The Treatment of Cognitive Impairment Associated with Parkinson's Disease

Cognitive impairment and dementia associated with Parkinson''s disease (PD) are common and often have devastating effects upon the patient and their family. Early cognitive impairment in PD is frequent, and the functional impact may be underestimated. Optimal management will rely upon better identification of the predominant symptoms and greater knowledge of their pathophysiological basis. The management of dementia in PD (PD‐D) also has to consider the significant neuropsychiatric burden that frequently accompanies the cognitive decline, as well as fluctuations in attention. Atypical anti‐psychotics have a limited role at present in treating PD‐D, although new drugs are under development. The mainstay of drug management for people with PD‐D is cholinesterase inhibitors, although recent trials have suggested that the N‐methyl‐D aspartate antagonist memantine may also have some benefit. Disease modification remains the ultimate goal for preventing the inexorable decline in PD‐D, although effective interventions are still some way off. Limited benefit may, however, be possible through exercise programmes and so‐called “medical foods”, although randomised trials are required to confirm largely anecdotal observations.     

Prevalence of dementia subtypes in a developing country: a clinicopathological study

OBJECTIVES:

To assess the distribution of dementia subtypes in Brazil using a population-based clinicopathological study.

METHOD:

Brains from deceased individuals aged ≥50 years old were collected after the next of kin signed an informed consent form and provided information through standardized questionnaires. Post-mortem clinical diagnoses were established in consensus meetings, and only cases with moderate or severe dementia or without cognitive impairment were included in the analysis. Immunohistochemical neuropathological examinations were performed following the universally accepted guidelines. A diagnosis of Alzheimer''s disease was made when there were at least both a moderate density of neuritic plaques (Consortium to Establish a Register for Alzheimer''s disease B or C) and Braak stage III for neurofibrillary tangle distribution. For the diagnosis of vascular dementia, at least three zones or strategic areas had to be affected by infarcts, lacunae, or microinfarcts.

RESULTS:

From 1,291 subjects, 113 cases were classified as having moderate or severe dementia, and 972 cases were free of cognitive impairment. The neuropathological diagnoses of the dementia sub-group were Alzheimer''s disease (35.4%), vascular dementia (21.2%), Alzheimer''s disease plus vascular dementia (13.3%), and other causes of dementia (30.1%). Small-vessel disease, which alone was not considered sufficient for a vascular dementia diagnosis, was present in 38.9% of all of the dementia cases and in 16.8% of the group without cognitive impairment (odds ratio = 2.91; 95% confidence interval, 1.53-5.51), adjusted for age, sex, and education.

CONCLUSIONS:

The relatively high frequencies of vascular dementia and small-vessel disease in the dementia sub-group constitute relevant findings for public health initiatives because control of vascular risk factors could decrease the prevalence of dementia in developing countries.     

Seoul Neuropsychological Screening Battery-Dementia Version (SNSB-D): A Useful Tool for Assessing and Monitoring Cognitive Impairments in Dementia Patients

The Seoul Neuropsychological Screening Battery (SNSB) is one of the standardized neuropsychological test batteries widely used in Korea. However, it may be a bit too lengthy for patients with decreased attention span; and it does not provide the score of global cognitive function (GCF), which is useful for monitoring patients longitudinally. We sought to validate a dementia version of SNSB (SNSB-D) that was shorter than the original SNSB and contained only scorable tests with a GCF score of 300. We administered SNSB-D to patients with mild cognitive impairment (MCI) (n=43) and Alzheimer''s disease (AD) (n=93), and normal controls (NC) (n=77). MCI and AD groups had GCF scores significantly different from NC group, and GCF scores were able to distinguish patients with Clinical Dementia Rating of 0.5 and 1. Test-retest reliability was high, with a correlation coefficient of 0.918 for AD, 0.999 for MCI, and 0.960 for NC. The GCF score significantly correlated with the Mini-Mental State Examination (MMSE). Through ROC-curve analysis, GCF scores were found to yield more accurate diagnoses than the MMSE. The SNSB-D is a valid, reliable tool for assessing the overall cognitive function, and can be used to monitor cognitive changes in patients with dementia.     

Isoform‐specific upregulation of FynT kinase expression is associated with tauopathy and glial activation in Alzheimer's disease and Lewy body dementias

Cumulative data suggest the involvement of Fyn tyrosine kinase in Alzheimer''s disease (AD). Previously, our group has shown increased immunoreactivities of the FynT isoform in AD neocortex (with no change in the alternatively spliced FynB isoform) which associated with neurofibrillary degeneration and reactive astrogliosis. Since both the aforementioned neuropathological features are also variably found in Lewy Body dementias (LBD), we investigated potential perturbations of Fyn expression in the post‐mortem neocortex of patients with AD, as well as those diagnosed as having one of the two main subgroups of LBD: Parkinson''s disease dementia (PDD) and dementia with Lewy bodies (DLB). We found selective upregulation of FynT expression in AD, PDD, and DLB which also correlated with cognitive impairment. Furthermore, increased FynT expression correlated with hallmark neuropathological lesions, soluble β‐amyloid, and phosphorylated tau, as well as markers of microglia and astrocyte activation. In line with the human post‐mortem studies, cortical FynT expression in aged mice transgenic for human P301S tau was upregulated and further correlated with accumulation of aggregated phosphorylated tau as well as with microglial and astrocytic markers. Our findings provide further evidence for the involvement of FynT in neurodegenerative dementias, likely via effects on tauopathy and neuroinflammation.     

Brain fluorodeoxyglucose (FDG) PET in dementia

The purpose of this article is to present a selective and concise summary of fluorodeoxyglucose (FDG) positron emission tomography (PET) in dementia imaging. FDG PET is used to visualize a downstream topographical marker that indicates the distribution of neural injury or synaptic dysfunction, and can identify distinct phenotypes of dementia due to Alzheimer's disease (AD), Lewy bodies, and frontotemporal lobar degeneration. AD dementia shows hypometabolism in the parietotemporal association area, posterior cingulate, and precuneus. Hypometabolism in the inferior parietal lobe and posterior cingulate/precuneus is a predictor of cognitive decline from mild cognitive impairment (MCI) to AD dementia. FDG PET may also predict conversion of cognitively normal individuals to those with MCI. Age-related hypometabolism is observed mainly in the anterior cingulate and anterior temporal lobe, along with regional atrophy. Voxel-based statistical analyses, such as statistical parametric mapping or three-dimensional stereotactic surface projection, improve the diagnostic performance of imaging of dementias. The potential of FDG PET in future clinical and methodological studies should be exploited further.     

Analyzing the subcortical dementia syndrome of Parkinson's disease using the RBANS.

On mental status examinations, groups of equally impaired patients with subcortical (Huntington's disease, HD; Parkinson's disease, PD) or cortical (Alzheimer's disease, AD) dementias exhibit different patterns of neuropsychological deficits. Using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), classification accuracies of 90% or greater have been reported for individual patients with AD or HD. To test the generality of the RBANS classification algorithm, we studied patients with dementia (AD and PDD) and without dementia (PDND). Classification accuracies were AD: 87%, PDD: 78%, and PDND: 39%. Comparisons of performance on subtests of the RBANS showed that all groups performed more poorly on tests that require motor skill or rapid information processing and that memory performance by the PD groups was not improved by procedures that enhance encoding and facilitate retrieval. The RBANS is useful for discriminating patterns of cognitive impairment in PD and AD, but only if the diagnosis of dementia is established independent of the RBANS test results. Cognitive slowing is not specific to subcortical dementia and current concepts of memory dysfunction in PD may require re-examination.     

Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) is a nosological entity proposed as an intermediate state between normal aging and dementia. MCI seems to represent an early stage of Alzheimer's disease (AD) and there is a great interest in the relationship between MCI and the progression to AD. Some studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment. The aim of the present work was to evaluate the serum levels of some enzymatic antioxidant defences like superoxide dismutase (SOD) and glutathione peroxidase (GPX), as well as lipid peroxidation markers like MDA (malondialdehyde), in MCI and AD patients, compared with age-matched healthy controls. The subjects of this study (45 patients) consisted of 15 individuals with mild cognitive impairment (MCI), 15 with Alzheimer's disease (AD) and 15 healthy age-matched controls. Biochemical analyses showed a similar decrease of the main enzymatic antioxidant defences (SOD and GPX) and increased production of lipid peroxidation marker (MDA) in the serum of the MCI and AD patients, compared to age-matched control group. This study clearly demonstrates that oxidative stress damage occurs in patients with MCI and AD. Moreover, some enzymatic markers of oxidative stress are similar in MCI and AD patients, suggesting that oxidative damage could be one important aspect for the onset of AD.     

How early can we predict Alzheimer's disease using computational anatomy?

Computational anatomy with magnetic resonance imaging (MRI) is well established as a noninvasive biomarker of Alzheimer's disease (AD); however, there is less certainty about its dependency on the staging of AD. We use classical group analyses and automated machine learning classification of standard structural MRI scans to investigate AD diagnostic accuracy from the preclinical phase to clinical dementia. Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative were stratified into 4 groups according to the clinical status—(1) AD patients; (2) mild cognitive impairment (MCI) converters; (3) MCI nonconverters; and (4) healthy controls—and submitted to a support vector machine. The obtained classifier was significantly above the chance level (62%) for detecting AD already 4 years before conversion from MCI. Voxel-based univariate tests confirmed the plausibility of our findings detecting a distributed network of hippocampal-temporoparietal atrophy in AD patients. We also identified a subgroup of control subjects with brain structure and cognitive changes highly similar to those observed in AD. Our results indicate that computational anatomy can detect AD substantially earlier than suggested by current models. The demonstrated differential spatial pattern of atrophy between correctly and incorrectly classified AD patients challenges the assumption of a uniform pathophysiological process underlying clinically identified AD.     

Age‐associated memory impairment: The clinical syndrome

Clinical concepts of age‐associated memory impairment (AAMI) have inevitably been linked to distinctions between this entity and progressive dementia, particularly Alzheimer's disease (AD). Kral was perhaps the first modern clinician to attempt to delineate these distinctions. More recently, Folstein has suggested mental status boundaries between AAMI and progressive dementia, including AD. We have delineated clinically distinguishable stages of progressive cognitive impairment in AAMI and in AD. Present longitudinal investigations suggest clinical and mental status boundaries between these conditions.

Cumulatively, these studies indicate that relatively precise clinical criteria for a diagnosis of AAMI and for a definition of boundaries between AAMI and AD can presently be formulated for the selection of appropriate study populations.     

Circadian and sleep dysfunction in Alzheimer’s disease

Alzheimer's disease (AD) is a devastating and irreversible cognitive impairment and the most common type of dementia. Along with progressive cognitive impairment, dysfunction of the circadian rhythms also plays a pivotal role in the progression of AD. A mutual relationship among circadian rhythms, sleep, and AD has been well-recommended. The etiopathogenesis of the disturbances of the circadian system and AD share some general features that also unlock the outlook of observing them as a mutually dependent pathway. Indeed, the burden of amyloid β (Aβ), neurofibrillary tangles (NFTs), neuroinflammation, oxidative stress, and dysfunction of circadian rhythms may lead to AD. Aging can alter both sleep timings and quality that can be strongly disrupted in AD. Increased production of Aβ and reduced Aβ clearance are caused by a close interplay of Aβ, sleep disturbance and raised wakefulness. Besides Aβ, the impact of tau pathology is possibly noteworthy to the sleep deprivation found in AD. Hence, this review is focused on the primary mechanistic complexities linked to disruption of circadian rhythms, sleep deprivation, and AD. Furthermore, this review also highlights the potential therapeutic strategies to abate AD pathogenesis.     

L-Arginine and Alzheimer's Disease

Alzheimer''s disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration and loss of cognitive and memory functions. Although the exact causes of AD are still unclear, evidence suggests that atherosclerosis, redox stress, inflammation, neurotransmitter dysregulation, and impaired brain energy metabolism may all be associated with AD pathogenesis. Herein, we explore a possible role for L-arginine (L-arg) in AD, taking into consideration known functions for L-arg in atherosclerosis, redox stress and the inflammatory process, regulation of synaptic plasticity and neurogenesis, and modulation of glucose metabolism and insulin activity. L-arg, a precursor of nitric oxide and polyamine, exhibits multiple functions in human health and may play a prominent role in age-related degenerative diseases such as AD.     

Suspected non-Alzheimer's pathology – Is it non-Alzheimer's or non-amyloid?

Neurodegeneration, the progressive loss of neurons, is a major process involved in dementia and age-related cognitive impairment. It can be detected clinically using currently available biomarker tests. Suspected Non-Alzheimer Pathology (SNAP) is a biomarker-based concept that encompasses a group of individuals with neurodegeneration, but no evidence of amyloid deposition (thereby distinguishing it from Alzheimer's disease (AD)). These individuals may often have a clinical diagnosis of AD, but their clinical features, genetic susceptibility and progression can differ significantly, carrying crucial implications for precise diagnostics, clinical management, and efficacy of clinical drug trials.SNAP has caused wide interest in the dementia research community, because it is still unclear whether it represents distinct pathology separate from AD, or whether in some individuals, it could represent the earliest stage of AD. This debate has raised pertinent questions about the pathways to AD, the need for biomarkers, and the sensitivity of current biomarker tests.In this review, we discuss the biomarker and imaging trials that first recognized SNAP. We describe the pathological correlates of SNAP and comment on the different causes of neurodegeneration. Finally, we discuss the debate around the concept of SNAP, and further unanswered questions that are emerging.     

Correlation between C9ORF72 mutation and neurodegenerative diseases: A comprehensive review of the literature

Chromosome 9 open reading frame 72 (C9ORF72) encodes a 54-kDa protein with unknown function that is expressed at high levels in the central nervous system. The C9ORF72 hexanucleotide amplification is one of the most recently discovered repetitive amplification diseases related to neurodegeneration. Its association with amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum diseases has been fully established, although a causative role for C9ORF72 in Alzheimer''s disease (AD) and Parkinson''s disease (PD) remains to be established. Therefore, in this article, we will review the evidence for C9ORF72 as a causative factor in neurodegenerative diseases, the underlying mechanisms, and the potential for targeting C9ORF72 as a strategy to alleviate neurodegenerative disease progression.     

Effects of ApoE4 and maternal history of dementia on hippocampal atrophy

We applied an automated hippocampal segmentation technique based on adaptive boosting (AdaBoost) to the 1.5 T magnetic resonance imaging (MRI) baseline and 1-year follow-up data of 243 subjects with mild cognitive impairment (MCI), 96 with Alzheimer's disease (AD), and 145 normal controls (NC) scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). MCI subjects with positive maternal history of dementia had smaller hippocampal volumes at baseline and at follow-up, and greater 12-month atrophy rates than subjects with negative maternal history. Three-dimensional maps and volumetric multiple regression analyses demonstrated a significant effect of positive maternal history of dementia on hippocampal atrophy in MCI and AD after controlling for age, ApoE4 genotype, and paternal history of dementia, respectively. ApoE4 showed an independent effect on hippocampal atrophy in MCI and AD and in the pooled sample.     

Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.     

The role of inflammasome in Alzheimer's disease

Alzheimer's disease (AD) is a chronic, progressive and irreversible neurodegenerative disease with clinical characteristics of memory loss, dementia and cognitive impairment. Although the pathophysiologic mechanism is not fully understood, inflammation has been shown to play a critical role in the pathogenesis of AD. Inflammation in the central nervous system (CNS) is characterized by the activation of glial cells and release of proinflammatory cytokines and chemokines. Accumulating evidence demonstrates that inflammasomes, which cleave precursors of interleukin-1β (IL-1β) and IL-18 to generate their active forms, play an important role in the inflammatory response in the CNS and in AD pathogenesis. Therefore, modulating inflammasome complex assembly and activation could be a potential strategy for suppressing inflammation in the CNS. This review aims to provide insight into the role of inflammasomes in the CNS, with respect to the pathogenesis of AD, and may provide possible clues for devising novel therapeutic strategies.     

Both plasma retinol-binding protein and haptoglobin precursor allele 1 in CSF: Candidate biomarkers for the progression of normal to mild cognitive impairment to Alzheimer's disease

Cerebrospinal fluid (CSF) may be of valuable for exploring protein markers for the diagnosis of Alzheimer's disease (AD). The prospect of early detection and treatment, to slow progression, holds hope for aging populations with increased average lifespan. The aim of the present study was to investigate candidate CSF biological markers in patients with mild cognitive impairment (MCI) and AD and compare them with age-matched normal control subjects. In this report, we applied proteomics approaches to analyze 60 CSF samples derived from patients with neurodegenerative diseases such as MCI and AD. We classified patients by three groups: normal controls without cognitive dysfunction, MCI and AD. The AD group was subdivided into three groups by clinical severity according to clinical dementia rating (CDR), a well known clinical scale for dementia. We demonstrated a gradual decrease or absent of plasma retinol-binding protein (RBP) and haptoglobin precursor allele 1 in CSF from patients with MCI and AD compared to the age-matched normal subjects. Moreover, expression levels of both RBP and haptoglobin precursor allele 1 were observed to be very high in age-matched normal subjects. In contrast, the RBP and haptoglobin precursor allele 1 were much decreased in the MCI group; those expressions were more weak or absent in AD group, and correlated with disease severity and progression. These findings suggest that the CSF levels of both RBP and haptoglobin precursor allele 1 may be candidate biomarkers for the progression of normal to MCI to AD.     

Cognitive decline in Parkinson's disease is associated with slowing of resting-state brain activity: a longitudinal study

The pathophysiological mechanisms of Parkinson's disease (PD)-related dementia (PDD) are still poorly understood. Previous studies using electroencephalography (EEG) and magnetoencephalography (MEG) have demonstrated widespread slowing of oscillatory brain activity as a neurophysiological characteristic of PD-related dementia. Here, we use MEG to longitudinally study early changes in oscillatory brain activity in initially nondemented PD patients that may be associated with cognitive decline. Using a longitudinal design, resting-state MEG recordings were performed twice at an approximate 4-year interval in 14 healthy controls and 49 PD patients. Changes in peak frequency and in relative spectral power for 10 brain regions were analyzed in relation to clinical measures of cognitive and motor function. In contrast to healthy controls, PD patients showed a slowing of the dominant peak frequency. Furthermore, analysis per frequency band revealed an increase in theta power over time, along with decreases in alpha1 and alpha2 power. In PD patients, decreasing cognitive performance was associated with increases in delta and theta power, as well as decreases in alpha1, alpha2, and gamma power, whereas increasing motor impairment was associated with a theta power increase only. The present longitudinal study revealed widespread progressive slowing of oscillatory brain activity in initially nondemented PD patients, independent of aging effects. The slowing of oscillatory brain activity strongly correlated with cognitive decline and therefore holds promise as an early marker for the development of dementia in PD.     

Is encroachment of the carotid termination into the substantia innominata associated with its atrophy and cognition in Alzheimer's disease?

The internal carotid artery termination (CAT) ends in a T-shaped bifurcation just below the substantia innominata (SI), which contains cognitively strategic cholinergic neurons and undergoes atrophy in Alzheimer's disease (AD). This study investigated whether an elongated CAT with possible resulting encroachment into the SI would correlate with SI atrophy and with cognitive dysfunction in AD. We rated the degree of CAT encroachment upon the SI and measured SI volume on magnetic resonance imaging in 30 AD patients, 30 AD patients with subcortical small vessel disease, and 30 age-matched controls. CAT encroachment significantly correlated with SI volume after adjusting for age within the overall group and the groups with dementia. AD patients with higher CAT encroachment scores had lower SI volumes and lower attention, memory, and executive test scores. These data suggest that CAT encroachment may mechanically injure the SI, exacerbating cholinergic damage and contributing to cognitive impairment. This process may represent a possible previously underappreciated mechanism for interaction between large-vessel cerebrovascular disease and AD.