Regionally specific changes in the hippocampal circuitry accompany progression of cerebrospinal fluid biomarkers in preclinical Alzheimer's disease

Neuropathological and in vivo brain imaging studies agree that the cornu ammonis 1 and subiculum subfields of the hippocampus are most vulnerable to atrophy in the prodromal phases of Alzheimer's disease (AD). However, there has been limited investigation of the structural integrity of the components of the hippocampal circuit, including subfields and extra‐hippocampal white matter structure, in relation to the progression of well‐accepted cerebrospinal fluid (CSF) biomarkers of AD, amyloid‐β 1‐42 (Aβ) and total‐tau (tau). We investigated these relationships in 88 aging asymptomatic individuals with a parental or multiple‐sibling familial history of AD. Apolipoprotein (APOE) ?4 risk allele carriers were identified, and all participants underwent cognitive testing, structural magnetic resonance imaging, and lumbar puncture for CSF assays of tau, phosphorylated‐tau (p‐tau) and Aβ. Individuals with a reduction in CSF Aβ levels (an indicator of amyloid accretion into neuritic plaques) as well as evident tau pathology (believed to be linked to neurodegeneration) exhibited lower subiculum volume, lower fornix microstructural integrity, and a trend towards lower cognitive score than individuals who showed only reduction in CSF Aβ. In contrast, persons with normal levels of tau showed an increase in structural MR markers in relation to declining levels of CSF Aβ. These results suggest that hippocampal subfield volume and extra‐hippocampal white matter microstructure demonstrate a complex pattern where an initial volume increase is followed by decline among asymptomatic individuals who, in some instances, may be a decade or more away from onset of cognitive or functional impairment.     

Altered levels of cerebrospinal fluid reelin in frontotemporal dementia and Alzheimer's disease

Reelin is an essential glycoprotein for correct cytoarchitectonic organization during CNS development. Its function in the adult brain is far less well understood, but altered brain and blood reelin levels have been reported in some psychiatric disorders, and the possibility has been considered of an involvement of the reelin signaling pathway in neurodegeneration. Here we report, for the first time, the presence of detectable levels of reelin in rat and human cerebrospinal fluid (CSF) and show evidence for the involvement of a 180-kDa reelin fragment in two neurodegenerative disorders. This fragment was analyzed by Western blotting in CSF samples from 13 healthy control individuals and 14 frontotemporal dementia (FTD) and 20 Alzheimer's disease (AD) patients. Increased CSF 180-kDa reelin was found in FTD (161.7 +/- 6.7 arbitrary units; a.u.) and AD (151.4 +/- 3.8 a.u.) compared with control individuals (141.4 +/- 1.2 a.u., P < 0.05). Our results strongly suggest the involvement of reelin signaling in neurodegenerative pathologies.     

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.     

Cerebrospinal fluid tau levels in Alzheimer's disease are elevated when compared with vascular dementia but do not correlate with measures of cerebral atrophy

Increased tau levels are a well-established finding in Alzheimer's disease (AD). In contrast, the potential value of tau levels in the differential diagnosis of AD, vascular dementia (VD) and major depression warrants further investigation. The potential impact of psychotropic medication also needs to be established. We investigated cerebrospinal fluid (CSF) tau protein concentrations in 88 patients with AD, 23 patients with VD, 25 patients with major depression and 17 age-paralleled controls without cognitive impairment with respect to important clinical variables, type and dosage of psychotropic medication and cerebral changes as assessed by magnetic resonance imaging (MRI). The AD patients showed significantly elevated tau levels compared with patients with VD or major depression and controls. Tau levels obtained in the VD group were intermediate, with significant differences from both AD patients and patients with major depression and controls. Within the AD group, no significant correlation between tau levels, severity of dementia, age, duration of disease, type and dosage of psychotropic medication or MRI volumetric changes arose. A subgroup of AD patients without increased tau levels was characterized by a significantly larger percentage of patients with presenile onset.     

A longitudinal study of neuropsychological change in individuals with Parkinson's disease

OBJECTIVES: Neuropsychological changes in individuals with Parkinson's disease (PD) were studied longitudinally. METHODS: Sixty-nine idiopathic PD patients, with Mini-Mental State Examination (MMSE) scores falling within normal range, and 37 elderly control participants were given neuropsychological tests twice approximately two years apart. RESULTS: The PD group performed poorer than the control group on Semantic Fluency, Letter Fluency, Modified Wisconsin Card Sorting Task, and Block Design at test time 1. Two years later, the PD group showed significant decline in Semantic and Letter Fluency. A subset of 12 PD patients declined in mental status by second testing (>4 MMSE points). Cox proportional-hazards models were used to see if any baseline measures were associated with relative risk of decline in mental status. In the final model, Repetition performance and Age were significantly associated with cognitive decline. CONCLUSIONS: Consistent with previous studies, executive function tasks were those most susceptible to disease progression.     

A longitudinal study of neuropsychological change in individuals with Parkinson's disease

Neuropsychological changes in individuals with Parkinson's disease (PD) were studied longitudinally. Sixty-nine idiopathic PD patients, with Mini-Mental State Examination (MMSE) scores falling within normal range, and 37 elderly control participants were given neuropsychological tests twice approximately two years apart. The PD group performed poorer than the control group on Semantic Fluency, Letter Fluency, Modified Wisconsin Card Sorting Task, and Block Design at test time 1. Two years later, the PD group showed significant decline in Semantic and Letter Fluency. A subset of 12 PD patients declined in mental status by second testing (> or =4 MMSE points). Cox proportional-hazards models were used to see if any baseline measures were associated with relative risk of decline in mental status. In the final model, Repetition performance and Age were significantly associated with cognitive decline. Consistent with previous studies, executive function tasks were those most susceptible to disease progression.     

A harmonized longitudinal biomarkers and cognition database for assessing the natural history of preclinical Alzheimer's disease from young adulthood and for designing prevention trials

IntroductionLarge longitudinal biomarkers database focusing on middle age is needed for Alzheimer's disease (AD) prevention.MethodsData for cerebrospinal fluid analytes, molecular imaging of cerebral fibrillar β-amyloid with positron emission tomography, magnetic resonance imaging–based brain structures, and clinical/cognitive outcomes were harmonized across eight AD biomarker studies. Statistical power was estimated.ResultsThe harmonized database included 7779 participants with clinical/cognitive data: 3542 were 18∼65 years at the baseline, 5865 had longitudinal cognitive data for a median of 4.7 years, 2473 participated in the cerebrospinal fluid studies (906 had longitudinal data), 2496 participated in the magnetic resonance imaging studies (1283 had longitudinal data), and 1498 participated in the positron emission tomography amyloid studies (849 had longitudinal data). The database provides adequate power for detecting early biomarker changes, and demonstrates the feasibility of AD prevention trials on middle-aged individuals.DiscussionThe harmonized database is an optimum resource to design AD prevention trials decades before symptomatic onset.     

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.     

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid-β_1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimer's disease (AD) dementia, 2) cost-effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add-on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre- and post-biomarker counseling.     

Interleukin-12 is reduced in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

Interleukin-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines, such as Interferon-gamma and Tumor Necrosis Factor-alpha. There is little information about the involvement of IL-12 in the pathophysiology of Alzheimer's disease (AD) and other tauopathies. OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with AD and frontotemporal dementia (FTD). PATIENTS AND METHODS: We measured by immunoassay cerebrospinal fluid (CSF) IL-12 levels in 19 patients with AD and 7 patients with FTD in comparison with CSF IL-12 levels in 30 patients with non-inflammatory neurological diseases served as neurological control patients (NCTRL). IL-12 levels were correlated with age, age of disease onset, disease duration, MMSE score, and rate of dementia progression. Abeta42 and Total tau (tau(T)) levels in CSF were also measured. RESULTS: Patients with AD had significantly lower CSF IL-12 levels compared with NCTRL patients (p<0.001). Patients with FTD had also lower CSF IL-12 levels compared with NCTRL patients (p<0.05). Age, sex, disease duration and MMSE score did not affect IL-12 levels in any of the groups. In AD a significant positive correlation was noted between IL-12 levels and tau(T) levels (Rs=0.46, p=0.048). CONCLUSIONS: Our findings may suggest a reduced inflammatory reaction during the course of AD and FTD. A neurotrophic role of IL-12 and other proinflammatory cytokines cannot be excluded.     

Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla)

The two major histopathologic hallmarks of Alzheimer's disease (AD) are amyloid beta protein (Aβ) plaques and neurofibrillary tangles (NFT). Aβ pathology is a common feature in the aged nonhuman primate brain, whereas NFT are found almost exclusively in humans. Few studies have examined AD‐related pathology in great apes, which are the closest phylogenetic relatives of humans. In the present study, we examined Aβ and tau‐like lesions in the neocortex and hippocampus of aged male and female western lowland gorillas using immunohistochemistry and histochemistry. Analysis revealed an age‐related increase in Aβ‐immunoreactive plaques and vasculature in the gorilla brain. Aβ plaques were more abundant in the neocortex and hippocampus of females, whereas Aβ‐positive blood vessels were more widespread in male gorillas. Plaques were also Aβ40‐, Aβ42‐, and Aβ oligomer‐immunoreactive, but only weakly thioflavine S‐ or 6‐CN‐PiB‐positive in both sexes, indicative of the less fibrillar (diffuse) nature of Aβ plaques in gorillas. Although phosphorylated neurofilament immunostaining revealed a few dystrophic neurites and neurons, choline acetyltransferase‐immunoreactive fibers were not dystrophic. Neurons stained for the tau marker Alz50 were found in the neocortex and hippocampus of gorillas at all ages. Occasional Alz50‐, MC1‐, and AT8‐immunoreactive astrocyte and oligodendrocyte coiled bodies and neuritic clusters were seen in the neocortex and hippocampus of the oldest gorillas. This study demonstrates the spontaneous presence of both Aβ plaques and tau‐like lesions in the neocortex and hippocampus in old male and female western lowland gorillas, placing this species at relevance in the context of AD research. J. Comp. Neurol. 521:4318–4338, 2013. © 2013 Wiley Periodicals, Inc.     

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.     

Progression of brain atrophy in the early stages of Parkinson's disease: A longitudinal tensor‐based morphometry study in de novo patients without cognitive impairment

The presence of brain atrophy and its progression in early Parkinson's disease (PD) are still a matter of debate, particularly in patients without cognitive impairment. The aim of this longitudinal study was to assess whether PD patients who remain cognitively intact develop progressive atrophic changes in the early stages of the disease. For this purpose, we employed high‐resolution T1‐weighted MR imaging to compare 22 drug‐naïve de novo PD patients without cognitive impairment to 17 age‐matched control subjects, both at baseline and at three‐year follow‐up. We used tensor‐based morphometry to explore the presence of atrophic changes at baseline and to compute yearly atrophy rates, after which we performed voxel‐wise group comparisons using threshold‐free cluster enhancement. At baseline, we did not observe significant differences in regional atrophy in PD patients with respect to control subjects. In contrast, PD patients showed significantly higher yearly atrophy rates in the prefrontal cortex, anterior cingulum, caudate nucleus, and thalamus when compared to control subjects. Our results indicate that even cognitively preserved PD patients show progressive cortical and subcortical atrophic changes in regions related to cognitive functions and that these changes are already detectable in the early stages of the disease. Hum Brain Mapp 35:3932–3944, 2014. © 2014 Wiley Periodicals, Inc .     

Your algorithm might think the hippocampus grows in Alzheimer's disease: Caveats of longitudinal automated hippocampal volumetry

Hippocampal atrophy rate—measured using automated techniques applied to structural MRI scans—is considered a sensitive marker of disease progression in Alzheimer's disease, frequently used as an outcome measure in clinical trials. Using publicly accessible data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined 1‐year hippocampal atrophy rates generated by each of five automated or semiautomated hippocampal segmentation algorithms in patients with Alzheimer's disease, subjects with mild cognitive impairment, or elderly controls. We analyzed MRI data from 398 and 62 subjects available at baseline and at 1 year at MRI field strengths of 1.5 T and 3 T, respectively. We observed a high rate of hippocampal segmentation failures across all algorithms and diagnostic categories, with only 50.8% of subjects at 1.5 T and 58.1% of subjects at 3 T passing stringent segmentation quality control. We also found that all algorithms identified several subjects (between 2.94% and 48.68%) across all diagnostic categories showing increases in hippocampal volume over 1 year. For any given algorithm, hippocampal “growth” could not entirely be explained by excluding patients with flawed hippocampal segmentations, scan–rescan variability, or MRI field strength. Furthermore, different algorithms did not uniformly identify the same subjects as hippocampal “growers,” and showed very poor concordance in estimates of magnitude of hippocampal volume change over time (intraclass correlation coefficient 0.319 at 1.5 T and 0.149 at 3 T). This precluded a meaningful analysis of whether hippocampal “growth” represents a true biological phenomenon. Taken together, our findings suggest that longitudinal hippocampal volume change should be interpreted with considerable caution as a biomarker. Hum Brain Mapp 38:2875–2896, 2017. © 2017 Wiley Periodicals, Inc.     

The relationship of cerebrospinal fluid monoamine metabolites with clinical response to tetrahydroaminoacridine in patients with Alzheimer's disease

Summary The effect of tetrahydroaminoacridine (THA) on the cerebrospinal fluid (CSF) monoamine metabolites was studied in 22 patients with Alzheimer's disease in an open treatment trial. The CSF monoamine metabolites were assayed at baseline and after 4 weeks' active THA treatment with 100 mg/d. A statistically significant increase in the CSF homovanillic acid (HVA) and in 5-hydroxyindoleacetic acid (5-HIAA) content was found. The increase of the CSF 5-HIAA level correlated significantly with improvement in cognitive tests and in the Instrumental Activities of Daily Living Scale. We conclude that besides its anticholinesterase activity THA enhances also the monoaminergic neurotransmission in the brain and that the clinical improvement during THA treatment may be partly mediated through the monoaminergic system.     

Stereological analysis of neuropil threads in the hippocampal formation: relationships with Alzheimer's disease neuronal pathology and cognition

Although neuropil threads are thought to account for 85–90% of cortical tau pathology in brain ageing, their clinical significance remains controversial. Previous studies have measured densities, rather than absolute numbers, and most did not take into account possible interactions among the pathological hallmarks of Alzheimer's disease (AD). We report here stereological estimates of total neurofibrillary tangle (NFT) and neuron numbers as well as total amyloid volume and neuropil thread (NT) length, in the hippocampus and entorhinal cortex of 19 very old individuals (age range: 83–101 years) with various degrees of cognitive decline. Total NT length in all areas studied increased in mildly demented cases but showed a marked decrease in Clinical Dementia Rating (CDR) scale 3 cases. Both total NFT and neuron numbers were related to NT length in the CA1 field and entorhinal cortex. A strong positive relationship was also present between the total NFT numbers in the entorhinal cortex and NT length in the CA1 field and dentate gyrus. Total NT length in the CA1 field was related to both CDR scores and presence or absence of dementia explaining 7% and 37% of their variability respectively. In multivariate models, this relationship was highly dependent on the severity of NFT formation in this area. Our data reveal that NT formation in hippocampal subdivisions and entorhinal cortex accompanies AD neuronal pathology in early stages of the degenerative process, yet its rate may decrease in severe dementia. In terms of clinicopathological correlations, NT length in the hippocampal formation does not represent an independent marker of dementia severity.     

Neuropsychiatric symptoms predict change in quality of life of Alzheimer disease patients: A two-year follow-up study

Aim:  To examine the effect of neuropsychiatric symptoms on longitudinal changes in the quality of life (QOL) of patients with Alzheimer disease (AD).
Methods:  First, we investigated whether neuropsychiatric symptoms at baseline predict changes in the QOL of AD patients over time. Then we examined the associations between changes in neuropsychiatric symptoms and changes in QOL. QOL was assessed using the Japanese version of the Quality of Life–Alzheimer Disease (QOL–AD) scale and other clinical instruments [the Mini-Mental State Examination, The Neuropsychiatry Inventory (NPI)] at baseline and again two years later in 96 AD patients among 140 AD patients at baseline. We performed a multiple regression analysis of the baseline QOL–AD score, NPI score (mood, psychosis, and euphoria factor), Mini-Mental State Examination score, and other clinical instrument variables (e.g. Activities-of-Daily-Living scores) to determine their contribution to the change in QOL–AD score.
Results:  While the total QOL–AD score based on the patients' responses did not change significantly, the total QOL–AD score derived from the caregivers' responses declined. Both the Activities-of-Daily-Living score and the mood factor of the NPI score predicted the change in the QOL–AD score as assessed by the caregivers' responses. In addition, there was a significant correlation between the changes in two factors of the NPI, i.e. the mood and psychosis factor, and the changes in the QOL–AD score based on the caregivers' responses.
Conclusions:  The presence of specific neuropsychiatric symptoms (mood and psychosis symptoms) was associated with changes in the QOL of AD patients during the follow-up period.     

A longitudinal study of Alzheimer's disease: rates of cognitive and functional decline

OBJECTIVE: To measure rates of decline in cognition and function in patients with Alzheimer's disease (AD) and to investigate their accelerating risk factors in Korea. METHODS: This study presents longitudinal data on a community-based sample of 107 patients with AD, followed at 6 months and 12 months. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini Mental State Examination (MMSE) and the Disability Assessment for Dementia Scale (DAD) were given. Mixed model analyses were conducted using the following independent variables: times of repeated assessment (0, 6 or 12 months), severity of dementia assessed by the Functional Assessment Staging (FAST) and individual indicators as covariates. RESULTS: Average annual rates of decline in the MMSE, the ADAS-cog and the DAD were 2.3, 11.4 and 15.1 points, respectively. Neither gender, duration of formal education, nor duration of AD since onset was significant predictors of cognitive and functional decline. Patterns of functional decline in total DAD, instrumental ADLs, planning and organization and performance subscale are linear as MMSE score declines, while those of the basic ADLs and the initiation are curvilinear. CONCLUSION: This naturalistic observational study measured rates of cognitive and functional decline in AD, and can provide reference data for further longitudinal studies or clinical trials. Further study will be necessary to determine whether linear or curvilinear pattern in functional decline is due to progression of AD itself or statistical artifact.