Markers Of Alzheimer's Disease Research Articles

Investigating the relationship between allocentric spatial working memory and biomarker status in preclinical and prodromal Alzheimer’s disease

The 4 Mountain Test (4MT) is a test of allocentric spatial working memory and has been proposed as an earlier marker of predementia Alzheimer’s disease (AD) than episodic verbal memory. We here compare the 4MT to the CERAD word list memory recall in both cognitively normal (CN) and mild cognitive impairment (MCI) cases with or without cerebrospinal fluid markers (CSF) of Alzheimer’s disease pathology. Linear regression was used to assess the influence of CSF determined Aβ-plaque (Aβ-/+) or neurofibrillary tau tangles (Tau-/+) on 4MT and CERAD recall performance. Analyses were performed in the full sample and the CN and MCI sub-samples. Pearson correlations were calculated to examine the relationship between 4MT and tests of psychomotor speed, verbal memory, cognitive flexibility, verbal fluency, and visuo-spatial perception. Analyses showed no significant differences in 4MT scores between Aβ-/Aβ+, nor Tau-/Tau + participants, irrespective of cognitive status. In contrast, CERAD recall scores were lower in both Aβ+ compared to Aβ- (p<.01), and Tau + compared to Tau- participants (p<.01) in the full sample analyses. There were no significant differences in CERAD recall performance between Aβ- vs. Aβ+ and Tau- vs. to Tau + in the in CN/MCI sub-samples. 4MT scores were significantly correlated with tests of psychomotor speed, cognitive flexibility, and visuo-spatial perception in the full sample analyses. In conclusion, the CERAD recall outperformed the 4MT as a cognitive marker of CSF determined AD pathology. This suggests that allocentric working memory, as measured by the 4MT, may not be used as an early marker of predementia AD.

How Helpful are Blood and Cerebrospinal Fluid Biomarkers for the Early Diagnosis of Alzheimer's Disease?

Early diagnosis of Alzheimer's disease (AD) relies on imaging and fluid biomarkers to objectively detect and quantitatively evaluate brain AD pathologies. Amyloid- and tau-PET scans recently enabled clinicians to make definitive diagnoses based on abnormal amyloid/tau deposition in the human brain. Since PET scans and blood-based biomarkers are mutually complementary, the identification of suitable blood-based biomarkers is essential for screening brain AD pathologies. According to the National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework published in 2018, AD is defined by its underlying pathologic processes, which can be diagnosed in vivo using suitable biomarkers. These biomarkers are categorized under the ATN classification system, including β amyloid deposition (A), pathologic tau (T), and neurodegeneration (N). Originally, all the ATN fluid biomarkers were assessed using cerebrospinal fluid, but currently these biomarkers can be quantified using blood samples. Among those blood-based ATN biomarkers, the plasma levels of Aβ42/40 ratio, p-tau, and neurofilament light chain (NfL) representing "A," "T," and "N" biomarkers, respectively, are useful in the early diagnosis of AD. However, further studies and additional data are required before utilizing these blood-based biomarkers as stand-alone diagnostic markers for AD.

Hippocampal Volume and Episodic Associative Memory Identify Memory Risk in Subjective Cognitive Decline Individuals in the CIMA-Q Cohort, Regardless of Cognitive Reserve Level and APOE4 Status.

Subjective cognitive decline (SCD) was proposed to identify older adults who complain about their memory but perform within a normal range on standard neuropsychological tests. Persons with SCD are at increased risk of dementia meaning that some SCD individuals experience subthreshold memory decline due to an underlying progression of Alzheimer's disease (AD). Our main goal was to determine whether hippocampal volume and APOE4, which represent typical AD markers, predict inter-individual differences in memory performance among SCD individuals and can be used to identify a meaningful clinical subgroup. Neuropsychological assessment, structural MRI, and genetic testing for APOE4 were administered to one hundred and twenty-five older adults over the age of 65 from the CIMAQ cohort: 66 SCD, 29 individuals with mild cognitive impairment (MCI), and 30 cognitively intact controls (CTRLS). Multiple regression models were first used to identify which factor (hippocampal volume, APOE4 allele, or cognitive reserve) best predicted inter-individual differences in a Face-name association memory task within the SCD group. Hippocampal volume was found to be the only and best predictor of memory performance. We then compared the demographic, clinical and cognitive characteristics of two SCD subgroups, one with small hippocampal volume (SCD/SH) and another with normal hippocampal volume (SCD/NH), with MCI and CTRLS. SCD/SH were comparable to MCI on neuropsychological tasks evaluating memory (i.e., test of delayed word recall), whereas SCD/NH were comparable to CTRLS. Thus, using hippocampal volume allows identification of an SCD subgroup with a cognitive profile consistent with a higher risk of conversion to AD.

Pathological (Dis)Similarities in Neuronal Exosome-Derived Synaptic and Organellar Marker Levels Between Alzheimer's Disease and Frontotemporal Dementia.

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD.

Plasma biomarkers of neurodegeneration in mild cognitive impairment with Lewy bodies.

Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma Aβ42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another. Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort. Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011). Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls.

Proteomics analysis of plasma from middle-aged adults identifies protein markers of dementia risk in later life.

A diverse set of biological processes have been implicated in the pathophysiology of Alzheimer's disease (AD) and related dementias. However, there is limited understanding of the peripheral biological mechanisms relevant in the earliest phases of the disease. Here, we used a large-scale proteomics platform to examine the association of 4877 plasma proteins with 25-year dementia risk in 10,981 middle-aged adults. We found 32 dementia-associated plasma proteins that were involved in proteostasis, immunity, synaptic function, and extracellular matrix organization. We then replicated the association between 15 of these proteins and clinically relevant neurocognitive outcomes in two independent cohorts. We demonstrated that 12 of these 32 dementia-associated proteins were associated with cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, or neuroinflammation. We found that eight of these candidate protein markers were abnormally expressed in human postmortem brain tissue from patients with AD, although some of the proteins that were most strongly associated with dementia risk, such as GDF15, were not detected in these brain tissue samples. Using network analyses, we found a protein signature for dementia risk that was characterized by dysregulation of specific immune and proteostasis/autophagy pathways in adults in midlife ~20 years before dementia onset, as well as abnormal coagulation and complement signaling ~10 years before dementia onset. Bidirectional two-sample Mendelian randomization genetically validated nine of our candidate proteins as markers of AD in midlife and inferred causality of SERPINA3 in AD pathogenesis. Last, we prioritized a set of candidate markers for AD and dementia risk prediction in midlife.

The MINT Sprint 2.0: A picture naming test for detection of naming impairments in Alzheimer's disease and in preclinical AD.

Evidence on the onset of naming deficits in Alzheimer's disease (AD) is mixed. Some studies showed an early decline, but others did not. The present study introduces evidence from a novel naming test. Cognitively normal (n=138), mild cognitive impairment (MCI; n=21), and Alzheimer's disease (AD; n=31) groups completed an expanded Multilingual Naming Test with a time-pressured administration procedure (MINT Sprint 2.0). Cerebrospinal fluid biomarkers classified participants as true controls (n=61) or preclinical AD (n=26). Total correct MINT Sprint 2.0 scores exhibited good sensitivity and specificity (>0.85) for discriminating true controls from cognitively impaired (MCI/AD) groups and showed significant differences between true controls and preclinical AD groups. Time measurement did not improve classification, but percent resolved scores exhibited promise as an independent AD marker. Naming deficits can be detected in the earliest stages of AD with tests and procedures designed for this purpose.

Breathing cessation events that compose the apnea–hypopnea index are distinctively associated with the adverse outcomes in Alzheimer’s disease

BackgroundPrevious studies challenge the impact of obstructive sleep apnea (OSA) once patients are diagnosed with Alzheimer’s disease (AD). Nevertheless, OSA recognizably disrupts sleep, and relevant associations between sleep, AD pathological markers, and cognition have been demonstrated. We aimed to further explore this, evaluating the associations between each breathing cessation event that compose the apnea–hypopnea index (AHI) and the sleep structure to finally investigate whether this was related to increased levels of AD markers and higher cognitive decline.MethodsObservational, prospective study, including consecutive patients diagnosed with mild-moderate AD. The participants were submitted to overnight polysomnography followed by a cerebrospinal fluid collection for AD pathological markers levels determination. Neuropsychological assessment was performed at baseline and after 12 months of follow-up.ResultsThe cohort was composed of 116 patients (55.2% females) with a median [p25;p75] age of 76.0 [72.0;80.0] years and an AHI of 25.9 [15.1;48.5], which was mainly defined by the presence of hypopneas and obstructive apneas. These were distinctively associated with the sleep structure, with obstructive apneas being related to arousals and sleep lightening and hypopneas being related to an increased number of arousals only. Despite having a lower frequency, mixed and central apneas also presented associations with the sleep structure, particularly increasing the time spent in the lighter sleep stages. In relation to AD pathological markers, obstructive and mixed apneas were related to an augment in neurofilament light levels while hypopneas were associated with a higher phosphorylated-tau/amyloid-beta protein ratio. Hypopneas were the most important event for an increased cognitive decline at the 12-month follow-up.ConclusionsOur findings highlight the importance of a patient-centered approach, with a comprehensive and detailed analysis of the AHI to effectively predict the different outcomes and tailor the appropriate therapeutic strategies.

Identification of diagnostic biomarkers in Alzheimer's disease by integrated bioinformatic analysis and machine learning strategies.

Alzheimer's disease (AD) is the most prevalent form of dementia, and is becoming one of the most burdening and lethal diseases. More useful biomarkers for diagnosing AD and reflecting the disease progression are in need and of significance. The integrated bioinformatic analysis combined with machine-learning strategies was applied for exploring crucial functional pathways and identifying diagnostic biomarkers of AD. Four datasets (GSE5281, GSE131617, GSE48350, and GSE84422) with samples of AD frontal cortex are integrated as experimental datasets, and another two datasets (GSE33000 and GSE44772) with samples of AD frontal cortex were used to perform validation analyses. Functional Correlation enrichment analyses were conducted based on Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Reactome database to reveal AD-associated biological functions and key pathways. Four models were employed to screen the potential diagnostic biomarkers, including one bioinformatic analysis of Weighted gene co-expression network analysis (WGCNA)and three machine-learning algorithms: Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) analysis. The correlation analysis was performed to explore the correlation between the identified biomarkers with CDR scores and Braak staging. The pathways of the immune response and oxidative stress were identified as playing a crucial role during AD. Thioredoxin interacting protein (TXNIP), early growth response 1 (EGR1), and insulin-like growth factor binding protein 5 (IGFBP5) were screened as diagnostic markers of AD. The diagnostic efficacy of TXNIP, EGR1, and IGFBP5 was validated with corresponding AUCs of 0.857, 0.888, and 0.856 in dataset GSE33000, 0.867, 0.909, and 0.841 in dataset GSE44770. And the AUCs of the combination of these three biomarkers as a diagnostic tool for AD were 0.954 and 0.938 in the two verification datasets. The pathways of immune response and oxidative stress can play a crucial role in the pathogenesis of AD. TXNIP, EGR1, and IGFBP5 are useful biomarkers for diagnosing AD and their mRNA level may reflect the development of the disease by correlation with the CDR scores and Breaking staging.

1520-P: Metabolic Dysregulation in Probable Alzheimer’s Disease

Insulin resistance, T2D, and chronic inflammation increase risk of developing mild cognitive impairment and Alzheimer’s disease (AD). We report here baseline data from a multicenter, randomized, placebo-controlled Phase 3 study (NCT04669028) in patients with mild to moderate AD evaluating the effects of NE3107, an oral small molecule, blood-brain permeable anti-inflammatory insulin sensitizer that binds extracellular signal-regulated kinase. Inclusion criteria are diagnosis and progression of AD, supportive brain scan and Hachinski scale to exclude vascular dementia, Clinical Dementia Rating (CDR) score of 1-2, and Mini Mental State Exam (MMSE) score of 14-24. Primary outcomes are changes in cognition and function from baseline to 30 wks. Secondary outcomes include changes in neuropsychological deficits, functional performance, and regulation of glycemia. Aβ+ subjects were older and had worse MMSE, ADAS-Cog12 and AD Composite Scores than Aβ-patients, but had less evidence of inflammation (lower CRP) and less insulin resistance (lower fasting glucose, less IFG and T2D, lower fasting insulin and HOMA2-IR, and less hypertension) (Table). Metabolic dysregulation (elevated C1q, increased CGM mean and MAGE, increased cholesterol, triglycerides, and waist-hip ratio) was also observed independent of Aβ and APOEε4 status. Inflammation and insulin resistance may contribute to AD even in the absence of classical risk markers for AD. Disclosure C.L.Reading: Employee; BioVie, Inc. C.Ahlem: Employee; Biovie, Inc. J.M.Palumbo: Employee; BioVie, Zynerba, Other Relationship; Merck Sharp &amp; Dohme Corp. M.A.Testa: Stock/Shareholder; Phase V Technologies, Inc. D.C.Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows.

Novel Isolation Method Reveals Sex-Specific Composition and Neurotoxicity of Small Extracellular Vesicles in a Mouse Model of Alzheimer's Disease.

We developed a new method to isolate small extracellular vesicles (sEVs) from male and female wild-type and 5xFAD mouse brains to investigate the sex-specific functions of sEVs in Alzheimer's disease (AD). A mass spectrometric analysis revealed that sEVs contained proteins critical for EV formation and Aβ. ExoView analysis showed that female mice contained more GFAP and Aβ-labeled sEVs, suggesting that a larger proportion of sEVs from the female brain is derived from astrocytes and/or more likely to bind to Aβ. Moreover, sEVs from female brains had more acid sphingomyelinase (ASM) and ceramide, an enzyme and its sphingolipid product important for EV formation and Aβ binding to EVs, respectively. We confirmed the function of ASM in EV formation and Aβ binding using co-labeling and proximity ligation assays, showing that ASM inhibitors prevented complex formation between Aβ and ceramide in primary cultured astrocytes. Finally, our study demonstrated that sEVs from female 5xFAD mice were more neurotoxic than those from males, as determined by impaired mitochondrial function (Seahorse assays) and LDH cytotoxicity assays. Our study suggests that sex-specific sEVs are functionally distinct markers for AD and that ASM is a potential target for AD therapy.

The dynamic functional role of triggering receptor expressed on myeloid cells 2 (TREM2) assessed with cerebrospinal fluid and positron emission tomography measures

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) regulates several microglial activities and is essential for microglia to switch to an activated state. The role of TREM2 in the pathogenesis of Alzheimer’s disease (AD) is unclear, however. Following its role in microglial activity, the ectodomain of TREM2 is cleaved into the soluble proteolytic end product of TREM2 (sTREM2), which is released from the transmembrane domain into the cerebrospinal fluid (CSF) and, therefore, CSF sTREM2 is considered a biomarker of TREM2 activity.MethodTo examine the role of TREM2, we explored the relationships between CSF sTREM2, amyloid‐beta (Aβ42), phosphorylated tau‐181 (p‐tau‐181), and total‐tau (t‐tau) in a cohort of 495 participants (100 patients with AD, 257 patients with MCI, and 138 controls) whose data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Associations between CSF sTREM2 and 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET), 18F‐florbetapir (18F‐AV45) PET, and grey matter volume (GMV) were also investigated.ResultCSF sTREM2 levels were stable across AD, MCI and cognitively normal subgroups. In the whole cohort, CSF sTREM2 positively correlated with age (r = 0.214,p&lt;0.001), CSF Aβ42 (r = 0.118,p = 0.009), CSF t‐tau (r = 0.423,p&lt;0.001), and CSF p‐tau‐181 (r = 0.396,p&lt;0.001), and negatively correlated with MMSE score (r = ‐0.105,p = 0.019). CSF sTREM2, t‐tau and p‐tau‐181 could significantly predict CSF Aβ42 levels, while CSF sTREM2 and Aβ42 could significantly predict CSF p‐tau‐181 and t‐tau levels. Higher CSF sTREM2 was associated with greater amyloid load, decreased glucose metabolism, and reduced GMV in MCI, but not in AD, in certain brain regions.ConclusionCSF sTREM2 levels were comparable across clinical groups, and with CSF sTREM2 correlating with markers of AD and neuronal damage, we predict that changes in neuropathological processes occurring in relation to changes in CSF sTREM2 levels are a result of alterations in TREM2 function, rather than quantity. Taken together with the relationships between CSF sTREM2 and imaging findings, these results suggest that sTREM2 appears early on in the AD trajectory, probably in response to early microglial activation in MCI in response to evolving pathological processes.

FLAIR MRI biomarkers of the Normal‐Appearing Brain Matter (NABM) are related to APOE‐4 status and CSF markers Aβ42 and Tau

AbstractBackgroundReduced amyloid‐beta‐42 (Aβ42) and elevated total tau (t‐tau) protein concentrations in the CSF are characteristic of Alzheimer’s disease (AD) pathology [1]. Aβ42 contributes to extracellular plaque formation between neurons [2]. The total level of tau, a microtubule‐stabilizer in neuron axons [3], is associated with neuronal death [1]. Additionally, presence of ApoE4 (ε4) alleles is an established identifier for increased risk of AD [4]. Non‐invasive imaging‐based correlates of the CSF markers are lacking. This study examines correlations of novel FLAIR texture, intensity, and volume biomarkers, along with white matter lesion (WML) burden, with Aβ42, t‐tau, and ε4 status.MethodFLAIR volumes (n = 4044) from the ADNI database were used for analysis with CSF biomarkers. A subset (n = 921) was used for ε4 analysis based on available data. Normal‐appearing brain matter (NABM) was obtained by removing CSF and WML. Macrostructural damage (MAD), microstructural damage (MID), and integrity (MII) texture biomarkers [5] were extracted from each NABM volume (Fig. 1), along with median intensity, NABM/ICV ratio, and normalized WML volume [5]. Relationships between FLAIR biomarkers and AD markers were described using parametric statistical analyses. Statistical significance was set at p&lt;0.05.ResultAll FLAIR biomarkers were statistically significantly correlated with CSF Aβ42 levels. All features except MID and WML burden were significantly correlated with CSF t‐tau levels (Table 1). MAD, MID, and WML burden showed negative correlations with Aβ42, while MAD showed a positive correlation with t‐tau. Opposite trends were seen with MII, intensity, and NABM/ICV (Fig. 2). Significant differences between groups without and with one ε4 allele were found in all FLAIR biomarkers except WML burden. Significant differences in MAD, MII and NABM/ICV were found between groups with one and two ε4 alleles (Table 2).ConclusionFLAIR biomarkers were inversely associated with CSF Aβ42 concentrations, suggesting they may be surrogate markers of Aβ plaque formation. They were associated with CSF t‐tau concentrations, suggesting they could also be indicators of GM degeneration and neuronal death. They could also be indicators for patients at increased risk of AD, as they demonstrated significant differences with the presence of ε4. Further longitudinal studies are required to establish the exact mechanism of neurodegeneration.

Interaction between APOE4 and lifestyle on neuroimaging biomarkers and cognition in cognitively unimpaired older adults

AbstractBackgroundAPOE4 is the main genetic risk factor for Alzheimer’s disease (AD). Recent findings suggest that lifestyle factors could modulate the association between APOE4 and cognitive impairment and/or dementia risk. However, a comprehensive assessment of the interactions between lifestyle and APOE4 status on neuroimaging and cognitive markers of aging and AD is still missing. Our objective is to assess this question in cognitively normal elderly.MethodBaseline data of 134 cognitively unimpaired older adults (mean age: 69) from the Age‐Well study were analysed. They underwent lifestyle questionnaires (physical and cognitive activity, and diet), neuropsychological assessment (global cognition, memory, attention and executive functions) and multimodal neuroimaging (structural MRI, FDG‐ and Florbetapir‐PET). Interactions between lifestyle and APOE4 status on neuroimaging and cognition were assessed for each lifestyle factor separately.ResultThere was an interaction between APOE4 status and cognitive activity on neuroimaging measures (p‐values&lt;.04), such that higher cognitive engagement was associated with lower grey matter volume in the parahippocampal cortex and lower brain perfusion in the entorhinal and perirhinal cortices in APOE4 carriers only (Figure 1A). However, greater cognitive engagement was associated with increased cognitive performance (global cognition, executive function and attention, all p‐values&lt;.005), and this irrespective of APOE4 status (i.e., no cognitive activity x APOE4 status interaction; Figure 1B). For diet, interactions were evidenced (p‐values &lt;.04) such that higher adherence to the Mediterranean diet was associated with i) higher brain glucose metabolism in the medial temporal lobe (Figure 2A) and ii) higher performance on attention tests (Figure 2B) in APOE4 carriers only. No interactions were found for physical activity.ConclusionOur results indicate that APOE4 carriers with higher cognitive activity had lower brain outcomes but preserved cognition, suggesting that enriched cognitive engagement promotes cognitive resilience in this population. On the other hand, APOE4 carriers with higher adherence to the Mediterranean diet had greater cerebral metabolism and greater attention capacities. Overall, this suggests that distinct lifestyle factors differentially help APOE4 carriers to resist or cope with brain alteration and postpone cognitive decline.ClinicalTrials.gov Identifier: NCT02977819.

Perplexity and its structural cerebral correlates: A promising marker for cognitive decline?

AbstractBackgroundRecent studies identified linguistic changes as a promising marker of early Alzheimer´s disease (AD) and mild cognitive impairment (MCI). Perplexity – i.e. a measure of content complexity and therefore predictability of speech – is considered as a predictive marker of AD and MCI in otherwise healthy elderly (Frankenberg et al., 2019). A higher score indicates a reduced predictability, i.e. for persons with high variability in their speech, the perplexity feature will have a very high value. However, the underlying brain structures are still unknown.MethodPerplexity was automatically examined in voice recordings of extensive autobiographical interviews obtained in 38 participants in their mid‐70ties (N = 26 cognitively healthy, N = 12 with MCI) from the Interdisciplinary Longitudinal Study on Adult Development and Aging (ILSE). Perplexities of 1‐gram and 2‐gram language models are investigated: The 1‐gram language model considers one word at a time, the 2‐gram language model considers each word in the context of its predecessor. Whole‐brain correlations between gray matter and perplexity were controlled for total intracranial volume, sex and education.ResultsAnalyses yielded significant positive correlations between measures of perplexity and right parahippocampal gyrus, right middle occipital gyrus, left middle temporal gyrus and right superior temporal gyrus (1 gram) as well as left precuneus and left anterior cingulate (2 gram).ConclusionThe correlation of perplexity with parahippocampal gyrus is paralleled by associations between this structure and autobiographical memory (Frankenberg et al., submitted). The superior temporal gyrus points to planum temporale, while the precuneus is involved in motor coordination and is connected to the anterior cingulate, which is associated with functions such as error detection and attention. The middle temporal gyrus is also considered to be language‐relevant in particular for lexical‐semantic and conceptual semantic aspects and the middle occipital gyrus is discussed as the Occipital Word Form Sensitive Area.

Linguistic markers of Alzheimer’s in Spanish speakers: Automated metrics for free speech and verbal fluency tasks

AbstractBackgroundAutomated speech analysis can reveal objective, scalable markers of Alzheimer’s disease (AD). Yet, few studies have targeted Spanish, the most spoken language in Latin America, where AD is quickly escalating. Also, most research presents low interpretability, targeting linguistic features unrelated to the disorder’s core neuropsychological profile. Working with Hispanics, we have validated novel automated metrics capturing critical lexico‐semantic targets for AD: semantic granularity (coarseness of concepts) and ongoing semantic variability (conceptual closeness of successive words) –Figure 1A. I aim to describe and illustrate these metrics via two experiments comparing AD patients and healthy controls (HCs) on free speech and verbal fluency tasks. To test for specificity, replications were conducted in Parkinson’s disease (PD) and behavioral variant frontotemporal dementia cohorts.MethodIn Experiment‐1, 21 AD patients, 16 HCs, and 18 PD patients performed spontaneous and semi‐spontaneous speech tasks. In Experiment‐2, 32 AD patients, 27 HCs, 19 PD patients, and 32 bvFTD patients performed phonological and semantic fluency tasks. In both studies, responses were transcribed and lemmatized. Semantic granularity scores were computed on Python’s NLTK library to access WordNet, a lexical taxonomy leading from hypernyms (top node: ‘entity’) to hyponyms (e.g., ‘dog’). Each word’s granularity is defined as the distance between its node and ‘entity’ (Figure 1B). Ongoing semantic variability was analyzed with a FastText model pre‐trained with Spanish corpora. Each unique word in the vocabulary was assigned a vector, and the distance between words was quantified with the cosine of the angle between their assigned vectors (Figure 1C). Extracted features from both dimensions were analyzed through ANOVAs and XGBoost classifiers.ResultsIn Experiment‐1, relative to HCs, AD (but not PD) patients used more unspecific and fewer specific concepts, alongside more discontinuous conceptual choices. These features robustly classified between AD patients and HCs, but not between PD patients and HCs. In Experiment‐2, only AD patients exhibited reduced semantic granularity, which contributed to robust subject‐level classification. Ongoing semantic variability failed to distinguish among groups.ConclusionThese novel digital metrics can reveal objective, interpretable, and specific markers of AD in Spanish speakers, providing culture‐specific data for a vast but understudied linguistic community.

Head-to-head comparison of plasma p-tau181, p-tau231 and glial fibrillary acidic protein in clinically unimpaired elderly with three levels of APOE4-related risk for Alzheimer's disease

Plasma phosphorylated tau (p-tau) and glial fibrillary acidic protein (GFAP) both reflect early changes in Alzheimer's disease (AD) pathology. Here, we compared the biomarker levels and their association with regional β-amyloid (Aβ) pathology and cognitive performance head-to-head in clinically unimpaired elderly (n = 88) at three levels of APOE4-related genetic risk for sporadic AD (APOE4/4 n = 19, APOE3/4 n = 32 or non-carriers n = 37). Concentrations of plasma p-tau181, p-tau231 and GFAP were measured using Single molecule array (Simoa), regional Aβ deposition with 11C-PiB positron emission tomography (PET), and cognitive performance with a preclinical composite. Significant differences in plasma p-tau181 and p-tau231, but not plasma GFAP concentrations were present between the APOE4 gene doses, explained solely by brain Aβ load. All plasma biomarkers correlated positively with Aβ PET in the total study population. This correlation was driven by APOE3/3 carriers for plasma p-tau markers and APOE4/4 carriers for plasma GFAP. Voxel-wise associations with amyloid-PET revealed different spatial patterns for plasma p-tau markers and plasma GFAP. Only higher plasma GFAP correlated with lower cognitive scores. Our observations suggest that plasma p-tau and plasma GFAP are both early AD markers reflecting different Aβ-related processes.

Bone Marrow-Derived Mesenchymal Stem Cells and γ-Secretase Inhibitor Treatments Suppress Amyloid-β25-35-Induced Cognitive Impairment in Rat Dams and Cortical Degeneration in Offspring.

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and ensuing cognitive impairment. Progressive deposition of extracellular amyloid beta (Aβ) aggregates (plaques) and intracellular hyperphosphorylated Tau protein (p-Tau) are the core pathological markers of AD but may precede clinical symptoms by many years, presenting a therapeutic window of opportunity. Females are more frequently afflicted by AD than males, necessitating evaluation of novel treatments for the female population. The current study examined the protective efficacies of intravenous bone marrow-derived mesenchymal stem cells (BM-MSCs) and oral gamma-secretase inhibitor-953 (GSI-953) during pregnancy on cognitive impairment in rat dams and neurodegeneration in offspring induced by intracerebroventricular injection of Aβ25-35 prior to pregnancy. The Aβ25-35 (AD) group exhibited significant (P < 0.001) impairments in the Y-maze and novel object recognition test performance prior to conception. Histological analysis of the offspring cortex revealed substantial dendritic shrinkage and activation of microglial cells, while neurochemical analysis demonstrated significant increases in the proinflammatory cytokine interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). In contrast, BM-MSC or GSI-953 treatment of dams following Aβ25-35 injection significantly (P < 0.001) reduced the number and size of activated microglial cells, markedly increased dendrite length, and reversed proinflammatory cytokine elevations in offspring. Moreover, BM-MSC or GSI-953 treatment reversed the Aβ25-35-induced amyloid precursor protein and p-Tau elevations in the offspring brain; these changes were accompanied by upregulation of the brain-derived neurotrophic factor and downregulation of glycogen synthase kinase-3β in the serum and brain. Treatment with BM-MSCs or GSI-953 also reversed Aβ25-35-induced elevations in different gene expressions in the neonatal cortex. Finally, treatment of dams with BM-MSCs or GSI-953 prevented the Aβ25-35-induced disruption of newborn brain development. Thus, BM-MSC and GSI-953 treatments have broad-spectrum effects against Aβ25-35-induced brain pathology, including the suppression of neural inflammation, restoration of developmental plasticity, and promotion of neurotrophic signaling.

Plasma levels of phosphorylated tau and neurofilament light chain as potential biomarkers for Alzheimer’s disease: A biochemical analysis in Pakistani population

The National Institute on Aging-Alzheimer's Association's research framework in 2018 proposed a molecular construct for the diagnosis of Alzheimer’s disease (AD). Nonetheless, the clinical exclusionary strategy is still the mainstay of AD diagnosis in Pakistan. We looked at the plasma levels of amyloid beta-42 (Aβ-42), phosphorylated tau (P-tau), and neurofilament light (NFL) in patients with Alzheimer's clinical syndrome (ACS) and healthy controls (HC) from the Pakistani population to keep pace with the global efforts towards establishing accessible and affordable biochemical diagnostic markers for AD in Pakistan.Consultant neurologists screened patients who presented with cognitive impairment to three large tertiary care hospitals in Karachi, and after receiving informed consent, recruited participants with ACS and HC from the same facilities. We collected 5cc of blood in EDTA tubes along with demographic and lifestyle information of the subjects. Plasma aliquots were stored at −80°C after centrifugation. For analysis it was thawed at 4℃ and levels of the three proteins were measured through ELISA.Data from 28 ACS patients and 28 age matched healthy controls were evaluated. Among demographic factors, education and depression were related with health status (p = 0.03 and 0.003, respectively). NFL and P-tau mean values demonstrated a significant difference between the ACS and control groups (p = 0.003 and 0.006), however Aβ42 did not (p = 0.114). ROC analysis showed that plasma P-tau and NFL, with AUCs of 0.717 and 0.735, respectively, could substantially distinguish ACS from the HC group (p = 0.007 and 0.003, respectively). Both plasma P-tau (r = −0.389; p = 0.004) and NFL (r = −0.424; p = 0.001) levels were significantly and negatively correlated with individuals' MMSE scores. NFL and plasma P-tau show promise in differentiating AD patients from healthy individuals. However, similar larger studies are needed to validate our findings.

Assessing adipokines as potential biomarkers of dementia, Alzheimer's disease, and mild cognitive impairment: A systematic review and meta-analysis.

Midlife obesity and late-life weight loss confer a greater risk for developing dementia and Alzheimer's disease (AD), but the exact mechanisms behind this phenomenon are currently unknown. The answer could lie on the involvement of gastrointestinal factors, such as adipokines (e.g., leptin, adiponectin, and resistin) and ghrelin. In this context, we conducted a pre-registered systematic review and meta-analysis of 42 cross-sectional and 13 longitudinal studies targeting the associations between leptin, adiponectin, resistin, and ghrelin and the prevalence of general dementia, AD, and mild cognitive impairment (MCI). We also examined the relationship between the four gastrointestinal factors and neurocognitive outcomes and AD-related cerebrospinal fluid biomarkers. Patients with AD had lower blood leptin and higher resistin levels than cognitively normal participants. Lower leptin and higher resistin were associated with higher degree of cognitive impairment. Additionally, lower late-life leptin levels might be associated with higher prospective risk of dementia and AD, although more studies are needed to corroborate this. Results in ghrelin and adiponectin were not conclusive, with age, sex distribution, obesity, and severity of dementia seemingly acting as moderators across several analyses. Our work might contribute to the identification of new preclinical blood markers of MCI and AD.