Effects of age and Alzheimer's disease on hippocampal subfields

Growing interest has developed in hippocampal subfield volumetry over the past few years and an increasing number of studies use the automatic segmentation algorithm implemented in FreeSurfer. However, this approach has not been validated on standard resolution T1‐weighted magnetic resonance (MR) as used in most studies. We aimed at comparing hippocampal subfield segmentation using FreeSurfer on standard T1‐weighted images versus manual delineation on dedicated high‐resolution hippocampal scans. Hippocampal subfields were segmented in 133 individuals including 98 cognitively normal controls aged 19–84 years, 17 mild cognitive impairment and 18 Alzheimer's disease (AD) patients using both methods. Intraclass correlation coefficients (ICC) and Bland–Altman plots were computed to assess the consistency between both methods, and the effects of age and diagnosis were assessed from both measures. Low to moderate ICC (0.31–0.74) were found for the subiculum and other subfields as well as for the whole hippocampus, and the correlations were very low for cornu ammonis (CA)1 (<0.1). FreeSurfer CA1 volume estimates were found to be much lower than those obtained from manual segmentation, and this bias was proportional to the volume of this structure so that no effect of age or AD could be detected on FreeSurfer CA1 volumes. This study points to the differences in the anatomic definition of the subfields between FreeSurfer and manual delineation, especially for CA1, and provides clue for improvement of this automatic technique for potential clinical application on standard T1‐weighted MR. Hum Brain Mapp 36:463–474, 2015. © 2014 Wiley Periodicals, Inc.     

Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease

Alzheimer''s disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer''s disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.     

Relations between personality changes and cerebrospinal fluid biomarkers of Alzheimer's disease pathology

Specific changes in personality profiles may represent early non-cognitive symptoms of Alzheimer's disease (AD). Evaluating the subject's personality changes may add significant clinical information, as well as help to better understand the interaction between personality change, cognitive decline, and cerebral pathology. With this study we aimed to describe the relationship between personality changes and cerebrospinal fluid (CSF) markers of AD pathology at early clinical stages of the disease. One hundred and ten subjects, of whom 66 cognitively impaired patients (57 with mild cognitive impairment (MCI), and 9 with mild dementia) and 44 healthy controls, had neuropsychological examination as well as lumbar puncture to determine concentrations of CSF biomarkers of AD pathology (amyloid beta_1-42 (Aβ_1-42), phosphorylated tau (ptau-181), and total-tau (tau)). The Revised NEO Personality Inventory (NEO-PI-R) was administered twice, once to evaluate subjects' current personality and once to assess personality traits retrospectively 5 years before evaluation. Subjects with an AD CSF biomarker profile showed significant increase in neuroticism and decrease in conscientiousness over time as compared to non-AD CSF biomarker group. In regression analysis controlling for global cognition as measured by the MMSE score, increasing neuroticism and decreasing extraversion, openness to experience and conscientiousness were associated with lower Aβ_1-42 concentrations but not with tau and ptau-181 concentrations. Our findings suggest that early and specific changes in personality are associated with cerebral AD pathology. Concentrations of CSF biomarkers, additionally to severity of the cognitive impairment, significantly contribute in predicting specific personality changes.     

Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease

The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.     

Vitamin B12 levels in serum and cerebrospinal fluid of people with Alzheimer's disease

Vitamin B12 levels in the serum and the cerebrospinal fluid (CSF) were compared between patients with Alzheimer's disease (AD) and senile dementia of Alzheimer's type (SDAT) (AD group) and patients with multi-infarct dementia (MID group). The B12 levels in the serum and the CSF were 742 +/- 359 pg/ml and 28 +/- 7 pg/ml (mean +/- SD), respectively, in the AD group, and 962 +/- 254 pg/ml and 50 +/- 26 pg/ml, respectively, in the MID group. CSF B12 levels were significantly lower in the AD group than in the MID group, whereas the serum levels were not different. At the same time, the serum levels of almost all patients were within the normal range, whereas the CSF levels were 25 pg/ml or lower in 10 of 12 AD patients. Therefore, this low level in the CSF is considered to be a characteristic finding in the AD group.     

Spatial correlation maps of the hippocampus with cerebrospinal fluid biomarkers and cognition in Alzheimer's disease: A longitudinal study

This study is an observational study that takes the existing longitudinal data from Alzheimer''s disease Neuroimaging Initiative to examine the spatial correlation map of hippocampal subfield atrophy with CSF biomarkers and cognitive decline in the course of AD. This study included 421 healthy controls (HC), 557 patients of stable mild cognitive impairment (s‐MCI), 304 Alzheimer''s Disease (AD) patients, and 241 subjects who converted to be AD from MCI (c‐MCI), and 6,525 MRI scans in a period from 2004 to 2019. Our findings revealed that all the hippocampal subfields showed their accelerated atrophy rate from cognitively normal aging to stable MCI and AD. The presubiculum, dentate gyrus, and fimbria showed greater atrophy beyond the whole hippocampus in the HC, s‐MCI, and AD groups and corresponded to a greater decline of memory and attention in the s‐MCI group. Moreover, the higher atrophy rates of the subiculum and CA2/3, CA4 were also associated with a greater decline in attention in the s‐MCI group. Interestingly, patients with c‐MCI showed that the presubiculum atrophy was associated with CSF tau levels and corresponded to the onset age of AD and a decline in attention in patients with c‐MCI. These spatial correlation findings of the hippocampus suggested that the hippocampal subfields may not be equally impacted by normal aging, MCI, and AD, and their atrophy was selectively associated with declines in specific cognitive domains. The presubiculum atrophy was highlighted as a surrogate marker for the AD prognosis along with tau pathology and attention decline.     

Dynamic changes of anandamide in the cerebrospinal fluid of Parkinson's disease patients

A correct balance between endocannabinoid and dopamine‐dependent systems is believed to underlie physiological motor control. We measured the levels of the endocannabinoid anandamide in the cerebrospinal fluid of Parkinson's disease (PD) patients. Subjects were divided into three groups: newly diagnosed de novo patients, subjects undergoing drug withdrawal, and patients under pharmacological therapy. These groups were compared to age‐matched control subjects. Anandamide levels in untreated patients were more than doubled as compared to controls. However, chronic dopaminergic replacement restored control anandamide levels. Abnormal anandamide increase might reflect a compensatory mechanism occurring in course of PD, aimed at normalizing dopamine depletion. © 2010 Movement Disorder Society     

Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus

Lysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid‐β. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown. This study aimed to quantify lysosomal vesicles at amyloid plaques in the human hippocampus. Lysosome‐associated membrane protein 1 (LAMP1)‐positive vesicles accumulated in both diffuse (Aβ42‐positive/AT8‐negative) and neuritic (Aβ42‐positive/AT8‐positive) plaques in all regions were analysed. In contrast to mouse models of Alzheimer's disease, however, not all amyloid plaques accumulated LAMP1‐positive lysosomal vesicles. Even at neuritic plaques, LAMP1 immunoreactivity was more abundant than phospho‐tau (AT8). Further, lysosomal vesicles colocalised weakly with phospho‐tau such that accumulation of lysosomal vesicles and phospho‐tau appeared to be spatially distinct events that occurred within dystrophic neurites. This quantitative study shows that diffuse plaques, as well as neuritic plaques, contain LAMP1 immunoreactivity in the human hippocampus.     

Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease

Brain insulin resistance (IR), which depends on insulin‐receptor‐substrate‐1 (IRS‐1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312‐IRS‐1 (ineffective insulin signaling) and lower p‐panTyr‐IRS‐1 (effective insulin signaling) in neural origin‐enriched plasma exosomes of AD patients vs. controls. Here, we hypothesized that these exosomal biomarkers associate with brain atrophy in AD. We studied 24 subjects with biomarker‐supported probable AD (low CSF Aβ₄₂). Exosomes were isolated from plasma, enriched for neural origin using immunoprecipitation for L1CAM, and measured for pSer₃₁₂‐ and p‐panTyr‐IRS‐1 phosphotypes. MPRAGE images were segmented by brain tissue type and voxel‐based morphometry (VBM) analysis for gray matter against pSer₃₁₂‐ and p‐panTyr‐IRS‐1 was conducted. Given the regionally variable brain expression of IRS‐1, we used the Allen Brain Atlas to make spatial comparisons between VBM results and IRS‐1 expression. Brain volume was positively associated with P‐panTyr‐IRS‐1 and negatively associated with pSer₃₁₂‐IRS‐1 in a strikingly similar regional pattern (bilateral parietal‐occipital junction, R middle temporal gyrus). This volumetric association pattern was spatially correlated with Allen Human Brain atlas normal brain IRS‐1 expression. Exosomal biomarkers of brain IR are thus associated with atrophy in AD as could be expected by their pathophysiological roles and do so in a pattern that reflects regional IRS‐1 expression. Furthermore, neural‐origin plasma exosomes may recover molecular signals from specific brain regions. Hum Brain Mapp 38:1933–1940, 2017. © 2017 Wiley Periodicals, Inc.     

Limited expression of heparan sulphate proteoglycans associated with Aβ deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease

N. M. Timmer, M. K. Herbert, J. W. Kleinovink, A. J. Kiliaan, R. M. W. de Waal and M. M. Verbeek (2010) Neuropathology and Applied Neurobiology 36, 478–486
Limited expression of heparan sulphate proteoglycans associated with Aβ deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease Aims: Alzheimer's disease (AD) is characterized by deposition of the amyloid beta (Aβ) peptide in brain parenchyma and vasculature. Several proteins co‐deposit with Aβ, including heparan sulphate proteoglycans (HSPG). HSPG have been suggested to contribute to Aβ aggregation and deposition, and may influence plaque formation and persistence by stimulating Aβ fibrillization and by protecting Aβ against degradation. Mouse models for AD, expressing the human amyloid precursor protein (APP), produce Aβ deposits similar to humans. These models may be used to study disease pathology and to develop new therapeutic interventions. We aimed to investigate whether co‐deposition of HSPG in AD brains can be replicated in the APPswe/PS1dE9 mouse model for AD and if a temporal association of HSPG with Aβ exists. Methods: We studied the co‐deposition of several HSPG and of the glycosaminoglycan side chains of HSPG in the APPswe/PS1dE9 model at different ages by immunohistochemistry. Results: We found that, although APPswe/PS1dE9 mice did develop severe Aβ pathology with age, co‐deposition of HS glycosaminoglycan chains and the various HSPG (agrin, perlecan and glypican‐1) was scarce (<10–30% of the Aβ deposits were stained). Conclusions: Our data suggest that the molecular composition of Aβ deposits in the APPswe/PS1dE9 mouse, with respect to the several HSPG investigated in this study, does not accurately reflect the human situation. The near absence of HSPG in Aβ deposits in this transgenic mouse model may, in turn, hinder the translation of preclinical intervention studies from mice to men.     

Cerebrospinal fluid Tau/α‐synuclein ratio in Parkinson's disease and degenerative dementias

Although alpha‐synuclein is the main constituent of Lewy bodies, cerebrospinal fluid determination on its own does not seem fundamental for the diagnosis of synucleinopathies. We evaluated whether the combination of classical biomarkers, Aβ_1–42, total tau, phosphorylated tau, and α‐synuclein can improve discrimination of Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, and frontotemporal dementia. Aβ_1–42, total tau, phosphorylated tau, and α‐synuclein were measured in a series of patients with Parkinson's disease (n = 38), dementia with Lewy bodies (n = 32), Alzheimer's disease (n = 48), frontotemporal dementia (n = 31), and age‐matched control patients with other neurological diseases (n = 32). Mean α‐synuclein levels in cerebrospinal fluid were significantly lower in the pathological groups than in cognitively healthy subjects. An inverse correlation of α‐synuclein with total tau (r = ?0.196, P < .01) was observed. In the group of patients with Parkinson's disease, Aβ_1–42, total tau, and phosphorylated tau values were similar to controls, whereas total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios showed the lowest values. Cerebrospinal fluid α‐synuclein alone did not provide relevant information for Parkinson's disease diagnosis, showing low specificity (area under the curve, 0.662; sensitivity, 94%; specificity, 25%). Instead, a better performance was obtained with the total tau/α‐syn ratio (area under the curve, 0.765; sensitivity, 89%; specificity, 61%). Combined determination of α‐synuclein and classical biomarkers in cerebrospinal fluid shows differential patterns in neurodegenerative disorders. In particular, total tau/α‐synuclein and phosphorylated tau/α‐synuclein ratios can contribute to the discrimination of Parkinson's disease. © 2011 Movement Disorder Society     

Vascular risk factors are associated with longitudinal changes in cerebrospinal fluid tau markers and cognition in preclinical Alzheimer's disease

IntroductionVascular factors increase the risk of Alzheimer's disease (AD). We investigated the associations between such factors, longitudinal AD cerebrospinal fluid biomarkers, and cognition.Methods433 cognitively normal participants were classified into four biomarker groups using their baseline amyloid (A+/−) and tau status (T+/−). 184 participants had undergone serial cerebrospinal fluid collection. Frequencies of risk factors and the Framingham Risk Score (FRS) were compared, and we tested the influence of risk factors on change in biomarker concentrations and cognition.ResultsThe absence of obesity, presence of hypertension, and a high FRS were associated with an increase in tau levels, particularly in A+T+ individuals. Risk factors were not associated with amyloid. Depression was associated with higher cognitive scores, whereas high FRS was associated with lower scores and a faster decline.DiscussionOur results demonstrate that vascular risk factors may enhance neurodegeneration but not amyloid accumulation in preclinical AD.     

Macrophage colony stimulating factor is associated with excretion of amyloid‐β peptides from cerebrospinal fluid to peripheral blood

Background: The process of aggregation of brain amyloid‐β peptides (Aβ) is thought to be associated with the pathogenesis of Alzheimer's disease (AD). Amyloid‐β peptides are produced by sequential endoproteolysis by β‐site amyloid‐β protein precursor‐cleaving enzyme (BACE) followed by presenilin (PS)/γ‐secretase. There are several species of Aβ due to cleavage diversity of PS/γ‐secretase. The predominant species in human cerebrospinal fluid (CSF) or plasma is Aβ40, whereas Aβ42 is much more aggregatable and accumulated in senile plaques. The level of Aβ in the brain is determined by the balance between the generation and clearance of Aβ, including transport across the brain–blood barrier (BBB). Although the processes of Aβ generation and degradation have been studied in some detail, knowledge of the Aβ transport process across the BBB is limited. So far, low‐density lipoprotein receptor‐related protein (LRP1), P‐glycoprotein (P‐gp), and insulin‐like growth factor‐1 (IGF‐1) have been identified to modify the excretion of brain Aβ to the blood. Methods: To investigate whether macrophage colony stimulating factor (M‐CSF) has a role in the Aβ transport process, human Aβ was injected into the lateral ventricle of the brain of M‐CSF‐deficient (op/op) mice. Then, plasma and brain Aβ levels were measured by ELISA to determine the time‐course of Aβ movement from the brain to the plasma. Result: When human Aβ40 was injected into mouse lateral ventricles, the efflux of Aβ from the CSF to the blood was transiently decreased and delayed in M‐CSF‐deficient mice. Moreover, endogenous plasma Aβ40 levels were lower in M‐CSF‐deficient mice. Conclusion: The results indicate that M‐CSF deficiency impairs excretion of human‐type Aβ40 from the CSF to blood. We propose that M‐CSF may be a novel factor that facilitates the excretion of Aβ from the CSF to the blood via the BBB.