβ-driven and immune-mediated responses with altered L-arginine metabolism, and they suggest that arginase and S6K1 inhibition by L-norvaline may delay the progression of AD.     

Role of Synucleins in Alzheimer’s Disease

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-β protein (Aβ) has been identified as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of α-synuclein (α-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on investigating the role of Aβ and Tau; however, recent studies suggest that α-syn might also play a role in the pathogenesis of AD. For example, fragments of α-syn can associate with amyloid plaques and Aβ promotes the aggregation of α-syn in vivo and worsens the deficits in α-syn tg mice. Moreover, α-syn has also been shown to accumulate in limbic regions in AD, Down’s syndrome, and familial AD cases. Aβ and α-syn might directly interact under pathological conditions leading to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Aβ and α-syn might also result in oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Aβ and α-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD.     

Neurobiology of Delusions in Alzheimer’s Disease

Alzheimer’s disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities. Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.     

High avidity HSV-1 antibodies correlate with absence of amnestic Mild Cognitive Impairment conversion to Alzheimer’s disease

Amnestic Mild Cognitive Impairment (aMCI) is an alteration in cognitive abilities that can progress to Alzheimer’s disease (AD), a condition in which herpes simplex type 1 (HSV-1) infection might play a pathogenetic role. Prognostic indexes capable of predicting aMCI conversion to AD are only partially understood. The objective of the present work is to verify whether HSV-1 immune responses is involved in conversion of aMCI to AD and correlate with grey matter brain morphometry. Two homogeneous groups of individuals who did or did not convert to AD over a 24-months period were selected after retrospective analysis of a cohort of patients with a diagnosis of aMCI. The selection of subjects was based on: a) clinical follow-up; b) neurocognitive evaluation at baseline and after 24 months; c) availability of serum and DNA samples at baseline. 36 aMCI individuals, 21 of whom did (aMCI-converters) and 15 of whom did not (aMCI-non-converters) convert to AD, were included in the study. HSV-1 antibody (Ab) titers, avidity index and APOE genotyping were performed in all the enrolled individuals at baseline. Brain magnetic resonance imaging (MRI) by 1.5T scanner results at baseline were available as well in most (29/36) of these individuals. HSV-1-specific Ab titers were increased at baseline in aMCI-non-converters, and the avidity of these Ab was significantly higher in aMCI-non-converter compared to aMCI-converter (p = 0.0018). Receiver operating characteristics analysis showed that HSV-1 avidity had a predictive value in distinguishing between aMCI-non-converters and aMCI-converters (p < 0.0001). Notably, a positive correlation was detected as well between HSV-1 antibody titers and MRI-evaluated cortical volumes in the left hippocampus and amigdala (p_corr < 0.05). In conclusion, stronger HSV-1-specific humoral responses associate with protection against AD conversion and better-preserved cortical volumes. These results reinforce the hypothesis for a role for HSV-1 in the pathogenesis of AD.     

Diagnosis and Management of Neuropsychiatric Symptoms in Alzheimer’s Disease

Purpose of Review

To explore the most recent developments in the effective diagnosis and treatment of neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD).

Recent Findings

The clinical diagnosis of NPS in AD is facilitated by the use of the Neuropsychiatric Inventory (NPI). CT and MRI scans can be useful for detecting structural changes indicating AD. Other promising diagnostic methodologies that are less frequently used in the clinical setting include positron emission tomography (PET) scans for detecting amyloid and blood tests for detecting serum biomarkers. Numerous pharmaceutical agents have been studied for their use in managing NPS, with antipsychotics being popular for managing agitation but also having significant side effects. Non-pharmacological interventions, such as reminiscence therapy and the Describe, Investigate, Create, Evaluate (DICE) approach may be able to provide treatment without such adverse effects.

Summary

Diagnosing AD and the comorbid NPS remains primarily a clinical endeavor with CT and MRI scans sometimes used, but evidence is amassing for the use of other imaging modalities and different lab tests for convenient and empiric diagnosis of AD to distinguish it from other psychiatric illnesses. The number of pharmacologic treatments for NPS that are safe as well as efficacious remains limited, yet non-pharmacologic interventions have clear clinical utility. In addition to searching for more successful pharmacological treatments, further research should focus on novel diagnostic tests and non-pharmacologic therapies.