Classical Alzheimer's Disease Research Articles

Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.

Blood-based biomarkers are gaining grounds for Alzheimer's disease (AD) detection. However, two key obstacles need to be addressed: the lack of methods for multi-analyte assessments and the need for markers of neuroinflammation, vascular, and synaptic dysfunction. Here, we evaluated a novel multi-analyte biomarker platform, NULISAseq CNS disease panel, a multiplex NUcleic acid-linked Immuno-Sandwich Assay (NULISA) targeting ~120 analytes, including classical AD biomarkers and key proteins defining various disease hallmarks. The NULISAseq panel was applied to 176 plasma samples from the MYHAT-NI cohort of cognitively normal participants from an economically underserved region in Western Pennsylvania. Classical AD biomarkers, including p-tau181 p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were also measured using Single Molecule Array (Simoa). Amyloid pathology, tau pathology, and neurodegeneration were evaluated with [11C] PiB PET, [18F]AV-1451 PET, and MRI, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA biomarkers and AD pathologies. Spearman correlations were used to compare NULISA and Simoa. NULISA concurrently measured 116 plasma biomarkers with good technical performance, and good correlation with Simoa measures. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET+ participants, including TIMP3, which regulates brain Aβ production, the neurotrophic factor BDNF, the energy metabolism marker MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET+ participants. Markers with tau PET-dependent longitudinal changes included the microglial activation marker CHIT1, the reactive astrogliosis marker CHI3L1, the synaptic protein NPTX1, and the cerebrovascular markers PGF, PDGFRB, and VEFGA; all previously linked to AD but only reliably measured in cerebrospinal fluid. SQSTM1, the autophagosome cargo protein, exhibited a significant association with neurodegeneration status after adjusting age, sex, and APOE ε4 genotype. Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes. Further validation of the identified inflammation, synaptic, and vascular markers will be important for establishing disease state markers in asymptomatic AD.

Comparative interactome mapping of Tau-protein in classical and rapidly progressive Alzheimer's disease identifies subtype-specific pathways.

Tau is a key player in Alzheimer's disease (AD) and other Tauopathies. Tau pathology in the brain directly correlates with neurodegeneration in AD. The recent identification of a rapid variant of AD demands an urgent need to uncover underlying mechanisms leading to differential progression in AD. Accordingly, we aimed to dissect the underlying differential mechanisms of toxicity associated with the Tau protein in AD subtypes and to find out subtype-dependent biomarkers and therapeutic targets. To identify and characterise subtype-specific Tau-associated mechanisms of pathology, we performed comparative interactome mapping of Tau protein in classical AD (cAD) and rapidly progressive AD (rpAD) cases using co-immunoprecipitation coupled with quantitative mass spectrometry. The mass spectrometry data were extensively analysed using several bioinformatics approaches. The comparative interactome mapping of Tau protein revealed distinct and unique interactors (DPYSL4, ARHGEF2, TUBA4A and UQCRC2) in subtypes of AD. Interestingly, an analysis of the Tau-interacting proteins indicated enrichment of mitochondrial organisation processes, including negative regulation of mitochondrion organisation, mitochondrial outer membrane permeabilisation involved in programmed cell death, regulation of autophagy of mitochondrion and necroptotic processes, specifically in the rpAD interactome. While, in cAD, the top enriched processes were related to oxidation-reduction process, transport and monocarboxylic acid metabolism. Overall, our results provide a comprehensive map of Tau-interacting protein networks in a subtype-dependent manner and shed light on differential functions/pathways in AD subtypes. This comprehensive map of the Tau-interactome has provided subsets of disease-related proteins that can serve as novel biomarkers/biomarker panels and new drug targets.

The cerebrospinal fluid soluble TREM‐1 concentration in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI)

AbstractBackgroundThe most prevalent form of dementia in the world is Alzheimer Disease (AD), a common neurodegenerative condition. Amyloid peptides, phosphorylated tau proteins, and neuroinflammation are the disease’s hallmarks. Finding new biomarkers that can assist in early AD detection is crucial due to the late appearance of the disease symptoms. Triggering receptor expressed on myeloid cell 1 (TREM‐1) is hypothesized that may contribute to the development of AD by causing neuroinflammation. Due of its significance in inflammatory responses, it has been regarded as a promising biomarker. Literature data indicate that TREM‐1 could be potential biomarker of AD severity. Therefore the purpose of our research was to measure the concentration of soluble TREM‐1 in cerebrospinal fluid of AD and MCI patients and non‐demented controls and compare it with classical AD biomarkers.MethodThe concentrations of TREM‐1 were measured in cerebrospinal fluid (CSF) of 20 AD patients and 15 MCI patients as well as 11 non‐demented controls using multiplexing method. Classical biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181 were assessed by immunoenzyme assays.ResultTREM‐1 concentrations were significantly higher in AD and MCI patients in comparison to non‐demented controls. Moreover, in MCI patients, the levels of this protein were significantly higher than in AD patients. Additionally, increased CSF levels of TREM‐1 correlated positively with Tau, pTau181 in the whole study group.ConclusionFindings of our research suggest that TREM‐1 could be early indicator of AD pathology. However, follow‐up studies on larger study group are needed.

Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. Plasma was obtained from participants (N=837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD-inflammatory biomarker correlations showed significant associations between AD and inflammatory biomarkers suggesting peripheral inflammatory interactions with increasing AD pathology. Biomarker associations parsed out by clinical diagnosis (normal, MCI, and dementia) reveal changes in strength of the correlations across the cognitive continuum. Unique AD-inflammatory biomarker correlations in a community-based cohort reveal a new avenue for utilizing plasma-based biomarkers in the assessment of AD and related dementias. Large community cohorts studying sex, age, and APOE genotype effects on biomarkers are few. It is unknown how biomarker-biomarker associations vary through aging and dementia. Six AD (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNFα, IL6, IL8, IL10, and GFAP) were used to examine associations between biomarkers. Plasma biomarkers suggesting increasing cerebral AD pathology corresponded to increases in peripheral inflammatory markers, both pro-inflammatory and anti-inflammatory. Strength of correlations, between pairs of classic AD and inflammatory plasma biomarker, changes throughout cognitive progression to dementia.

The assessment of ubiquitin C‐terminal hydrolase‐1 (UCH‐L1) in patients with Alzheimer’s disease

AbstractBackgroundAlzheimer's disease is a debilitating disease that leads to a disability of the patient and it is therefore interesting not only from a medical but also from a legal point of view. Despite progress in studies on pathological mechanisms underlying the Alzheimer's disease (AD) still remains incurable. One of the mechanisms responsible for the oligomerization / aggregation of misfolded or damaged proteins in AD may be dysfunction of the ubiquitin‐proteasome system (UPS), including the highly abundant neuronal enzyme ubiquitin carboxyl‐terminal hydrolase L1 (UCHL‐1). UCHL‐1 is involved in the regulation of proteasomal degradation of damaged proteins. The presence of UCH‐L1 was found in neurofibrillary tangles in the AD brain. The aim of the present study was to measure UCHL1 levels in the cerebrospinal fluid (CSF) patients with AD and evaluate a relationship between concentrations of UCHL1 and classical neurochemical dementia biomarkers.MethodThe concentrations of UCHL‐1 and classical AD biomarkers were measured in 30 subjects, including AD patients and individuals from control group by means of multiplexing assay.ResultThe CSF concentration of UCHL‐1 was significantly higher in AD group in comparison with cognitively normal individuals. Additionally, in the whole study group levels of UCHL‐1 correlated negatively with decreased concentration of Aβ 1‐42, MMSE. Furthermore, the significant relationship between UCHL‐1 and tau proteins was also revealed.ConclusionThe study suggest a potential role of UCHL‐1 protein in the pathology of AD and its potential usefulness as a candidate biomarker of AD, but these investigations need to be further confirmed.

Ultrahigh Sensitive Detection of Tau Protein as Alzheimer's Biomarker via Microfluidics and Nanofunctionalized Optical Fiber Sensors

Alzheimer's disease (AD) is one of the most common neurodegenerative illnesses displaying the highest death rate in the elderly. However, the existing AD diagnostic system remains elusive due to lack of a technology that may ensure enough sensitivity and reproducibility, detection accuracy, and specificity. Herein, a straightforward approach is reported to realize lab‐on‐fiber (LoF) technology for AD biomarker detection based on a D‐shaped single‐mode fiber combined with nanometer‐scale metal‐oxide film. The proposed sensing system, which permits the generation of lossy‐mode resonance (LMR), remarkably increases the evanescent field of light guided through the fiber, and hence the fiber‐surrounding medium interaction. Moreover, such optical sensors are highly repeatable in results and can safely be embedded into a compact and stable microfluidic system. Herein, the specific detection of Tau protein (as one of the classical AD biomarkers that is highly correlated with AD progression) in a complex biofluid with a detection limit of 10−12 m and over a wide concentration range (10−3–10 μg mL−1) is successfully demonstrated. The proposed LoF biosensor is an appealing solution for rapid, sub‐microliter dose and highly sensitive detection of analytes at low concentrations, hereby having the potential toward early screening and personalized medicine in AD.

Neuronal ER-Signalosome Proteins as Early Biomarkers in Prodromal Alzheimer's Disease Independent of Amyloid-β Production and Tau Phosphorylation.

There exists considerable interest to unveil preclinical period and prodromal stages of Alzheimer's disease (AD). The mild cognitive impairment (MCI) is characterized by significant memory and/or other cognitive domains impairments, and is often considered the prodromal phase of AD. The cerebrospinal fluid (CSF) levels of β-amyloid (βA), total tau (t-tau), and phosphorylated tau (p-tau) have been used as biomarkers of AD albeit their significance as indicators during early stages of AD remains far from accurate. The new biomarkers are being intensively sought as to allow identification of pathological processes underlying early stages of AD. Fifty-three participants (75.4 ± 8.3 years) were classified in three groups as cognitively normal healthy controls (HC), MCI, and subjective memory complaints (SMC). The subjects were subjected to a battery of neurocognitive tests and underwent lumbar puncture for CSF extraction. The CSF levels of estrogen-receptor (ER)-signalosome proteins, βA, t-tau and p-tau, were submitted to univariate, bivariate, and multivariate statistical analyses. We have found that the components of the ER-signalosome, namely, caveolin-1, flotilin-1, and estrogen receptor alpha (ERα), insulin growth factor-1 receptor β (IGF1Rβ), prion protein (PrP), and plasmalemmal voltage dependent anion channel 1 (VDAC) could be detected in the CSF from all subjects of the HC, MCI, and SMC groups. The six proteins appeared elevated in MCI and slightly increased in SMC subjects compared to HC, suggesting that signalosome proteins undergo very early modifications in nerve cells. Using a multivariate approach, we have found that the combination of ERα, IGF-1Rβ, and VDAC are the main determinants of group segregation with resolution enough to predict the MCI stage. The analyses of bivariate relationships indicated that collinearity of ER-signalosome proteins vary depending on the stage, with some pairs displaying opposed relationships between HC and MCI groups, and the SMC stage showing either no relationships or behaviors similar to either HC or MCI stages. The multinomial logistic regression models of changes in ER-signalosome proteins provide reliable predictive criteria, particularly for the MCI. Notably, most of the statistical analyses revealed no significant relationships or interactions with classical AD biomarkers at either disease stage. Finally, the multivariate functions were highly correlated with outcomes from neurocognitive tests for episodic memory. These results demonstrate that alterations in ER-signalosome might provide useful diagnostic information on preclinical stages of AD, independently from classical biomarkers.

Personality Impact on Alzheimer's Disease - Signature and Vascular Imaging Markers: A PET-MRI Study.

Several studies postulated that personality is an independent determinant of cognitive trajectories in old age. This study explores the impact of personality on widely used Alzheimer's disease (AD) and vascular imaging markers. We examined the association between personality and three classical AD imaging markers (centiloid-based-amyloid load, MRI volumetry in hippocampus, and media temporal lobe atrophy), and two vascular MRI parameters (Fazekas score and number of cortical microbleeds) assessed at baseline and upon a 54-month-follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of imaging markers including sex, personality factors, presence of APOE ɛ4 allele and cognitive evolution over time. Cortical GM volumes were negatively associated with higher levels of Conscientiousness both at baseline and follow-up. In contrast, higher scores of Openness were related to better preservation of left hippocampal volumes in these two time points and negatively associated with medial temporal atrophy at baseline. Amyloid load was not affected by personality factors. Cases with higher Extraversion scores displayed higher numbers of cortical microbleeds at baseline. Personality impact on brain morphometry is detected only in some among the routinely used imaging markers. The most robust associations concern the positive role of high levels of Conscientiousness and Openness on AD-signature MRI markers. Higher extraversion levels are associated with increased vulnerability to cortical microbleeds pointing to the fact that the socially favorable traits may have a detrimental effect on brain integrity in old age.

Neurodegeneration: 2022 update.

Here, we review a collection of recent manuscripts and research trends on the neuropathology of neurodegeneration that are considered by the author to be among the potentially most impactful. To the greatest extent possible, we chose to focus on histopathological studies that are most relevant to experimental and diagnostic neuropathology. While there has been an abundance of important recent discoveries and developments in neurodegenerative disease research, there was a deliberate effort here to provide balance to prevent disease categories and experimental approaches from overshadowing the others. The result is a diverse series of outstanding studies, together showing the landscape of progress across neurodegenerative disorders. One is a stereological study examining dystrophic microglia in aging. We highlight the first large genetic study of primary age-related tauopathy, showing convergence and divergence from classical Alzheimer's disease. There were further advances in the neuropathological criteria and staging of chronic traumatic encephalopathy. Links suggesting a causal role for TMEM106B in TDP-43 proteinopathy emerged. Attempts to subtype Alzheimer's disease on the molecular level were made. Evidence for a role for the VEGF family in cognitive impairment was advanced. Comparison of gene expression profiles from myeloid cells in peripheral blood and brain tissues from Parkinson's disease patients revealed pathways that may lead to new mechanistic insights and biomarkers. A large autopsy series identified an increased frequency of central nervous system developmental malformations in Huntington's disease. A robust and reliable system for assessing Lewy body pathology was proposed. Finally, we continue to be plagued by the COVID-19 pandemic, with lingering concerns of a long-term link with neurodegeneration.

Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease

Amyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD.

Aducanumab and the “post-amyloid” era of Alzheimer research?

Aducanumab and the “post-amyloid” era of Alzheimer research?

Decoding perineuronal net glycan sulfation patterns in the Alzheimer's disease brain.

The extracellular matrix (ECM) of the brain comprises unique glycan "sulfation codes" that influence neurological function. Perineuronal nets (PNNs) are chondroitin sulfate-glycosaminoglycan (CS-GAG) containing matrices that enmesh neural networks involved in memory and cognition, and loss of PNN matrices is reported in patients with neurocognitive and neuropsychiatric disorders including Alzheimer's disease (AD). Using liquid chromatography tandem mass spectrometry (LC-MS/MS), we show that patients with a clinical diagnosis of AD-related dementia undergo a re-coding of their PNN-associated CS-GAGs that correlates to Braak stage progression, hyperphosphorylated tau (p-tau) accumulation, and cognitive impairment. As these CS-GAG sulfation changes are detectable prior to the regional onset of classical AD pathology, they may contribute to the initiation and/or progression of the underlying degenerative processes and implicate the brain matrix sulfation code as a key player in the development of AD clinicopathology.

Author Response: Blood Biomarkers of Traumatic Brain Injury and Cognitive Impairment in Older Veterans.

We would like to thank Drs. Wisniewski and Fossati for their insightful comments on our recent article1 examining blood biomarkers associated with traumatic brain injury (TBI) and cognitive impairment (CI) in CNS-enriched exosomes. We agree that our findings of differences between the TBI and CI groups do not seem to be solely due to TBI and are most likely explained by TBI-associated CI. Indeed, our results suggest that phosphorylated tau, neurofilament light, tumor necrosis factor alpha, interleukin 6, and glial fibrillary acidic protein could differentiate non–TBI-CI from TBI-CI. Drs. Wisniewski and Fossati astutely pointed out differences between 2 different biomarker articles published by our group. These studies used different assays analyzed in separate laboratories, and study participants were different, although overlapping. However, due to the small sample size, we cannot discount the possibility of type II error in our findings with regard to Aβ42. Nonetheless, our results—along with several other imaging and biomarker studies—suggest that TBI-CI is likely to differ from classic Alzheimer disease biomarkers. We appreciate the ability to clarify the results of our article. This research is an important step to disentangling the neuropathologic underpinnings of CI after TBI, and we are excited about the inroads being made into this rapidly evolving field.

Changes in the Brain Extracellular Matrix Sulfation Code in Alzheimer's Disease

Alzheimer's Disease (AD) is a neurodegenerative disorder associated with synapse dysfunction and neurocircuit hyperactivation. Neural networks involved in memory and cognition are regulated by extracellular matrices known as perineuronal nets (PNNs), and these unique matrix structures are reduced in the human AD brain. PNNs are comprised of chondroitin sulfate glycosaminoglycan (CS-GAG) lattices that consist of five differentially-sulfated CS isomers (CS-A, -C, -D, -E and -O), with their relative abundance comprising a “sulfation code” that controls key biological functions including neuroplasticity (CS-A), protein-glycan binding (CS-O, CS-D), and neuroinflammation (CS-C, CS-E). Although changes in CS-GAGs promote PNN dysfunction, synapse reorganization, and neurocircuit hyperactivation in rodents, it is unknown if such changes are features in human AD brain. Using LC-MS/MS analysis, we report a decrease in the nonsulfated ΔO (p=0.0002) in the middle frontal gyrus (MFG) of human AD brain compared to controls. This effect was offset by an increase in the monosulfated ΔC (p=0.024) and trending increase in the disulfated ΔE (p=0.067), which yielded an increase in overall CS-GAG sulfation (p<0.0001). We next sought to determine whether changes in CS-GAGs in AD also associate with Braak stage and topographic distribution of neurofibrillary tangles including phosphorylated tau (P-tau). We found that more advanced Braak stage associated with a decrease in the non-sulfated ΔO (p<0.0001), increases in the sulfated ΔC (p=0.011) and ΔE (p=0.047), and a trending increase in the ΔD (p=0.093), which yielded a Braak stage-dependent increase in overall CS-GAG sulfation (p<0.0001). Antibody labeling against P-tau S396 showed robust accumulation within layer V of the MFG neocortex of AD patients, and whereas P-tau burden was inversely correlated with ΔO (p=0.0017), it was positively correlated with ΔC (p=0.0037), ΔD (p=0.0189), ΔE (p=0.0014), as well as with overall CS sulfation (p<0.0001). Finally, as the increase in Braak stage and P-tau accumulation associate with cognitive decline in AD, we correlated cognitive function (assessed using the Mini-Mental State Examination-MMSE) with changes in CS-GAG sulfation patterns within the MFG. We report that MMSE scoring correlated positively with ΔO (p<0.0006) and negatively with ΔE (p=0.0062) and CS sulfation (p<0.0001) but did not associate with changes in ΔC, ΔD, or ΔA isomer abundance. Since the changes in CS-GAG sulfation reported herein were present prior to the regional onset of classical AD pathology (e.g. Braak III/IV, prior to tangle formation in the MFG), they may play an active role to initiate and/or progress underlying degenerative processes and thus represents a novel target for the prevention and treatment of AD.

Different patterns of hippocampal subfield pathology in Lewy body disease and Alzheimer's disease

Coughlin and colleagues [1] recently examined the association between hippocampal α-synuclein (SYN) and tau pathologies in 49 autopsy-confirmed cases of Lewy body diseases (LBD) - 30 with no/low Alzheimer disease (AD) co-pathology (LBD - AD) and 19 with moderate/high AD co-pathology (LBD + AD) aged at death 77.3 and 78.6 years, and disease duration 15.8 and 9.1 years, respectively, and 30 AD patients with a mean age of 74.4 years. 67% and 89%, respectively, were neocortical, 27% and 11%, respectively, limbic LBD stage, with only very few brainstem predominant forms [2]. LBD - AD and LBD + AD had similar severity and distribution of SYN pathology, subfield CA 2/3 being most severely affected, while CA1/subiculum and entorhinal cortex (ERC) were the most affected regions in AD. Tau pathology in both LBD - AD and LBD + AD was greatest in about two thirds, suggesting that tau burden in LBD was similar to the distribution of SYN in subfield CA 2/3, thus diverging from that in classical AD and contributing to memory dysfunction in LBD. β-Amyloid severity and distribution were similar between LBD + AD and AD.

Hippocampal subregional volume changes in elders classified using positron emission tomography‐based Alzheimer's biomarkers of β‐amyloid deposition and neurodegeneration

Changes in hippocampal subfield volumes (HSV) along the Alzheimer's disease (AD) continuum have been scarcely investigated to date in elderly subjects classified based on the presence of β-amyloid aggregation and signs of neurodegeneration. We classified patients (either sex) with mild dementia compatible with AD (n=35) or amnestic mild cognitive impairment (n=39), and cognitively unimpaired subjects (either sex; n=26) using [11 C]PIB-PET to assess β-amyloid aggregation (A+) and [18 F]FDG-PET to account for neurodegeneration ((N)+). Magnetic resonance imaging-based automated methods were used for HSV and white matter hyperintensity (WMH) measurements. Significant HSV reductions were found in A+(N)+ subjects in the presubiculum/subiculum complex and molecular layer, related to worse memory performance. In both the A+(N)+ and A+(N)- categories, subicular volumes were inversely correlated with the degree of Aβ deposition. The A-(N)+ subgroup showed reduced HSV relative to the A-(N)- subgroup also in the subiculum/presubiculum. Combining all (N)- subjects, HSV were lower in subjects presenting significant cognitive decline irrespective of A+/A- classification (controlling for WMH load); these between-group differences were detected again in the presubiculum, but also involved the CA4 and granular layer. These findings demonstrate that differential HSV reductions are detectable both in (N)+ and (N)- categories along the AD continuum, and are directly related to the severity of cognitive deficits. HSV reductions are larger both in A+(N)+ and A+(N)- subjects in direct proportion to the degree of Aβ deposition. The meaningful HSV reductions detected in the A-(N)+ subgroup highlights the strength of biomarker-based classifications outside of the classical AD continuum.

A novel mutation in PSEN1 (p.Arg41Ser) in an Argentinian woman with early onset Parkinsonism

IntroductionMutations in presenilin-1 (PSEN1) account for the majority of cases of familial autosomal dominant early-onset Alzheimer's disease (AD) as well as in sporadic forms. Atypical presentations are reported including extrapyramidal signs. In the last years, a pleiotropic effect of some PSEN1 variants has been reported in Parkinson's disease (PD). Objectiveto report a new PSEN1 mutation characterized by early-onset Parkinsonism (EOPD) without dementia or classical AD biomarkers phenotype. Patient and methodsAn Argentinian 46 years old woman was diagnosed with EOPD at 35 years old with no family history of neurodegenerative disorders. Her medical history included iron deficiency and anemia since childhood.A brain MRI showed moderate frontal atrophy. 18FDG-PET and PiB-PET as well as CSF biomarkers were inconclusive for AD. Two neuropsychological examinations were compatible with a mild non amnestic cognitive impairment. Whole blood DNA was extracted and whole exome sequencing and analysis was performed. Results and conclusionA heterozygous novel missense PSEN1 mutation (position 14:73637540, A > T, pArg41Ser) was identified as a likely causative mutation in this patient. To the best of our knowledge, this case is the first PSEN1 mutation with a l-dopa responsive Parkinsonism lacking distinctive classical AD biomarkers. This case opens a new window to explore the pathophysiological link among PSEN1 and EOPDs and contributes to increase the phenotypes of PSEN1 variants.

Diagnostic performance of new and classic CSF biomarkers in age-related dementias.

The identification of diagnostic-prognostic biomarkers of dementia has become a global priority due to the prevalence of neurodegenerative diseases in aging populations. The objective of this study was to assess the diagnostic performance of cerebrospinal fluid (CSF) biomarkers across patients affected by either Alzheimer’s disease (AD), tauopathies other than AD (TP), or vascular dementia (VD), and cognitively normal subjects (CNS). One hundred fifty-three patients were recruited and tested for classical AD CSF biomarkers- Amyloid-ß42 and tau proteins - and novel candidate biomarkers - neurofilament (NF-) light and microRNA (miR) -21, -125b, -146a, and -222.All dementia patients had significantly higher concentrations of NF-light compared to CNS, with the TP group displaying the highest NF-light values. A significant inverse correlation was also observed between NF-light and cognitive impairment. Of the four miRNAs analyzed, miR-222 levels were significantly increased in VD patients compared to both CNS and AD. In addition, while NF-light showed a better diagnostic performance than miR-222 and classical AD biomarkers in differentiating TP and VD from CNS, classical AD biomarkers revealed higher performance in discriminating AD from non-AD disorders.Overall, our results suggest that CSF NF-light and miR-222 are promising biomarkers that may help to diagnose non-AD disorders.

Parkinsonism in genetic and sporadic Alzheimer's disease.

Alzheimer disease (AD) is a neurodegenerative disease characterized by deposition of pathologically aggregated amyloid-β in the extracellular space and pathologically aggregated tau protein in the intracellular space. Mainly affected brain areas are the temporal and the parietal lobe, which cause the classical AD phenotype consisting of increasing forgetfulness and difficulties to orientate. However, AD pathology is not restricted to these brain areas and spreads through the brain as the disease progresses, which can lead to a number of additional symptoms and to atypical presentations. Motor symptoms in AD are the topic of this chapter. Even though motor symptoms are usually not severe and seldomly treated, motor symptoms are quite frequent and can be observed in the majority of AD cases. Motor symptoms are especially frequent in cases with early onset and long disease duration, for example in Apolipoprotein E e4 carriers and in familial early onset AD. In severe cases treatment with pharmacological approaches might be considered. However, treatment strategies largely rely on expert opinions. Due to potential positive impact on prognosis non-pharmacological treatment and exercise might be considered in less advanced cases.

Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer\u2019s disease mouse model

Alzheimer's disease (AD) is an intractable progressive neurodegenerative disease characterized by cognitive decline and dementia. An inflammatory neurodegenerative pathway, involving Caspase-1 activation, is associated with human age-dependent cognitive impairment and several classical AD brain pathologies. Here, we show that the nontoxic and blood–brain barrier permeable small molecule Caspase-1 inhibitor VX-765 dose-dependently reverses episodic and spatial memory impairment, and hyperactivity in the J20 mouse model of AD. Cessation of VX-765 results in the reappearance of memory deficits in the mice after 1 month and recommencement of treatment re-establishes normal cognition. VX-765 prevents progressive amyloid beta peptide deposition, reverses brain inflammation, and normalizes synaptophysin protein levels in mouse hippocampus. Consistent with these findings, Caspase-1 null J20 mice are protected from episodic and spatial memory deficits, neuroinflammation and Aβ accumulation. These results provide in vivo proof of concept for Caspase-1 inhibition against AD cognitive deficits and pathologies.