Pathogenesis of Depression in Alzheimer's Disease.

Depression is a prevalent occurrence among Alzheimer's disease (AD) patients, yet its underlying mechanism remains unclear. Recent investigations have revealed that several pathophysiological changes associated with Alzheimer's disease can lead to mood disorders. These alterations include irregularities in monoamine neurotransmitters, disruptions in glutamatergic synaptic transmission, neuro-inflammation, dysfunction within the hypothalamic-pituitary-adrenocortical (HPA) axis, diminished levels of brain-derived neurotrophic factor (BDNF), and hippocampal atrophy. This review consolidates research findings from pertinent fields to elucidate the mechanisms underlying depression in Alzheimer's disease, aiming to provide valuable insights for the study of its mechanisms and clinical treatment.

APOE ε4-associated downregulation of the IL-7/IL-7R pathway in effector memory T cells: Implications for Alzheimer's disease.

INTRODUCTION: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs). RESULTS: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. DISCUSSION: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. HIGHLIGHTS: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells.

Sirt1 protects against hippocampal atrophy and its induced cognitive impairment in middle-aged mice.

BACKGROUND: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. RESULTS: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage. CONCLUSIONS: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

Hippocampal atrophy and quantitative EEG markers in mild cognitive impairment in temporal lobe epilepsy versus extra-temporal lobe epilepsy.

OBJECTIVE: Cognitive impairment in temporal lobe epilepsy is widely acknowledged as one of the most well-known comorbidities. This study aimed to explore cognitive impairment and to determine the potential clinical, radiological, and quantitative electroencephalography markers for cognitive impairment in temporal lobe epilepsy patients versus extra-temporal lobe epilepsy. METHODS: Forty-five patients with temporal lobe epilepsy and forty-five patients with extra-temporal lobe epilepsy were recruited for an administered digit span test, verbal fluency test, mini-mental state examination, digital symbol test, and Montreal cognitive assessment. Also, they were subjected to magnetic resonance imaging assessment for hippocampal atrophy and a quantitative electroencephalography assessment for electroencephalography markers (median frequency, peak frequency, and the alpha-to-theta ratio). RESULTS: Patients with extra-temporal lobe epilepsy showed non-significant higher epilepsy durations and a higher frequency of seizures. Temporal lobe epilepsy patients showed a more statistically significant family history of epilepsy (37.7%), more history of febrile convulsions (13.3%), higher hippocampal atrophy (17.8%), and lower cognitive scales, especially mini-mental state examination and Montreal cognitive assessment; lower digital symbol test, verbal fluency test, and backward memory of digit span test. Also, temporal lobe epilepsy patients had a strong negative correlation with electroencephalography markers: median frequency, peak frequency, and the alpha-to-theta ratio (r = - 0.68, P < 0.005 and r = - 0.64, P < 0.005 and r = - 0.66, P < 0.005 respectively). CONCLUSION: Cognitive impairment in patients with temporal lobe epilepsy was correlated with hippocampal atrophy and quantitative electroencephalography abnormalities, especially peak frequency, median frequency, and alpha-to-theta ratio that could be used alone for the identification of early cognitive impairment. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04376671.

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

AIMS: We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years. METHODS AND RESULTS: A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I-II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: -62 mm3 [95% confidence interval (CI) -81 to -42, P < 0.0001). This corresponded to a relative change of -1.8% (95% CI -2.3 to -1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with 'intensity of attention' as the only domain declining (LSmean -1.82 points, 95% CI -3.05 to -0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29). CONCLUSION: In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

Neurotensin agonist PD 149163 modulates the neuroinflammation induced by bacterial endotoxin lipopolysaccharide in mice model.

OBJECTIVE: The disruption of bidirectional communication between neuroendocrine and immune components by stressors leads to mental problems. The immunomodulation therapy of neuroinflammation-led psychiatric illness is an emerging area of research. Therefore, the present study aimed to evaluate immune modulation efficacy of PD 149163 (PD) against the lipopolysaccharide (LPS)-induced neuroinflammation. MATERIALS AND METHODS: The Swiss albino mice (female/12 weeks) were divided into six groups (6 mice/group): (I) Control: 0.9% NaCl; (II) LPS: 1 mg/kg BW, for 5 days; (III) LPS + PD Low: LPS 1 mg/kg BW (for 5 days) after that PD 100 µg/kg BW (for 21 days); (IV) LPS + PD High: LPS 1 mg/kg BW (for 5 days) after that PD 300 µg/kg BW (for 21 days); (V) PD Low: PD 100 µg/kg BW (for 21 days); (VI) PD High: PD 300 µg/kg BW (for 21 days). All treatments were given intraperitoneal. RESULTS: The LPS-induced weight loss (body and brain) was normalized to control after PD treatment. The PD enhanced superoxide dismutase (SOD) activity while decreased lipid hydroperoxide (LOOH) level altered in LPS-exposed mice. The significantly increased pro-inflammatory cytokines (IL-6 and TNF-α) in LPS exposure were also decreased by PD. Likewise, the LPS-induced HPA axis activation was stabilized by PD. In the hippocampus, the pyramidal cell layer thickness, pyramidal neurons number and size of CA1 and CA3 regions were reduced along with misalignment, shrinkage, and impairment of cytoarchitecture. In the co-treated group, the LPS-induced hippocampus disruption was reversed after PD exposure. CONCLUSION: We suggested that the PD modulates the LPS-induced neuroinflammation and psychiatric illness in a dose-dependent manner.

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer's Disease.

Early-onset Alzheimer's disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer's disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future.

Hearing loss is associated with hippocampal atrophy and high cortisol/dehydroepiandrosterone sulphate ratio in older adults.

OBJECTIVES: Hearing loss (HL) has been recognised as a prodromal symptom of cognitive disorder with aging. It is still uncertain if HL leads to cognitive impairment directly or through an indirect mechanism. DESIGN: Participants of this study underwent an auditory test, blood tests, and brain MRI. The atrophy rate of the hippocampus (HP) was calculated using voxel-based specific areas. A partial correlation analysis whilst controlling for the effect of age was performed to analyse the factors affecting hearing levels and HP atrophy rate (HP%). STUDY SAMPLE: Thirty-six older adults with hearing impairment. RESULTS: The group of participants with moderate or severe HL (n = 22) had higher cortisol/dehydroepiandrosterone sulphate (C/D) ratio, geriatric depression score (GDS) and HP% than the mild HL or normal hearing group (n = 14, p < 0.05). The HP% showed a significant positive correlation with the C/D ratio, GDS and the hearing level of high frequency (HF) (p < 0.05). The C/D ratio was positively correlated with the HP% and the hearing level of the HF (p < 0.05). CONCLUSIONS: Our results suggest that the HL is associated with the atrophy of HP and high C/D ratios in older adults; however, HL may not be causally related to hippocampal atrophy.

The timelines of MRI findings related to outcomes in adult patients with new-onset refractory status epilepticus.

OBJECTIVE: To identify the timelines of magnetic resonance imaging (MRI) abnormalities and their relationships with the clinical outcomes of patients with new-onset refractory status epilepticus (NORSE). METHODS: This retrospective observational study enrolled patients with NORSE who were admitted from March 2008 to July 2018. MRI abnormalities were analyzed visually with the readers blinded to the clinical characteristics of the patients. Poor functional outcome was defined as a Glasgow Outcome Scale score ≤ 3 at discharge. Subsequent pharmacoresistant epilepsy was defined as seizures not controlled by two or more anti-seizure medications 6 months after discharge. RESULTS: Among 39 patients with NORSE, 32 (82.1%) exhibited an MRI abnormality. The most common abnormalities were persisting mesial temporal lobe signal abnormality (51.3%); initial diffuse leptomeningeal enhancement within 16 days from seizure onset (15/35, 42.9%); and hippocampal atrophy, which started to appear 26 days after seizure onset (15/26, 57.7%). Only three patients had claustrum abnormalities. Patients with insular involvement had longer treatment delay than those without (24.0 vs 5.5 hours, respectively, P = .02). Duration of status epilepticus (SE) tended to have a linear association with hippocampal atrophy (P = .055). Patients with diffuse leptomeningeal enhancement were more likely to have a poor functional outcome and to develop subsequent pharmacoresistant epilepsy than those without this finding (93.3% vs 15.0%, P < .001; 75.0% vs 22.2%, P = .004, respectively); the results were significant even after adjusting for age, sex, and duration of SE. Hippocampal atrophy and diffuse cortical atrophy were also significantly associated with poor functional outcomes (P = .001 and P = .002, respectively), and patients with these conditions were more likely to develop subsequent pharmacoresistant epilepsy than those without these conditions, after adjusting for age and sex (P = .035 and P = .048, respectively), but not after adjusting for duration of SE. SIGNIFICANCE: Initial diffuse leptomeningeal enhancement and later hippocampal atrophy were associated with a poor functional outcome and subsequent pharmacoresistant epilepsy.

Sex differences in the association of APOE ε4 genotype with longitudinal hippocampal atrophy in cognitively normal older people.

BACKGROUND AND PURPOSE: The aim of this study was to determine the effects of apolipoprotein E ε4 (APOE ε4) genotype and sex together on longitudinal change in adjusted hippocampal volume [hippocampal volume:intracranial volume ratio (HpVR)] across the Alzheimer's disease (AD) continuum. METHODS: At baseline, we included 372 individuals with normal cognition (NC), 738 individuals with mild cognitive impairment (MCI) and 271 patients with mild AD from the Alzheimer's Disease Neuroimaging Initiative database. We examined the effects of the APOE ε4 by sex interaction on longitudinal change in HpVR within the overall sample and within each diagnostic group. RESULTS: Female gender was found to be associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Similarly, APOE ε4 was associated with longitudinal reduction of HpVR in the NC and MCI groups, but not in the AD group. Further, female APOE ε4 carriers showed a greater longitudinal reduction of HpVR than their male counterparts in the NC group, but not in the MCI or AD group. However, due to the relatively short duration of follow-up visits in patients with AD, further studies are needed to replicate these findings. CONCLUSION: Female APOE ε4 carriers show a greater longitudinal reduction of HpVR than their male counterparts in cognitively normal older adults.

Nε-(carboxymethyl)-lysine, White Matter, and Cognitive Function in Diabetes Patients.

OBJECTIVE: To study the relationship of Nε-(carboxymethyl)-lysine level (CML) with microstructure changes of white matter (WM), and cognitive impairment in patients with type 2 diabetes mellitus (T2DM) and to discuss the potential mechanism underlying T2DM-associated cognitive impairment. METHODS: The study was performed in T2DM patients (n=22) with disease course ≥5 years and age ranging from 65 to 75 years old. A control group consisted of 25 sex- and age-matched healthy volunteers. Fractional anisotropy (FA) of several WM regions was analyzed by diffusion tensor imaging scan. Plasma CML levels were measured by enzyme-linked immunosorbent assay, and cognitive function was assessed by Mini-Mental State Examination and Montreal cognitive assessment (MoCA). RESULTS: The total Mini-Mental State Examination score in the patient group (25.72±3.13) was significantly lower than the control group (28.16±2.45) (p<0.05). In addition, the total MoCA score in the patient group (22.15±3.56) was significantly lower than the control group 25.63±4.12) (p<0.01). In the patient group, FA values were significantly decreased in the corpus callosum, cingulate fasciculus, inferior fronto-occipital fasciculus, parietal WM, hippocampus, and temporal lobes relative to corresponding regions of healthy controls (p<0.05). Plasma CML level was negatively correlated with average FA values in the global brain (r=-0.58, p<0.01) and MoCA scores (r=-0.47, p<0.05). CONCLUSIONS: In T2DM, WM microstructure changes occur in older patients, and elevations in CML may play a role in the development of cognitive impairment.

Glycosylation of Human Plasma Clusterin Yields a Novel Candidate Biomarker of Alzheimer's Disease.

Specific glycosylated peptides of clusterin are found associated with hippocampal atrophy. The glycosylation of clusterin from human plasma was comprehensively analyzed and characterized using mass spectrometry (MS)-based glycoproteomics analysis. All six known N-glycosylation sites are covered, three in the alpha subunit (α64N, α81N and α123N) and three in the beta subunit (ß64N, ß127N, and ß147N). More detailed structural characterization of clusterin glycopeptides was also performed, demonstrating the presence of glycosylated peptides and their corresponding glycans. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we have determined the differences in the glycoforms associated at each of the different glycosylation sites in plasma clusterin obtained from subjects of low hippocampal atrophy (n = 13) and high hippocampal atrophy (n = 14). In our pilot study, the ß64N site shows the most significant regulations between clinical groups. Eight ß64N glycoforms are significantly reduced in patients with high atrophy compared with those with low atrophy, which demonstrates the utility of clusterin isoforms as diagnostic and prognostic Alzheimer's disease (AD) markers. These results provide a novel and robust workflow suitable for rapid verification of specific clusterin glycoforms with utility as AD biomarkers.

Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease.

Tau alterations are now considered an executor of neuronal demise and cognitive dysfunction in Alzheimer's disease (AD). Mouse models combining amyloidosis and tauopathy and their parental counterparts are important tools to further investigate the interplay of abnormal amyloid-ß (Aß) and Tau species in pathogenesis, synaptic and neuronal dysfunction, and cognitive decline. Here, we crossed APP/PS1 mice with 5 early-onset familial AD mutations (5xFAD) and TauP301S (PS19) transgenic mice, denoted F(+)/T(+) mice, and phenotypically compared them to their respective parental strains, denoted F(+)/T(-) and F(-)/T(+) respectively, as controls. We found dramatically aggravated tauopathy (~10-fold) in F(+)/T(+) mice compared to the parental F(-)/T(+) mice. In contrast, amyloidosis was unaltered compared to the parental F(+)/T(-) mice. Tauopathy was invariably and very robustly aggravated in hippocampal and cortical brain regions. Most important, F(+)/T(+) displayed aggravated cognitive deficits in a hippocampus-dependent spatial navigation task, compared to the parental F(+)/T(-) strain, while parental F(-)/T(+) mice did not display cognitive impairment. Basal synaptic transmission was impaired in F(+)/T(+) mice compared to nontransgenic mice and the parental strains (≥40%). Finally, F(+)/T(+) mice displayed a significant hippocampal atrophy (~20%) compared to nontransgenic mice, in contrast to the parental strains. Our data indicate for the first time that pathological Aß species (or APP/PS1) induced changes in Tau contribute to cognitive deficits correlating with synaptic deficits and hippocampal atrophy in an AD model. Our data lend support to the amyloid cascade hypothesis with a role of pathological Aß species as initiator and pathological Tau species as executor.

Aberrant topological patterns of brain structural network in temporal lobe epilepsy.

OBJECTIVE: Although altered large-scale brain network organization in patients with temporal lobe epilepsy (TLE) has been shown using morphologic measurements such as cortical thickness, these studies, have not included critical subcortical structures (such as hippocampus and amygdala) and have had relatively small sample sizes. Here, we investigated differences in topological organization of the brain volumetric networks between patients with right TLE (RTLE) and left TLE (LTLE) with unilateral hippocampal atrophy. METHODS: We performed a cross-sectional analysis of 86 LTLE patients, 70 RTLE patients, and 116 controls. RTLE and LTLE groups were balanced for gender (p = 0.64), seizure frequency (Mann-Whitney U test, p = 0.94), age (p = 0.39), age of seizure onset (p = 0.21), and duration of disease (p = 0.69). Brain networks were constructed by thresholding correlation matrices of volumes from 80 cortical/subcortical regions (parcellated with Freesurfer v5.3 https://surfer.nmr.mgh.harvard.edu/) that were then analyzed using graph theoretical approaches. RESULTS: We identified reduced cortical/subcortical connectivity including bilateral hippocampus in both TLE groups, with the most significant interregional correlation increases occurring within the limbic system in LTLE and contralateral hemisphere in RTLE. Both TLE groups demonstrated less optimal topological organization, with decreased global efficiency and increased local efficiency and clustering coefficient. LTLE also displayed a more pronounced network disruption. Contrary to controls, hub nodes in both TLE groups were not distributed across whole brain, but rather found primarily in the paralimbic/limbic and temporal association cortices. Regions with increased centrality were concentrated in occipital lobes for LTLE and contralateral limbic/temporal areas for RTLE. SIGNIFICANCE: These findings provide first evidence of altered topological organization of the whole brain volumetric network in TLE, with disruption of the coordinated patterns of cortical/subcortical morphology.

Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer's disease.

The goal of this paper was to review the effectiveness of using 7-T MRI to study neuroimaging biomarkers for Alzheimer's disease (AD). The authors reviewed the literature for articles published to date on the use of 7-T MRI to study AD. Thus far, there are 3 neuroimaging biomarkers for AD that have been studied using 7-T MRI in AD tissue: 1) neuroanatomical atrophy; 2) molecular characterization of hypointensities; and 3) microinfarcts. Seven-Tesla MRI has had mixed results when used to study the 3 aforementioned neuroimaging biomarkers for AD. First, in the detection of neuroanatomical atrophy, 7-T MRI has exciting potential. Historically, noninvasive imaging of neuroanatomical atrophy during AD has been limited by suboptimal resolution. However, now there is compelling evidence that the high resolution of 7-T MRI may help overcome this hurdle. Second, in detecting the characterization of hypointensities, 7-T MRI has had varied success. PET scans will most likely continue to lead in the noninvasive imaging of amyloid plaques; however, there is emerging evidence that 7-T MRI can accurately detect iron deposits within activated microglia, which may help shed light on the role of the immune system in AD pathogenesis. Finally, in the detection of microinfarcts, 7-T MRI may also play a promising role, which may help further elucidate the relationship between cerebrovascular health and AD progression.

Harmonized benchmark labels of the hippocampus on magnetic resonance: the EADC-ADNI project.

BACKGROUND: A globally harmonized protocol (HarP) for manual hippocampal segmentation based on magnetic resonance has been recently developed by a task force from European Alzheimer's Disease Consortium (EADC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Our aim was to produce benchmark labels based on the HarP for manual segmentation. METHODS: Five experts of manual hippocampal segmentation underwent specific training on the HarP and segmented 40 right and left hippocampi from 10 ADNI subjects on both 1.5 T and 3 T scans. An independent expert visually checked segmentations for compliance with the HarP. Descriptive measures of agreement between tracers were intraclass correlation coefficients (ICCs) of crude volumes and similarity coefficients of three-dimensional volumes. RESULTS: Two hundred labels have been provided for the 20 magnetic resonance images. Intra- and interrater ICCs were >0.94, and mean similarity coefficients were 1.5 T, 0.73 (95% confidence interval [CI], 0.71-0.75); 3 T, 0.75 (95% CI, 0.74-0.76). CONCLUSION: Certified benchmark labels have been produced based on the HarP to be used for tracers' training and qualification.

Delphi definition of the EADC-ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance.

BACKGROUND: This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)-based manual hippocampal segmentation. METHODS: The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence-based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests. RESULTS: Agreement was significant on the inclusion of alveus/fimbria (P = .021), whole hippocampal tail (P = .013), medial border of the body according to visible morphology (P = .0006), and on this combined set of features (P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer's disease-related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter-rater (0.94) estimates. DISCUSSION: Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.

Relationship between hippocampal atrophy and neuropathology markers: a 7T MRI validation study of the EADC-ADNI Harmonized Hippocampal Segmentation Protocol.

OBJECTIVE: The pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP). METHODS: Temporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aß), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aß, and tau burden for each hippocampal subfield were obtained. RESULTS: We found significant correlations between hippocampal volume and Braak and Braak staging (ρ = -0.75, P = .001), tau (ρ = -0.53, P = .034), Aß burden (ρ = -0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aß in Cornu Ammonis (CA)1 (ρ = -0.58, P = .019) and subiculum (ρ = -0.75, P = .001), tau in CA2 (ρ = -0.59, P = .016), and CA3 (ρ = -0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001). CONCLUSIONS: The observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.

Operationalizing protocol differences for EADC-ADNI manual hippocampal segmentation.

BACKGROUND: Hippocampal volumetry on magnetic resonance imaging is recognized as an Alzheimer's disease (AD) biomarker, and manual segmentation is the gold standard for measurement. However, a standard procedure is lacking. We operationalize and quantitate landmark differences to help a Delphi panel converge on a set of landmarks. METHODS: One hundred percent of anatomic landmark variability across 12 different protocols for manual segmentation was reduced into four segmentation units (the minimum hippocampus, the alveus/fimbria, the tail, and the subiculum), which were segmented on magnetic resonance images by expert raters to estimate reliability and AD-related atrophy. RESULTS: Intra- and interrater reliability were more than 0.96 and 0.92, respectively, except for the alveus/fimbria, which were 0.86 and 0.77, respectively. Of all AD-related atrophy, the minimum hippocampus contributed to 67%; tail, 24%; alveus/fimbria, 4%; and the subiculum, 5%. CONCLUSIONS: Anatomic landmark variability in available protocols can be reduced to four discrete and measurable segmentation units. Their quantitative assessment will help a Delphi panel to define a set of landmarks for a harmonized protocol.

Memory impairment is not necessarily related to seizure frequency in mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: To investigate the effect of seizure frequency on memory, we performed a cross sectional study comparing mesial temporal lobe epilepsy (MTLE) patients with frequent and infrequent seizures. METHODS: We performed magnetic resonance imaging (MRI) hippocampal volume (HV) measurements and neuropsychological assessment in 22 patients with frequent seizures (at least one dyscognitive seizure [DS] per month) that were refractory to antiepileptic drugs and 20 patients with infrequent seizures (three or less DS per year and no event evolving to a bilateral convulsive seizure), all with MRI signs of hippocampal sclerosis (HS) on visual analysis. We also included 29 controls for comparison of volumetric data. RESULTS: There was no difference in memory performance between patients with frequent seizures and infrequent seizures. We observed a significant bilateral reduction of HV in patients with MTLE when compared to controls (p < 0.001). The degree of hippocampal atrophy (HA) between patients with frequent and infrequent seizures was not different. There was a negative correlation between seizure frequency and HV, with r = -0.3 for the HV ipsilateral to the HS and r = -0.55 for the contralateral side, thus, explaining only 9% and 30% of the HV loss. There was a positive correlation between age of onset and degree of HA (r = 0.37). SIGNIFICANCE: Our data suggest that seizure frequency does not explain most of the HV loss or memory impairment in MTLE. Memory impairment appears to be more influenced by hippocampal damage than by seizure frequency. Further studies are necessary to identify the factors that influence memory decline in patients with MTLE.