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We propose a new therapeutic strategy for Alzheimer's disease (AD). Brain peptide p3‐Alcβ37 is generated from the neuronal protein alcadein β through cleavage of γ‐secretase, similar to the generation of amyloid β (Aβ) derived from Aβ‐protein precursor/APP. Neurotoxicity by Aβ oligomers (Aβo) is the prime cause prior to the loss of brain function in AD. We found that p3‐Alcβ37 and its shorter peptide p3‐Alcβ9‐19 enhanced the mitochondrial activity of neurons and protected neurons against Aβo‐induced toxicity. This is due to the suppression of the Aβo‐mediated excessive Ca2+ influx into neurons by p3‐Alcβ. Successful transfer of p3‐Alcβ9‐19 into the brain following peripheral administration improved the mitochondrial viability in the brain of AD mice model, in which the mitochondrial activity is attenuated by increasing the neurotoxic human Aβ42 burden, as revealed through brain PET imaging to monitor mitochondrial function. Because mitochondrial dysfunction is common in the brain of AD patients alongside increased Aβ and reduced p3‐Alcβ37 levels, the administration of p3‐Alcβ9‐19 may be a promising treatment for restoring, protecting, and promoting brain functions in patients with AD. Synopsis: This study presents a novel therapeutic approach for treating Alzheimer's disease (AD) by utilizing a small peptide derived from the brain peptide p3‐Alcβ37. Mitochondrial activity of neurons is enhanced by brain p3‐Alcβ37 and a druggable shorter peptide p3‐Alcβ9‐19.Aβ‐induced neurotoxicity caused by excessive Ca2+ influx is suppressed by p3‐Alcβ peptides.Brain mitochondria viability of AD mice is improved by peripheral administration of p3‐Alcβ9‐19. [ABSTRACT FROM AUTHOR]

Background: The evaluation of 11C‐DPA‐713 binding using positron emission tomography for quantifying the translocator protein can be a sensitive approach in determining the level of glial activation induced by neuroinflammation. Herein, we aimed to investigate the relationship between regional 11C‐DPA713‐binding potential (BPND) and neuropsychiatric symptoms (NPS) in amyloid‐positive Alzheimer's disease (AD) patients. Methods: Fifteen AD patients were enrolled in this study. Correlations were evaluated between the 11C‐DPA713‐BPND and Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, including scores in its four domains: agitation, psychosis, affective, and apathy. 11C‐DPA713‐BPND values were compared between groups with and without the neuropsychiatric symptoms for which a relationship was observed in the abovementioned correlation analysis. Results: A positive correlation was found between the severity of agitation and 11C‐DPA713‐BPND in the Braak 1–3 area, including the amygdala, hippocampal and parahippocampal regions, and lingual and fusiform areas. An increase in the 11C‐DPA713‐BPND was observed in AD patients with agitation. We did not find any significant effects of possible confounding factors, such as age, duration of illness, education, gender, Mini‐Mental State Examination score, cerebrospinal fluid amyloid β 42/40 ratio, and apolipoprotein E4 positivity, on either the 11C‐DPA713‐BPND or agitation score. Conclusions: Neuroinflammation in the medial temporal region and its neighbouring area was shown to be associated with the development of agitation symptoms in AD patients. Our findings extend those of previous studies showing an association between some NPS and inflammation, suggesting that immunologically based interventions for agitation can serve as an alternative treatment for dementia. [ABSTRACT FROM AUTHOR]

Background: Posterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing. The underlying pathology in PCA is most commonly Alzheimer's disease (AD), but large‐scale biomarker and neuropathological studies are lacking. In this ongoing project we aim to describe demographic, clinical, biomarker and neuropathological correlates of PCA in a large‐scale international cohort. Method: We contacted 55 research centers conducting PCA research identified in a literature review (n=1353 papers) as well as additional sites recruited through the ISTAART Atypical AD Professional Interest Group (n=7 sites) requesting deidentified, single‐subject data from PCA patients (published and unpublished). Inclusion criteria were: 1. clinical diagnosis of PCA, 2. availability of AD biomarkers (PET or CSF) or 3. availability of autopsy diagnosis. Single‐subject demographic, clinical, fluid, neuroimaging and neuropathological data were collected. Result: As of January 2022, we have collected individual patient data from 390 participants evaluated at 14 sites in 10 countries (Table 1). In the preliminary sample, mean age at symptom onset was 63.1 ± 8.8 years, 62.3% of participants were female, and 78.3% presented with a "PCA‐pure" clinical syndrome by Crutch 2017 diagnostic criteria. APOE4 genotype was present in 45.6% (n=125). Preliminary results show that 82.9% (n=270) display predominant MRI atrophy and 91.9% (n=185) predominant FDG hypometabolism in posterior cortical regions. CSF amyloid markers were positive in 80.2% participants (n=187), while CSF phosphorylated tau markers were positive in 61.4% (n=184). Amyloid PET was positive in 85.2% (n=129) while tau PET was only available in 65 patients (positive in all, and all were amyloid positive). At autopsy (n=36, data from 4 centers), high AD neuropathologic changes were found in all but one patient, who had primary frontotemporal lobar degeneration with TDP‐43 type A pathology. Lewy bodies, argyrophilic grains and cerebral amyloid angiopathy were common co‐pathologies (Figure 1). Conclusion: In a large international cohort, PCA is strongly associated with positive AD biomarkers and neuropathology. Data collection is ongoing, and we further aim to identify clinical features associated with non‐AD underlying causes of PCA. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) biomarkers reflect the pathological process underlying Alzheimer's disease (AD) and improve the accuracy of AD diagnosis. AT(N) classification using these CSF biomarkers has been used within the research framework to identify points on AD continuum. However, there has been little research into the utility of AT(N) classification in clinical practice. Methods: We measured the CSF levels of amyloid‐β (Aβ) 42, Aβ40, phosphorylated tau (Thr181), total tau (tTau), and neurofilament light chain (NfL) in samples from clinical cases, comprising 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non‐ACS. The concordance between two A‐markers (i.e., Aβ42 alone and the Aβ42/Aβ40 ratio) and the two N‐markers (i.e., tTau and NfL) were analyzed. We evaluated the prevalence of biological AD (i.e., A+T+) and the percentage of each AT(N) category identified using the CSF biomarkers in the ACS and non‐ACS samples. Results: The concordance of A‐markers was not significantly different between the ACS (87.4%) and non‐ACS (74.1%) groups. However, the frequency of discordant cases with AAβ42‐alone+/AAβ‐ratio− was significantly higher in the non‐ACS (23.8%) than in the ACS group (7.4%). The concordance of two N‐markers was 40.4% in the ACS group and 24.4% in the non‐ACS group. In the ACS samples, the frequency of biological AD in Ntau+ cases was 95% and that in NNfL+ cases was 65%. When the Aβ42/Aβ40 ratio was used as the A‐marker, the proportion of biological AD was 64.3% in ACS samples and 24.4% in non‐ACS samples. Notably, the proportion of AD continuum in the non‐ACS group was substantially different when the A‐marker was Aβ42 alone than when it was the Aβ42/Aβ40. Conclusions: Although the AT(N) classification system was intended for use in research, it may also be also useful for clinical diagnosis. As an A‐marker, the Aβ42/Aβ40 ratio reflects Aβ deposition more accurately than Aβ42 alone. As an N‐marker, NfL reflects neurodegeneration more accurately than tTau, particularly in non‐ACS patients. Thus, we recommend the use of AT(N) classification in clinical practice that is defined by CSF levels of AAβ‐ratioTNNfL. [ABSTRACT FROM AUTHOR]

Background: In daily clinical practice, we often encounter cases with atypical clinical symptoms and imaging findings, even amoung those diagnosed with Alzheimer's disease. Method: Forty‐nine cases of undiagnosed patients with atypical clinical symptoms or imaging findings underwent both amyloid PET and cerebrospinal fluid(CSF) examinations.They were divided into amyloid‐positive group(n = 25) and amyloid‐negative group(n = 24).The cerebrospinal fluid findings,neuropsychological examination findings,MRI findings,and SPECT findings were compared between the two groups. Result: CSF findings showed significant differences in amyloid‐β42,amyloid‐β42/40, and P‐tau between the two groups.There was no significant difference in MRI findings.SPECT findings showed a significant difference in decreased blood flow in the right parietal lobe and bilateral precuneus. Conclusion: In dementia patients with atypical clinical symptoms and imaging findings, CSF findings and decreased blood flow in the right parietal lobe and bilateral precuneus are suggested to be useful indicators to distinguish whether amyloid is involved in the back ground pathology. [ABSTRACT FROM AUTHOR]

Background: Corticobasal syndrome (CBS) is clinically characterized by asymmetric cortical and extrapyramidal deficits. CBS is caused by various pathological conditions including primary tauopathy and Alzheimer's disease (AD). To clarify whether there are differences in clinical features of CBS between AD pathology and non‐AD pathology, we classified CBS patients based on AT(N) system by cerebrospinal fluid (CSF) biomarkers and assessed the clinical characteristics of the classified groups. Method: We assessed retrospectively 19 CBS patients (7 males and 12 females) diagnosed by neurologists at our hospital between 2014 to 2021. They all fulfilled the clinical symptoms of probable or possible CBS according to the Armstrong criteria of corticobasal degeneration. CSF AT(N) biomarkers, A marker: Aβ42 and Aβ42/Aβ40 ratio, T marker: phosphorylated tau (Thr181) [p‐tau], N marker: total tau [t‐tau] and neurofilament light chain [NfL], were evaluated. The positive/negative of each biomarker was judged according to the cutoff value calculated in a cohort independent of this study. We used Aβ42/Aβ40 ratio as the A marker and NfL as the N marker in this study. Each patient was classified AT(N) group. Clinical characteristics were compared between biological AD (i.e., A+T+) group and non‐AD group. Result: The concordance of A markers (Aβ42 and Aβ42/Aβ40 ratio) was 68.4%, and that of N markers (t‐tau and NfL) was 15.8% in patients with CBS. NfL had more positive rates than t‐tau in CBS patients. Based on CSF biomarker profile, CBS patients were classified as AD group (n = 4, 21%), Alzhehimer's and concomitant suspected non‐Alzheimer's pathologic change group (n = 2, 11%) and non‐AD pathologic change group (n = 13, 68%). AD group showed lower scores of MMSE (p = 0.037), more frequent presence of Gerstmann syndrome (p = 0.007), predominance of right limb symptoms (p = 0.015), and more common in non‐motor symptoms onset (p = 0.029) than non‐AD group. Conclusion: By applying the AT(N) classification to CBS patients, we found that 21% of patients exhibited AD pattern by CSF biomarkers. The clinical differences between AD group and non‐AD group may reflect the different pathological backgrounds. NfL could be more sensitive than t‐tau as the N marker in detecting neurodegeneration of CBS. [ABSTRACT FROM AUTHOR]

Background: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative condition that which is caused by abnormal expansion of GGC repeat in NOTCH2NLC. Despite the increase of the reported patients with NIID, how the repeat sequence and length in NOTCH2NLC affect the development of NIID remains unclear. We report the genetic characterization of repeat expansion and sequence of NOTCH2NLC in Japanese patients with NIID. Methods: Fifteen patients clinically diagnosed with adult‐onset NIID were genetically analyzed. Repeat expansion in NOTCH2NLC was examined by repeat‐primed PCR. Repeat length was determined by amplicon length PCR. Repeat length and sequence were analyzed by Nanopore long read sequence. Results: Repeat primed PCR analysis revealed a sawtooth pattern in 15 patients who were clinically suspected as having NIID. This suggests the presence of repeat expansion in NOTCH2NLC. Next, we performed amplicon‐length PCR to determine the repeat size. The mean repeat length of was 8.2±1.5 (range 7 to 10) in normal allele and 92.5±12.8 (range: 71 to 110) in expanded allele. To define the repeat length and sequence, we performed Nanopore long read sequencer. The repeat size was 138.6±69.0 (range: 95 to 361) in expanded allele. The GGC repeat length was 114.5±36.6 (range: 44 to 194). One patient carried pure GGC repeat expansion, and remaining patients carried others trinucleotide repeat including GGA, AGC, and GAC. Most frequent trinucleotide insertion was GGA at the end of GGC repeat, which is commonly observed in normal allele. We identified two patients who carried bi‐allelic GGC expansions. Conclusion: Abnormal repeat expansion in NOTCH2NLC was identified as heterozygous or bi‐allelic state in patients with NIID. There was heterogeneity of length and sequence in expanded repeat expansion of NOTCH2NLC. The further study is required to understand how genetic heterogeneity correlates with clinical presentations of patients with NIID. [ABSTRACT FROM AUTHOR]

Background: Primary prevention of cognitive decline is important while development of disease modifying drugs for early Alzheimer's Disease (AD) is progressing rapidly. As a screening tool for early detection of cognitive decline, blood‐based biomarkers prior to invasive testing such as cerebral spinal fluid examination and positron emission tomography scanning could be beneficial. In our small‐scale pilot study, plasma‐free amino acid (PFAA) profiles of AD patients and mild cognitive impairment (MCI) due to AD were shown to be significantly different from those of cognitively healthy elderly. In order to examine the clinical significance of PFAAs as a novel biomarker, we started an MCI cohort study that enrolls hundreds of MCI subjects to determine practical biomarkers for MCI screening among generally healthy subjects, and to distinguish stable MCI and AD‐converted MCI. The results of interim baseline analysis regarding MCI screening will be presented here. Method: MCI subjects from 6 medical sites in Japan (MCI, n=117) and age‐gender‐matched community dwellers in 3 different cities in Japan (healthy control, n=117) were included in the current analysis. At baseline visit, plasma samples were collected under fasting condition. The concentrations of PFAAs and plasma amines were analyzed with LC/MS or LC/MS/MS and serum biochemistry tests were done. Observation of the clinical status of MCI subjects for 3 years after the blood collection is ongoing. Result: Several PFAAs including essential amino acids of MCI subjects were significantly lower than those of healthy control. There were no significant differences in plasma amine concentrations between MCI and control group. In addition, several serum biochemistry parameters including serum albumin of MCI subjects were significantly lower. These differences were independent of age and gender. Conclusion: Both PFAAs including essential amino acids and serum biochemistry including albumin were shown to be potential biomarkers for MCI screening. The validation of this results will be conducted in another subset in this MCI cohort study. For further investigation, we will conduct multivariable analysis and create the robust algorithm for MCI screening. Also, observation of the clinical status of MCI subjects will continue to distinguish stable MCI and AD‐converted MCI. [ABSTRACT FROM AUTHOR]

Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-β (Aβ42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived Aβ-like peptides (APL1β) that are generated by β- and γ-cleavages at a concentration of ∼4.5 nM. These novel peptides, APL1β25, APL1β27 and APL1β28, were not deposited in AD brains. Interestingly, most γ-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of Aβ42 cause a parallel increase in the production of APL1β28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1β28 levels are higher than in non-AD controls, while the relative Aβ42 levels are unchanged or lower. Most strikingly, the relative APL1β28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1β28 in the CSF as a candidate surrogate marker for the relative level of Aβ42 production in the brain. [ABSTRACT FROM AUTHOR]