Cerebral Amyloid Angiopathy,Subcortical White Matter Disease and Dementia: Literature Review and Study in OPTIMA

Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEε4 carriers and a significant negative relationship in ApoEε2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain.     

Age‐Associated White Matter Lesions: The MRC Cognitive Function and Ageing Study

Cerebral white matter lesions (WML) are common in the aging brain and are associated with dementia and depression. They are associated with vascular risk factors and small vessel disease, suggesting an ischemic origin, but recent pathology studies suggest a more complex pathogenesis. Studies using samples from the population‐representative Medical Research Council Cognitive Function and Ageing Study neuropathology cohort used post‐mortem magnetic resonance imaging to identify WML for further study. Expression of hypoxia‐related molecules and other injury and protective cellular pathways in candidate immunohistochemical and gene expression microarray studies support a role for hypoxia/ischemia. However, these approaches also suggest that immune activation, blood–brain barrier dysfunction, altered cell metabolic pathways and glial cell injury contribute to pathogenesis. These abnormalities are not confined to WML, but are also found in apparently normal white matter in brains with lesions, suggesting a field effect of white matter abnormality within which lesions arise. WML are an active pathology with a complex pathogenesis that may potentially offer a number of primary and secondary intervention targets.     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.     

Cortical somatostatin-like immunoreactivity in cases of Alzheimer's disease and senile Dementia of the Alzheimer type

The activity of choline acetyltransferase (ChAT) and the concentration of somatostatin-like immunoreactive material (SLI) have been measured in 8 brain regions from 12 normal individuals and 12 cases of presenile and senile dementia of the Alzheimer type. ChAT activity was significantly lower in all 8 brain regions of demented patients and the SLI concentration was significantly reduced in 7 of the 8. There were correlations between the extent of the reductions of ChAT activity and SLI concentration in four brain regions, and a greater reduction of parietal cortex SLI in younger patients than in the more elderly.     

Decreased oligodendrocyte nuclear diameter in Alzheimer's disease and lewy body dementia

To better understand the pathogenesis of dementia, it is important to understand histopathologic changes in neurodegenerative diseases because they might highlight key aspects of the degenerative process. In this study, the nuclear diameter of neurons and oligodendrocytes in selected temporal lobe areas were determined in autopsy tissue sections from patients with Alzheimer's disease (AD), Lewy body dementia (LBD) and controls. Our morphometric studies targeted neurons in the CA4 region of the pyramidal cell layer of the hippocampus, neurons in the granular layer of the dentate gyrus and oligodendrocytes in parahippocampal white matter. Mean neuronal nuclear diameters were not different among the studied groups. However, our studies revealed a statistically significant reduction of mean oligodendrocyte nuclear diameter in AD and LBD relative to controls. The reduction of the mean nucleus diameter of oligodendrocytes in LBD was independent of the presence of associated AD pathology in LBD. These findings for the first time identify decreased oligodendrocyte nucleus diameter as a morphologic feature of AD and LBD and may lead to a better understanding of the role of oligodendrocytes in AD and LBD pathogenesis.     

White matter microstructural damage in Alzheimer's disease at different ages of onset

White matter (WM) microstructural damage and its relationship with cortical abnormalities were explored in early-onset Alzheimer's disease (EOAD) compared with late-onset AD (LOAD) patients. Structural and diffusion tensor magnetic resonance images were obtained from 22 EOAD patients, 35 LOAD patients, and 40 healthy controls. Patterns of WM microstructural damage and cortical atrophy, as well as their relationships, were assessed using tract-based spatial statistics, tractography and voxel-based morphometry. Compared with LOAD, EOAD patients had a more severe and distributed pattern of WM microstructural damage, in particular in the posterior fibers of cingulum and corpus callosum. In both groups with Alzheimer's disease, but especially in LOAD patients, correlations between cingulum and corpus callosum fractional anisotropy and parietal, temporal, and frontal cortical volumes were found. In conclusion, WM microstructural damage is more severe in EOAD compared with LOAD patients. Such damage follows different patterns of topographical distribution in the 2 patient groups.     

Stereological Investigation of Age‐Related Changes of the Capillaries in White Matter

We, for the first time, investigated the age‐related changes of the capillaries in white matter using immunohistochemistry and stereological techniques. Ten young female (7 months) and 10 aged female (27 months) rats were used. The total length, total volume, and total surface area of the capillaries in white matter of aged rats were all significantly lower than those of young rats. The age‐related changes of the capillaries in white matter may have important implications for age‐related white matter atrophy and age‐related cognitive impairments. Anat Rec 293:1400–1407, 2010. © 2010 Wiley‐Liss, Inc.     

TDP‐43 pathology in Alzheimer's disease,dementia with Lewy bodies and ageing

Intracellular inclusions consisting of TAR DNA binding protein‐43 (TDP‐43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP‐43 in AD staging scheme. This scheme has not been applied to the assessment of TDP‐43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP‐43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post‐mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP‐43 and staged according to the TDP‐43 in AD staging scheme. TDP‐43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP‐43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP‐43 pathology and higher TDP‐43 in AD stage, suggesting that this type of TDP‐43 pathology may partly be an age‐associated phenomenon. Significantly higher prevalence of TDP‐43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP‐43 pathology. The validity of the TDP‐43 in AD staging scheme is not limited to AD and should be applied to assess TDP‐43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP‐43 pathology in age associated neurodegeneration.     

Diffusion MRI detects early brain microstructure abnormalities in 2‐month‐old 3×Tg‐AD mice

The 3×Tg‐AD mouse is one of the most studied animal models of Alzheimer's disease (AD), and develops both amyloid beta deposits and neurofibrillary tangles in a temporal and spatial pattern that is similar to human AD pathology. Additionally, abnormal myelination patterns with changes in oligodendrocyte and myelin marker expression are reported to be an early pathological feature in this model. Only few diffusion MRI (dMRI) studies have investigated white matter abnormalities in 3×Tg‐AD mice, with inconsistent results. Thus, the goal of this study was to investigate the sensitivity of dMRI to capture brain microstructural alterations in 2‐month‐old 3×Tg‐AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K_┴) were found to be significantly lower in 3×Tg‐AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D_┴) were found to be elevated. In the fornix, K_┴ was lower for 3×Tg‐AD mice; in the dorsal hippocampus MD and D_┴ were elevated, as were FA, MD, and D_┴ in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3×Tg‐AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3×Tg‐AD mice compared with the age‐matched controls. Our results demonstrate that dMRI is able to detect widespread, significant early brain morphological abnormalities in 2‐month‐old 3×Tg‐AD mice.     

Age‐Related Changes of the Oligodendrocytes in Rat Subcortical White Matter

The age‐related changes, of the oligodendrocytes in rat subcortical white matter, were investigated in this study. The oligodendrocytes in subcortical white matter were labeled with anti‐2′,3′‐cyclic nucleotide 3′‐phosphodiesterase antibody (anti‐CNPase antibody, a specific marker of oligodendrocytes). The total number of CNPase⁺ cells was estimated with an unbiased stereological technique, the optical fractionator. In this study, we found that the total number of CNPase⁺ cells in the young male rats and aged male rats was 14.4 ± 1.2 × 10⁶ and 9.0 ± 1.0 × 10⁶, respectively. The total number of the CNPase⁺ cells in the subcortical white matter of aged rats was significantly decreased by 37.5% when compared to young male rats. This study demonstrated that there was an aged‐related decrease of the oligodendrocytes in subcortical white matter. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

No change in total length of white matter fibers in Alzheimer's disease

White matter changes have been reported as part of Alzheimer dementia. To investigate this, the total subcortical myelinated nerve fiber length was estimated in postmortem brains from eight females (age 79-88 years) with severe Alzheimer's disease (AD) and compared with brains from 10 female control subjects (age 74-92 years). A stereological method for estimating myelinated brain fibers includes sampling systematically, randomly from the white matter, and counting fibers in unbiased counting frames using light microscopy at approximately 6000x magnification. The diameter of each counted fiber was measured to obtain the diameter distribution of myelinated fibers in both groups. The mean total myelinated fiber length was 81,554 km in the AD group and 78,896 km in the control group (P=0.63). All other measured parameters were also unaffected in the AD brains: The mean fiber length density was 248 km/cm3 in the AD group and 247 km/cm3 in the control group; the volume of white matter was 329 cm3 (AD) and 321 cm3 (control) and the volume density of myelinated fibers to white matter tissue volume was 0.30 in AD group and 0.31 in the control group. This is the first study of subcortical brain white matter fiber length using a stereological method on postmortem brains from AD patients and control subjects.     

Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD‐DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α‐synuclein pathology. We found moderate‐severe vascular changes and high‐vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub‐set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α‐synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging‐related neurodegenerative disorders and characterize their end‐stage clinical syndromes.     

Assessment of activation of the plasma kallikrein-kinin system in frontal and temporal cortex in Alzheimer's disease and vascular dementia

Decreased cerebral blood flow and blood-brain barrier disruption are features of Alzheimer's disease (AD). The plasma kallikrein-kinin system modulates cerebrovascular tone through release of vasoactive bradykinin (BK). Cerebroventricular infusion of Aβ1-40 enhances BK release, suggesting that the activity of this system may be elevated in AD. We investigated the profile of the activating protease of this system, plasma kallikrein (PK), in frontal and temporal brain tissue from postmortem confirmed cases of AD, vascular dementia (VaD), and controls. Measurements of neuron specific enolase messenger ribonucleic acid (mRNA) and protein were used to adjust for neuronal loss. Adjusted PK mRNA was significantly increased in the frontal cortex in AD, and the frontal and temporal cortex in VaD. Similar trends were seen for PK protein level in AD and VaD. PK activity was significantly increased in the frontal and temporal cortex in AD. Increased PK activity in AD is likely to contribute to increased BK release and may thereby influence cerebral blood flow and vascular permeability.     

Enriched Environment and White Matter in Aging Brain

Normal aging is commonly associated with decreased cognitive functions, which could be conspicuously alleviated by enriched environment (EE) with physical, social, and sensory stimuli, suggesting that aging brain still has intriguing plasticity. Multiple researches have been carried out to explore the structural and the molecular changes in aging brain, which would be considered for evidences that EE regulated brain plasticity. Because there is no significant neuron loss in aging cerebral cortex and the white matter is crucial for cognitive functions, this review focused on the age‐related white matter changes and the effects of EE on aged white matter. Data from our stereology laboratory revealed that age‐related spatial memory declines had more to do with white matter alterations, which were due to marked demyelination and loss of oligodendrocytes in the white matter. We also demonstrated that EE recovered spatial memory impairment and increased white matter volume by promoting marked remyelination in aged brain. This review approached the issue that EE might contribute to normal aging and be beneficial for those suffering from demyelinated diseases. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Cerebral Hypoperfusion and the Energy Deficit in Alzheimer's Disease

There is a perfusion deficit in Alzheimer's disease (AD), commencing in the precuneus and spreading to other parts of the cerebral cortex. The deficit anticipates the development of dementia, contributes to brain damage, and is caused by both functional and structural abnormalities of the cerebral vasculature. Most of the abnormalities are probably secondary to the accumulation of Aβ but the consequent hypoperfusion may, in turn, increase Aβ production. In the early stages of disease, abnormalities that cause vasoconstriction predominate. These include cholinergic vascular denervation, inhibition of endothelial nitric oxide synthase, increased production of endothelin‐1 production and possibly also of angiotensin II. Patients with AD also have an increased prevalence of structural disease of cerebral microvessels, particularly CAA and capillary damage, and particularly in the later stages of disease these are likely to make an important contribution to the cerebral hypoperfusion. The metabolic abnormalities that cause early vascular dysfunction offer several targets for therapeutic intervention. However, for intervention to be effective it probably needs to be early. Prolonged cerebral hypoperfusion may induce compensatory circulatory changes that are themselves damaging, including hypertension and small vessel disease. This has implications for the use of antihypertensive drugs once there is accumulation of Aβ within the brain.     

Investigating the role of rare coding variability in Mendelian dementia genes (APP,PSEN1, PSEN2, GRN,MAPT, and PRNP) in late-onset Alzheimer's disease

The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.     

Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

Epidemiological studies reveal that metabolic disorders, and specifically type 2 diabetes (T2D), are relevant risk factors to develop Alzheimer's disease (AD) and vascular dementia (VaD), the most common causes of dementia. AD patients are in a tremendous need of new therapeutic options because of the limited success of available treatments. Natural polyphenols, and concretely Mangifera indica Linn extract (MGF), have been reported to have antiinflammatory, antioxidant and antidiabetic activities. The role of MGF in central complications associated with T2D, after long‐term treatment of db/db mice with MGF was analyzed. Metabolic parameters (body weight, glucose and insulin levels) as well as central complications including brain atrophy, inflammatory processes, spontaneous bleeding, tau phosphorylation and cognitive function in db/db mice treated with MGF for 22 weeks were assessed. MGF limits body weight gain in obese db/db mice. Insulin and C‐peptide levels, indicative of pancreatic function, were longer maintained in MGF‐treated animals. MGF reduced central inflammation by lowering microglia burden, both in the cortex and the hippocampus. Likewise, central spontaneous bleeding was significantly reduced in db/db mice. Cortical and hippocampal atrophy was reduced in db/db mice and tau hyperphosphorylation was lower after MGF treatment, resulting in partial recovery of learning and memory disabilities. Altogether, the data suggested that MGF treatment may provide a useful tool to target different aspects of AD and VaD pathology, and could lead to more effective clinical therapies for the prevention of metabolic related central complications associated with AD and VaD.     

White matter hyperintensities predict amyloid increase in Alzheimer's disease

Impaired amyloid clearance probably contributes to increased amyloid deposition in sporadic Alzheimer's disease (AD). Diminished perivascular drainage due to cerebral small-vessel disease (CSVD) has been proposed as a cause of reduced amyloid clearance. White matter hyperintensities (WMHs) are considered to reflect CSVD and can be measured using fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Amyloid deposition can be determined in vivo using Pittsburgh compound B ([(11)C]PiB) positron emission tomography (PET). We aimed to elucidate the association between WMH and the progression of amyloid deposition in patients with AD. Twenty-two patients with probable AD underwent FLAIR-MRI and [(11)C]PiB-PET examinations at baseline (BL) and after a mean follow-up (FU) interval of 28 months. The relationship between BL-WMH and the progression of cerebral amyloid between BL and FU was examined using a regions-of-interest (ROI) approach. The region-specific variability of this relationship was analyzed using a voxel-based method. The longitudinal analysis revealed a statistically significant association between the amount of BL-WMH and the progression of amyloid load between BL and FU (p = 0.006, adjusted R(2) = 0.375, standardized coefficient β = 0.384). The association was particularly observed in parieto-occipital regions and tended to be closer in regions adjacent to the brain surface. According to our knowledge, this is the first in vivo study in human being supporting the hypothesis that impaired amyloid clearance along perivascular drainage pathways may contribute to β-amyloid deposition in sporadic AD. The extent of WMH might be a relevant factor to be assessed in antiamyloid drug trials.     

Ethical issues in susceptibility genetic testing for late‐onset neurodegenerative diseases

Genome‐wide association studies have revolutionized our understanding of the genetic architecture of complex traits and diseases over the last decade. This knowledge is enabling clinicians, researchers, and direct‐to‐consumer genetics companies to conduct disease susceptibility testing based on powerful methods such as polygenic risk scoring. However, these technologies raise a set of complex ethical, legal, social, and policy considerations. Here we review and discuss a series of ethical dilemmas associated with susceptibility genetic testing for the two most common late‐onset neurodegenerative diseases, Alzheimer's and Parkinson's disease, including testing in asymptomatic individuals. Among others, these include informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. Importantly, appropriate counseling is a deciding factor for the ethical soundness of genetic testing, which poses a challenge for the regulation of these tests and the training of healthcare professionals. As genetic knowledge about these diseases continues growing and genetic testing becomes more widespread, it is increasingly important to raise awareness among researchers, medical practitioners, genetic counselors, and decision makers about the ethical, legal, and social issues associated with genetic testing for polygenic diseases.