An advanced white matter tract analysis in frontotemporal dementia and early-onset Alzheimer’s disease

Cortical and subcortical nuclei degenerate in the dementias, but less is known about changes in the white matter tracts that connect them. To better understand white matter changes in behavioral variant frontotemporal dementia (bvFTD) and early-onset Alzheimer’s disease (EOAD), we used a novel approach to extract full 3D profiles of fiber bundles from diffusion-weighted MRI (DWI) and map white matter abnormalities onto detailed models of each pathway. The result is a spatially complex picture of tract-by-tract microstructural changes. Our atlas of tracts for each disease consists of 21 anatomically clustered and recognizable white matter tracts generated from whole-brain tractography in 20 patients with bvFTD, 23 with age-matched EOAD, and 33 healthy elderly controls. To analyze the landscape of white matter abnormalities, we used a point-wise tract correspondence method along the 3D profiles of the tracts and quantified the pathway disruptions using common diffusion metrics – fractional anisotropy, mean, radial, and axial diffusivity. We tested the hypothesis that bvFTD and EOAD are associated with preferential degeneration in specific neural networks. We mapped axonal tract damage that was best detected with mean and radial diffusivity metrics, supporting our network hypothesis, highly statistically significant and more sensitive than widely studied fractional anisotropy reductions. From white matter diffusivity, we identified abnormalities in bvFTD in all 21 tracts of interest but especially in the bilateral uncinate fasciculus, frontal callosum, anterior thalamic radiations, cingulum bundles and left superior longitudinal fasciculus. This network of white matter alterations extends beyond the most commonly studied tracts, showing greater white matter abnormalities in bvFTD versus controls and EOAD patients. In EOAD, network alterations involved more posterior white matter – the parietal sector of the corpus callosum and parahipoccampal cingulum bilaterally. Widespread but distinctive white matter alterations are a key feature of the pathophysiology of these two forms of dementia.     

Blood-brain barrier integrity in the pathogenesis of Alzheimer’s disease

The blood–brain barrier (BBB) tightly controls the molecular exchange between the brain parenchyma and blood. Accumulated evidence from transgenic animal Alzheimer’s disease (AD) models and human AD patients have demonstrated that BBB dysfunction is a major player in AD pathology. In this review, we discuss the role of the BBB in maintaining brain integrity and how this is mediated by crosstalk between BBB-associated cells within the neurovascular unit (NVU). We then discuss the role of the NVU, in particular its endothelial cell, pericyte, and glial cell constituents, in AD pathogenesis. The effect of substances released by the neuroendocrine system in modulating BBB function and AD pathogenesis is also discussed. We perform a systematic review of currently available AD treatments specifically targeting pericytes and BBB glial cells. In summary, this review provides a comprehensive overview of BBB dysfunction in AD and a new perspective on the development of therapeutics for AD.     

Patterns of microRNA expression in normal and early Alzheimer’s disease human temporal cortex: white matter versus gray matter

MicroRNA (miRNA) expression was assessed in human cerebral cortical gray matter (GM) and white matter (WM) in order to provide the first insights into the difference between GM and WM miRNA repertoires across a range of Alzheimer's disease (AD) pathology. RNA was isolated separately from GM and WM portions of superior and middle temporal cerebral cortex (N = 10 elderly females, postmortem interval < 4 h). miRNA profiling experiments were performed using state-of-the-art Exiqon^© LNA-microarrays. A subset of miRNAs that appeared to be strongly expressed according to the microarrays did not appear to be conventional miRNAs according to Northern blot analyses. Some well-characterized miRNAs were substantially enriched in WM as expected. However, most of the miRNA expression variability that correlated with the presence of early AD-related pathology was seen in GM. We confirm that downregulation of a set of miRNAs in GM (including several miR-15/107 genes and miR-29 paralogs) correlated strongly with the density of diffuse amyloid plaques detected in adjacent tissue. A few miRNAs were differentially expressed in WM, including miR-212 that is downregulated in AD and miR-424 which is upregulated in AD. The expression of certain miRNAs correlates with other miRNAs across different cases, and particular subsets of miRNAs are coordinately expressed in relation to AD-related pathology. These data support the hypothesis that patterns of miRNA expression in cortical GM may contribute to AD pathogenetically, because the aggregate change in miRNA expression observed early in the disease would be predicted to cause profound changes in gene expression.     

Freezing of gait in Parkinson’s disease: gray and white matter abnormalities

Freezing of gait (FOG) is a disabling disorder that often affects Parkinson’s disease (PD) patients in advanced stages of the disease. To study structural gray matter (GM) and white matter (WM) changes in PD patients with and without FOG, twenty-one PD patients with FOG (PD-FOG), 16 PD patients without FOG (PD-nFOG) and 19 healthy subjects (HS) underwent a standardized MRI protocol. For the gray matter evaluation, cortical volume (CV), cortical thickness (CTh), and surface area (SA) were analyzed using the FreeSurfer pipeline. For the white matter evaluation, DTI images were analyzed using tracts constrained by underlying anatomy (TRACULA) toolbox in FreeSurfer. PD-FOG patients exhibited lower CTh than HS in the mesial surface of both cerebral hemispheres, including the superior frontal gyrus, paracentral lobule, posterior cingulate cortex, precuneus and pericalcarine cortex, and in the right dorsolateral prefrontal cortex. Moreover, significant WM changes were observed in PD-FOG patients in comparison with HS in the superior longitudinal fasciculus, uncinate fasciculus, cingulum cingulate gyrus and inferior longitudinal fasciculus (prevalently in the right hemisphere) and in the frontal radiations of the corpus callosum. DTI abnormalities in specific WM bundles correlated significantly with cognitive measures. The damage of multiple cortical areas involved in high-level gait control together with WM disruption between motor, cognitive and limbic structures may represent the anatomical correlate of FOG.     

A voxel-based morphometric study of cortical gray matter volume changes in Alzheimer’s disease with white matter hyperintensities

White matter hyperintensity (WMH) is commonly detected in patients with Alzheimer’s disease (AD), but its role in cortical impairment is unclear. This study investigated the effects of WMH on gray matter (GM) volume in patients with AD. We consecutively enrolled 84 patients with AD and 35 normal controls, who underwent brain MRI and were then classified according to WMH grade, based on a combination of deep white matter hyperintensity (DWMH) and periventricular white matter hyperintensity (PVWMH). The volume changes in GM were observed using voxel-based morphometry. It was found that global GM volume decreased with increasing WMH. Regional atrophies were in the dorsolateral frontal lobes, orbitofrontal gyri and insula (false discovery rate [FDR], p < 0.01). After controlling for PVWMH, DWMH affected cortical atrophy in the frontal lobe, insula and precuneus (FDR, p < 0.05), but PVWMH did not. Thus, WMH in AD is associated with GM volume reduction, especially in the frontal lobe, and DWMH is independently related to cortical atrophy.     

The ε4 genotype of apolipoprotein E and white matter integrity in Alzheimer's disease

BackgroundIn this multicenter study, we investigated a possible association between the APOE ε4 allele and white matter (WM) integrity in Alzheimer's disease (AD) using diffusion tensor imaging (DTI).MethodsWe analyzed fractional anisotropy (FA) and mean diffusivity (MD) as indices of WM integrity in 70 AD patients (35 APOE ε4 carriers, 35 noncarriers) and 56 healthy control (HC) subjects (28 APOE ε4 carriers, 28 noncarriers). APOE ε4 carriers and noncarriers were matched for age and gender within each diagnostic group.ResultsWe found significant effects of diagnosis (P_corrected < .05 [FWE]; i.e., smaller FA values and larger MD values in AD patients compared with HCs) and significant effects (P < .001) of APOE ε4 carrier status on MD in HCs but not in AD subjects.ConclusionsThe results indicate that APOE ε4 has a moderate effect on WM integrity in HCs, but no effect on WM integrity in manifest AD.     

Astrocyte and Alzheimer’s disease

The past several decades have given rise to more insights into the role of astrocytes in normal brain function and diseases. Astrocytes elicit an effect which may be neuroprotective or deleterious in the process of Alzheimer’s disease (AD). Impairments in astrocytes and their other functions, as well as physiological reactions of astrocytes to external injury, can trigger or exacerbate hyperphosphorylated tau and amyloid-beta (Aβ) pathologies, leading to the formation of both amyloid plaques and neurofibrillary tangles (NFTs), as well as neuronal dysfunction. This review addresses the involvement of astrocytes in the Aβ pathology, where the main mechanisms include the generation and clearance of Aβ, and the formation of NFTs. It is also discussed that metabolic dysfunction from astrocytes acts as an initiating factor in the pathogenesis of AD and a contributor to the onset and development of clinical presentation in AD.     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

Diet and Alzheimer’s disease

Alzheimer’s disease (AD) is increasing in prevalence. There are no known preventive or curative measures. There is evidence that oxidative stress, homocysteinerelated vitamins, fats, and alcohol have a role in the pathogenesis of AD. Some epidemiologic studies suggest that higher dietary intake of antioxidants, vitamins B₆, B₁₂, and folate, unsaturated fatty acids, and fish are related to a lower risk of AD, but reports are inconsistent. Modest to moderate alcohol intake, particularly wine, may be related to a lower risk of AD. The Mediterranean diet may also be related to lower AD risk. However, randomized clinical trials of supplements of vitamins E, B₁₂, B₆, and folate have shown no cognitive benefit, and randomized trials for other nutrients or diets in AD are not available. The existing evidence does not support the recommendation of specific supplements, foods, or diets for the prevention of AD.     

Treatments in Alzheimer’s disease

Journal of Neurology -     

Topological changes in white matter connectivity network in patients with Parkinson’s disease and depression

Brain Imaging and Behavior - Depression is the most common non-motor symptom accompanying Parkinson’s disease (PD) with high prevalence but unclear pathophysiological mechanism. Relatively...     

Oral frailty and neurodegeneration in Alzheimer’s disease

Frailty is a critical intermediate status of the aging process with a multidimensional and multisystem nature and at higher risk for adverse health-related outcomes,including falls,disability,hospitalizations,institutionalization,mortality,dementia,and Alzheimer’s disease.Among different frailty phenotypes,oral frailty has been recently suggested as a novel construct defined as a decrease in oral function with a coexisting decline in cognitive and physical functions.We briefly reviewed existing evidence on operational definitions of oral frailty,assessment and screening tools,and possible relationships among oral frailty,oral microbiota,and Alzheimer’s disease neurodegeneration.Several underlying mechanism may explain the oral health-frailty links including undernutrition,sarcopenia linked to both poor nutrition and frailty,psychosocial factors,and the chronic inflammation typical of oral disease.Oral microbiota may influence Alzheimer’s disease risk through circulatory or neural access to the brain and the interplay with periodontal disease,often causing tooth loss also linked to an increased Alzheimer’s disease risk.On this bases,COR388,a bacterial protease inhibitor targeting Porphyromonas gingivalis implicated in periodontal disease,is now being tested in a double-blind,placebocontrolled Phase II/III study in mild-to-moderate Alzheimer’s disease.Therefore,oral status may be an important contributor to general health,including Alzheimer’s disease and latelife cognitive disorders,suggesting the central role of preventive strategies targeting the novel oral frailty phenotype and including maintenance and improvement of oral function and nutritional status to reduce the burden of both oral dysfunction and frailty.     

Depression in Alzheimer’s disease and other dementias

Much of our current knowledge about depression in Alzheimer’s disease and other dementias is based on the 1991 National Instiute of Health Consensus Development Panel on the Diagnosis and Treatment of Depression in Late Life, and its subsequent 1997 update. However, much research has taken place since these reports. This article summarizes this research, particularly research that has taken place in the past year. Comorbid depression is common in all types of dementia. It may, however, appear to be different from classic depression. Unlike classic depression, the depression found in dementia may result from anatomic damage to the brain. This is most clearly demonstrated in vascular depression. The implications of this are many. Treatments for depression are designed for classic depression. For those with vascular depression (and other depressions associated with dementia) treatments may not be as efficacious. Newer strategies, including agents not commonly thought of as antidepressants, may be needed.     

Amyloid metabolism and secretases in Alzheimer’s disease

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid fibrils composed of the amyloid beta-protein (A beta) in senile plaques. A beta is derived from the beta-amyloid precursor protein (APP) after beta- and gamma-secretase cleavages. beta-secretase was recently identified to be a membrane-anchored aspartyl protease that is widely distributed in subcellular compartments, including Golgi, trans-Golgi network, and endosomes. Although definitive identification of gamma-secretase will require reconstituting its activity in vitro, mounting evidence suggests that gamma-secretase is an unusual intramembrane-cleaving aspartyl protease. Two intramembranous aspartate residues in presenilin (PS) are absolutely required for A beta generation. Three classes of gamma-secretase inhibitors can directly bind to PS, strongly supporting the hypothesis of PSI as gamma-secretase. These results provide the molecular basis for therapeutic interventions that reduce A beta accumulation in AD patients by inhibiting beta- or gamma-secretase.     

Topographical and cytopathological lesion analysis of the white matter in Binswanger’s disease brains

The purpose of the present study was to document the topographical and cytopathological lesions in the white matter (WM) of Binswangers disease (BD) brains. Subcortical WM lesions in each lobe and fiber bundle lesions related to the medial thalamic and hippocampal structures in clinicopathologically proven BD brains were evaluated by Klüver-Barrera staining using a grading score. Lesions in the frontal subcortical WM of BD brains, brains from non-neurological patients, and brains with cerebral hemorrhage or large cortical infarcts were also examined immunohistochemically using molecular markers for axonal flow damage: amyloid precursor protein (APP); and for demyelinating axonopathy: encephalitogenic peptide (EP). Our results indicated that the WM lesions in BD were significantly more prominent in the frontal periventricular and subcortical regions as compared with other subcortical WM lesions, in the order of the parietal, occipital and temporal lobes. Fiber bundle lesions in the capsular genu, including the anterior thalamic peduncle, were also significantly more prominent in BD brains as compared with the other bundle lesions. Furthermore, the frequency of damaged nerve fibers labeled by the EP antiserum and APP immunoreactive fibers was significantly higher in BD brains as compared with the control brains. The grading scores for the WM damage correlated significantly with those for the APP and EP immunoreactive fibers in all brains, including the control brains. The axonal damage in the frontal WM lesions of the BD brains was clearly revealed in our study using immunohistochemistry for APP and EP.     

Alzheimer’s disease

Psychiatric Quarterly - It would appear, on the basis of this study, that Alzheimer’s disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly...