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Background: Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac light chain amyloidosis., Methods: This was a multicenter, open-label, randomized controlled trial. Patients with Mayo 2004 stage II to III light chain amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression, or organ progression (heart, kidney or liver). Hematologic progression was defined on the basis of a substantial increase in free light chain. An increase in either NT-proBNP (N-terminal pro B-type natriuretic peptide) or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated with a Cox regression model., Results: One hundred forty patients underwent randomization, with 70 in each group. The median age was 61 years (range, 33-78 years) with a male:female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32 of 70 (45.7%) patients in the doxycycline group and 30 of 70 (42.9%) patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio, 0.97 [95% CI, 0.59-1.60]; P =0.91). Cardiac progression occurred in 29 of 70 (41.4%) patients in the doxycycline group and 26 of 70 (37.1%) patients in the control group. The death rates for both groups by the end of follow-up was the same, 25 of 70 (35.7%). No significant differences were observed for either cardiac PFS (hazard ratio, 0.91 [95% CI, 0.54-1.55]; P =0.74) or overall survival (hazard ratio, 1.04 [95% CI, 0.60-1.81]; P =0.89)., Conclusions: Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac light chain amyloidosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03401372.

Since the role of estrogen in postmenauposal-associated dementia is still debatable, this issue urges the search for other medications. Dimethyl fumarate (DMF) is a drug used for the treatment of multiple sclerosis and has shown a neuroprotective effect against other neurodegenerative diseases. Accordingly, the present study aimed to evaluate the effect of DMF on an experimental model of Alzheimer disease (AD) using D-galactose (D-Gal) administered to ovariectomized (OVX) rats, resembling a postmenopausal dementia paradigm. Adult 18-month old female Wistar rats were allocated into sham-operated and OVX/D-Gal groups that were either left untreated or treated with DMF for 56 days starting three weeks after sham-operation or ovariectomy. DMF succeeded to ameliorate cognitive (learning/short- and long-term memory) deficits and to enhance the dampened overall activity (NOR, Barnes-/Y-maze tests). These behavioral upturns were associated with increased intact neurons (Nissl stain) and a reduction in OVX/D-Gal-mediated hippocampal CA1 neurodegeneration and astrocyte activation assessed as GFAP immunoreactivity. Mechanistically, DMF suppressed the hippocampal contents of AD-surrogate markers; viz., apolipoprotein (APO)-E1, BACE1, Aβ42, and hyperphosphorylated Tau. Additionally, DMF has augmented the neuroprotective parameters p-AKT, its downstream target CREB and BDNF. Besides, it activated AMPK, and enhanced SIRT-1, as well as antioxidant defenses (SOD, GSH). On the other hand, DMF inhibited the transcription factor NF-κB, IL-1β, adiponectin/adiponectin receptor type (AdipoR)1, GSK-3β, and MDA. Accordingly, in this postmenopausal AD model, DMF treatment by pursuing the adiponectin/AdipoR1, AMPK/SIRT-1, AKT/CREB/BDNF, AKT/GSK-3β, and APO-E1 quartet hampered the associated tauo-/amyloidopathy and NF-κB-mediated oxidative/inflammatory responses to advance insights into its anti-amnesic effect., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Dialysis-related amyloidosis (DRA) commonly develops in patients undergoing long-term dialysis and can lead to a decline in activities of daily living and quality of life (QOL), mainly owing to orthopedic complications., Methods: First, we determined utility scores of the EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) questionnaire in 1,323 patients with DRA who had undergone dialysis for more than 10 years and compared the score between those with and without DRA. Second, a 2-year follow-up was also performed, in which patients were divided into three groups: those complicated by DRA from the beginning, those with newly developed DRA within the 2-year period, and those not complicated by DRA throughout the survey period; changes in the EQ-5D-3L utility score were compared. In the group already complicated by DRA at the survey baseline, changes in the EQ-5D-3L utility score were compared according to the dialysis treatment method., Results: A total of 1,314 and 931 patients were included in the first and second studies, respectively. EQ-5D-3L utility scores among patients diagnosed with DRA were significantly lower than scores in those not diagnosed with DRA. The reduction in the EQ-5D-3L utility score over the 2-year follow-up was significantly greater in patients newly complicated by DRA during the follow-up period after enrollment but not in those complicated by DRA from the beginning, as compared with patients not complicated by DRA throughout the survey period. The reduction in utility score tended to be lower in patients routinely treated with a β2-microglobulin adsorption column than in untreated patients with DRA., Conclusion: Complication by DRA in patients undergoing long-term hemodialysis was significantly associated with a decline in QOL., Competing Interests: KT, KI, and HH received honoraria from Kaneka Medics. KT received a grant from Kaneka Medics. HA has no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Transgenic rodent models were created to decipher pathogenic mechanisms associated with Alzheimer's disease (AD), and behavioral apparatuses such as the Morris water maze (MWM) are used to assess cognition in mice. The IntelliCage was designed to circumvent issues of traditional behavioral tests, such as frequent human handling. The motivation to complete IntelliCage tasks is water consumption, which is less stressful than escaping from a pool in the MWM. Here, we examined behavioral performances of mice in the IntelliCage and MWM tasks. Twelve-month-old male and female APP/PS1 and non-transgenic mice first underwent 42 days of IntelliCage testing to assess prefrontal cortical and hippocampal function followed by MWM testing for six days. We found that females performed better in the IntelliCage while males performed superiorly in the MWM. Mechanistically, female APP/PS1 mice had a higher Amyloid-β plaque load throughout the brain, which is inconsistent with their performance in the IntelliCage. Collectively, these results inform scientists about the sex-based differences when testing animals in different behavioral paradigms that tap similar cognitive functions., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In clinical practice, the amy-PET is globally inspected to provide a binary outcome, but the role of a regional assessment has not been fully investigated yet., Objective: To deepen the role of regional amyloid burden and its implication on clinical-neuropsychological features., Materials: Amy-PET and a complete neuropsychological assessment (Trail Making Test, Rey Auditory Verbal Learning Test, semantic verbal fluency, Symbol Digit, Stroop, visuoconstruction) were available in 109 patients with clinical suspicion of Alzheimer's disease. By averaging the standardized uptake value ratio and ELBA, a regional quantification was calculated for each scan. Patients were grouped according to their overall amyloid load: correlation maps, based on regional quantification, were calculated and compared. A regression analysis between neuropsychological assessment and the regional amyloid-β (Aβ) load was carried out., Results: Significant differences were observed between the correlation maps of patients at increasing levels of Aβ and the overall dataset. The Aβ uptake of the subcortical gray matter resulted not related to other brain regions independently of the global Aβ level. A significant association of semantic verbal fluency was observed with ratios of cortical and subcortical distribution of Aβ which represent a coarse measure of differences in regional distribution of Aβ., Conclusion: Our observations confirmed the different susceptibility to Aβ accumulation among brain regions. The association between cognition and Aβ distribution deserves further investigations: it is possibly due to a direct local effect or it represents a proxy marker of a more aggressive disease subtype. Regional Aβ assessment represents an available resource on amy-PET scan with possibly clinical and prognostic implications.

Late-life anxiety has been associated with increased progression from normal cognition to amnestic MCI, suggesting that anxiety may be a neuropsychiatric symptom of Alzheimer's disease (AD) pathological changes and a possible marker of anatomical progression in preclinical AD. This study examined whether cortical or subcortical amyloidosis, indicating earlier or later stages of preclinical AD, was associated with greater self-reported anxiety among 118 cognitively normal volunteers, aged 65-90 years, and whether this association was stronger in APOEε4 carriers. Participants underwent Pittsburgh Compound B Positron Emission Tomography (PiB-PET) to assess fibrillar amyloid-β burden in cortical and subcortical regions, and measurement of anxiety using the Hospital Anxiety and Depression Scale-anxiety subscale. Higher PiB-PET measures in the subcortex (striatum, amygdala, and thalamus), but not in the cortex, were associated with greater anxiety, adjusting for demographics, cognition, and depression. Findings were similar using a cortico-striatal staging system and continuous PET measurements. Anxiety was highest in APOEε4 carriers with subcortical amyloidosis. This work supports in vivo staging of amyloid-β deposition in both cortical and subcortical regions as a promising approach to the study of neuropsychiatric symptoms such as anxiety in cognitively normal older individuals. Elevated anxiety symptoms in combination with high-risk biological factors such as APOEε4 and subcortical amyloid-β may identify participants closest to MCI for secondary prevention trials.

Objective: To examine the feasibility of using cross-sectional PET to identify cognitive decliners among β-amyloid (Aβ)-negative cognitively normal (CN) elderly adults., Methods: We determined the highest Aβ-affected region by ranking baseline and accumulation rates of florbetapir-PET regions in 355 CN elderly adults using 18 F-florbetapir-PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The banks of the superior temporal sulcus (BANKSSTS) were found as the highest Aβ-affected region, and Aβ positivity in this region was defined as above the lowest boundary of BANKSSTS standardized uptake value ratio of Aβ+ (ADNI-defined COMPOSITE region) CN individuals. The entire CN cohort was divided as follows: stage 0, BANKSSTS-COMPOSITE-; stage 1, BANKSSTS+COMPOSITE-; and stage 2, BANKSSTS+COMPOSITE+. Linear mixed-effect (LME) models investigated subsequent longitudinal cognitive change, and 18 F-flortaucipir (FTP)-PET was measured 4.8 ± 1.6 years later to track tau deposition., Results: LME analysis revealed that individuals in stage 1 (n = 64) and stage 2 (n = 99) showed 2.5 ( p < 0.05) and 4.8 ( p < 0.001) times faster memory decline, respectively, than those in stage 0 (n = 191) over >4 years of mean follow-up. Compared to stage 0, both stage 1 ( p < 0.05) and stage 2 ( p < 0.001) predicted higher FTP in entorhinal cortex., Conclusions: Nominally Aβ- CN individuals with high Aβ in BANKSSTS are at increased risk of cognitive decline, probably showing an earlier stage of Aβ deposition. Our findings may help elucidate the association between brain Aβ accumulation and cognition in Aβ- CN cohorts., Classification of Evidence: This study provides Class II evidence that in elderly CN individuals those with high PET-identified superior temporal sulcus Aβ burden have an increased risk of cognitive decline., (© 2020 American Academy of Neurology.)

Objective: To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline., Methods: 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer's disease dementia subjects from the Alzheimer's Disease Neuroimaging Initiative received ( 18 F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher's exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status., Results: No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects., Conclusions: Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia., Competing Interests: Competing interests: Liana G Apostolova received research support from General Electric Healthcare, Piramal and Eli Lilly, served on the speaker’s bureau for Eli Lilly & Company and Piramal Enterprises and on an advisory board for Eli Lilly & Company., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(-); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: -5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(-) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (-0.9% versus -2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(-). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy.

Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer's disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2α) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD. The present study investigated the ER stress pathway and its long-term modulation utilizing in vitro and in vivo experimental models of tauopathy (MAPT P301S)PS19 and amyloidosis (APP Swe ). We report that thapsigargin induces activating transcription factor-4 (ATF4) in primary cortical neurons (PCNs) derived from rat and APP Swe nontransgenic (nTg) and transgenic (Tg) mice. ISRIB mitigated the induction of ATF4 in PCNs generated from wild-type (WT) but not APP Swe mice despite partially restoring thapsigargin-induced translational repression in nTg PCNs. In vivo , C57BL/6J and PS19 mice received prolonged, once-daily administration of ISRIB. While the compound was well tolerated by PS19 and C57BL/6J mice, APP Swe mice treated per this schedule displayed significant mortality. Thus, the dose was reduced and administered only on behavioral test days. ISRIB did not improve learning and memory function in APP Swe Tg mice. While ISRIB did not reduce tau-related neuropathology in PS19 Tg mice, no evidence of ER stress-related dysfunction was observed in either of these Tg models. Taken together, the significance of ER stress and the relevance of these models to the etiology of AD require further investigation.

Background: The ongoing effort to prevent dialysis-related amyloidosis (DRA) has been hampered by lack of any way to measure DRA's severity. Yet, such measurement is essential for assessing the effect of DRA treatment. Accordingly, we developed a scoring system focused on the physical manifestations of DRA., Methods: Forty-four patients on maintenance hemodialysis with DRA, and 96 without it, were enrolled. The SF-36v2 Health Survey ascertained whether patients experienced general bodily pain and/or physical dysfunction with any attendant specific pain (dysfunction). If so, the association of those conditions with a finding of DRA was analyzed-including laboratory and radiographic data-and a scoring system reflecting the extent of that dysfunction was devised using the significant variables in the multivariate analysis., Results: Both dysfunction and general bodily pain were severe in patients with DRA. Presence of polyarthralgia, trigger finger, carpal tunnel syndrome (CTS), and dialysis-related spondyloarthropathy (DRS) were associated with that dysfunction after appropriate adjustments. The new scoring system used those four variables in the model, with a 3 given for polyarthralgia and DRS, and 2 for trigger finger and CTS (possible range 0-10). Based on the physical functioning score of SF-36v2, we categorized A-score into three stages: mild (A-score 3-4), moderate (5-7), and severe (8-10). The corresponding area under the receiver-operating characteristics curve for diagnosis of DRA was 0.9345 when we set the cutoff value as 4., Conclusion: This validated scoring system for quantitatively estimating the severity of DRA can serve as A useful measure in clinical practice.

Background: Our study examines depression and anxiety in patients with immunoglobulin light chain (AL) amyloidosis, and determines the associations between the mental health problems and patient characteristics (age, gender, race, marital status, alcohol consumption, smoking status and cardiac involvement)., Methods: Patients with AL amyloidosis who completed the 36-item Short Form General Health Survey (SF-36) during initial evaluation at a single center were studied. The SF-36 included assessments of depression, anxiety, role limitation due to emotional problems and the mental health subscale score., Results: From 1226 patients with AL amyloidosis, 37.0% reported depression and 46.7% reported anxiety. Patients with cardiac amyloidosis reported more anxiety (odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.03-1.61) and role limitation due to emotional problems (OR = 1.32, 95%CI 1.05-1.65). No significant association between cardiac involvement and depression was found (OR = 1.22, 95%CI 0.97-1.54). Men reported less anxiety (OR = 0.72, 95%CI 0.57-0.91). Patients  ≥65 years experienced greater role limitation (OR = 1.36, 95%CI 1.08-1.71). Smokers (p = 0.019) and women (p = 0.006) scored lower on mental health subscales., Conclusions: Many patients with AL amyloidosis suffer from depression, anxiety and functional limitations. Psychiatric assessment and treatment is important, and further research is needed to clarify the long-term effects of depression and anxiety in AL amyloidosis. This current study was registered in ClinicalTrials.gov as NCT00898235.

Background: The present study aimed to provide a contribution to the study of a rare disease, amyloid light-chain (AL) cardiac amyloidosis, which is the most common type of systemic amyloidosis. In AL amyloidosis prognosis is determined by cardiac involvement. Although the association between psychological distress (e.g. anxiety and depression) and AL cardiac amyloidosis is documented, very little is known about the psychosocial variables that may mediate the association., Aims: The aim of the study is therefore to examine the potential mediating role of life satisfaction in the relationship between cardiac symptom severity (independent variable) and anxious and depressive symptoms (dependent variables) in AL patients., Method: Forty-three AL amyloidosis patients (57.1% males) with cardiac amyloidosis were administered the Satisfaction with Life Scale, the State-Trait Anxiety Inventory and the Centre for Epidemiological Study-Depression Scale. Clinical variables such as months since cardiac symptom onset and cardiac symptom severity were collected., Results: Findings showed significant relationships between symptom severity and psychological disorders (e.g. anxiety and depression) and these were mediated by life satisfaction., Conclusion: Overall, findings highlight the importance of subjective well-being (e.g. life satisfaction) to reduce anxious and depressive symptoms and to improve general health in AL patients., (© The European Society of Cardiology 2015.)

The 2012 neuropathological criteria for the diagnosis of Alzheimer disease (AD) summarize the extent of AD neuropathological change with an ABC score, which is a composite of the Thal stage of amyloid deposition (A), the Braak stage of neurofibrillary tangles (NFTs) (B), and the CERAD neuritic plaque score (C). NFTs and neuritic plaques are well-established contributors to cognitive impairment, but whether the Thal amyloid stage independently predicts antemortem cognition remains unknown. We used the National Alzheimer's Coordinating Center autopsy data set to build adjacent-categories logit regression models with CDR-SOB and Mini-Mental State Examination (MMSE) scores as cognitive outcome variables. Increasing CERAD scores were independently associated with higher CDR-SOB scores, whereas increasing Braak NFT stages predicted both higher CDR-SOB and lower MMSE scores. Increasing Thal amyloid stages were not significantly independently associated with either outcome measure. Increasing ABC scores predicted higher CDR-SOB and lower MMSE scores. These results raise the possibility that Thal amyloid stages do not substantially contribute to predicting antemortem cognition compared to CERAD neuritic plaque scores and Braak NFT stages, and suggest that the diffuse amyloid deposits participating in the assignment of Thal amyloid stages are neutral with respect to clinically detectable cognitive and functional changes., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology., (© 2015 Wiley Periodicals, Inc.)

Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer. Earlier studies show its neuroprotection via regulating apoptosis, microglial functions, and synaptic plasticity. TMX also showed memory enhancement in ovariectomized mice, and protection from amyloid induced damage in hippocampal cell line. These reports encouraged us to explore the role of TMX in relevance to Alzheimer's disease (AD). We report here, the effect of TMX treatment a) on memory, and b) levels of neurotransmitters (acetylcholine (ACh) and dopamine (DA)) in breeding-retired-female mice injected with beta amyloid1-42 (Aβ1-42). Mice were treated with TMX (10mg/kg, i.p.) for 15 days. In Morris water maze test, the TMX treated mice escape latency decreased during training trials. They also spent longer time in the platform quadrant on probe trial, compared to controls. In Passive avoidance test, TMX treated mice avoided stepping on the shock chamber. This suggests that TMX protects memory from Aβ induced toxicity. In frontal cortex, ACh was moderately increased, with TMX treatment. In striatum, dopamine was significantly increased, 3,4-dihydroxyphenylacetic acid (DOPAC) level and DOPAC/DA ratio was decreased post TMX treatment. Therefore, TMX enhances spatial and contextual memory by reducing dopamine metabolism and increasing ACh level in Aβ1-42 injected-breeding-retired-female mice., (Copyright © 2015. Published by Elsevier Inc.)

Objective: Malnutrition is associated with mortality and impaired quality of life (QoL) in systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study was to determine whether nutritional counseling is beneficial to patients with AL., Methods: In this intervention study (ClinicalTrials.gov Identifier: NCT02055534), 144 treatment-naïve outpatients with AL were randomized to usual care (UC; n = 72) and nutritional counseling (NC; n = 72)., Results: In the randomized population, although patients in the NC group maintained a stable body weight (weight loss [WL] = 0.6 kg; 95% confidence interval [CI], -1.0 to 2.1; P = 0.214), those in the UC group demonstrated a significant decrease (WL = 2.1 kg; 95% CI, 0.2-4.1; P = 0.003). However, the difference in weight between groups was not significant (mean WL difference = 1.6 kg; 95% CI, -0.7 to 3.9; P = 0.179). Patients in the NC group demonstrated more satisfactory energy intake (≥75% of estimated requirements, odds ratio, 2.18; 95% CI, 1.04-4.57; P = 0.048) and a significant increase in the mental component summary of QoL (Short form-36) at 12 mo (mean difference, 8.1; 95% CI, 2.3-13.9; P = 0.007), which was restored to a mean score of 53 (95% CI, 50-53), over the healthy population norms. NC was also associated with better survival (crude hazard ratio, 0.57; 95% CI, 0.35-0.94; P = 0.028)., Conclusions: In outpatients with AL, NC was helpful in preserving body weight, effective in improving mental QoL, and associated with better survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Information detailing the experience of patients with light chain (AL) amyloidosis is lacking. The primary aim of this study was to gather data on the patient experience to understand the challenges in diagnosis and to gain insight into barriers to accessing appropriate care., Methods: Patients with amyloidosis, family members, and caregivers were invited to participate in an online 16-question survey (available from January 29 to February 5, 2015). Participants with AL amyloidosis were sent an eight-question follow-up survey., Results: The initial survey was completed by 533 participants (follow-up survey completed by 201 participants). AL amyloidosis was the most common diagnosis. For 37.1% of respondents, the diagnosis of amyloidosis was not established until ≥ 1 year after the onset of initial symptoms. Diagnosis was received after visits to 1, 2, 3, 4, or ≥ 5 physicians by 7.6%, 23.5%, 20.3%, 16.8%, and 31.8% of respondents, respectively. Correct diagnosis was most often made by hematologists/oncologists (34.1%). Treatments included chemotherapy (63.1%) and stem cell transplantation (38.9%) and were difficult to tolerate for 54.1% of respondents. A significant number of respondents felt uninformed about clinical trials. Nevertheless, approximately half (46.1%) believed that enrolling in a trial would enhance their care., Conclusions: Establishing a diagnosis of amyloidosis is difficult. Current treatments are difficult to tolerate and do not substantially improve quality of life for most patients. There is an urgent need for well-tolerated therapies with clear treatment benefit. Patient awareness of clinical trials can be improved, especially given that respondents indicated high willingness to participate.

Objective: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD)., Methods: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education., Results: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination., Conclusions: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials., (© 2015 American Academy of Neurology.)

Introduction: This study aimed to understand the symptomatic impact of amyloid light-chain (AL) amyloidosis from the patient's perspective., Methods: Four data sources were included: a literature review, review of online patient blogs, expert clinician interviews and patient interviews. Patients were recruited through the Amyloidosis Foundation and physician referral. Phone interviews were conducted and included open-ended concept elicitation questions. Thematic analysis was performed to identify symptoms and impacts. Descriptive statistics were used to characterize the sample. A conceptual model was developed depicting the impact of disease and treatment., Results: Two hundred seventy abstracts were identified; 10 articles were deemed relevant. No qualitative studies were identified, and only three studies included patient-reported measures. Ten patients completed interviews (mean age 61 [±8]; 7 male). Over 25 signs/symptoms were identified, including fatigue, weakness, dyspnea, neuropathy, edema, dizziness/lightheadedness, anorexia, diarrhea and constipation. Impacts included reduced physical and social functioning, and emotional impacts, including frustration, anxiety and depression. Findings from the blogs and expert interviews were consistent with patient reports., Conclusion: Symptoms can vary widely, but a core set of symptoms were common across patients. The conceptual model derived from this study can be used to ensure a patient-centered approach to drug development.

Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)

As many other metals, aluminum is a widely recognized neurotoxicant and its link with neurodegenerative disorders has been the subject of scientific debate. One proposal focuses on amyloid β deposition (amyloidogenesis) as the key player in triggering neuronal dysfunction the so-called amyloid cascade hypothesis. We undertook this study first to investigate the cognition status of workers exposed to Al dust in an Al factory in Southern Cairo, second, to evaluate serum amyloid precursor protein (APP) and cathepsin D (CD) enzyme activity to study the possible role of Al in amyloidogenesis, and finally to explore the relation between these potential biomarkers and cognitive functions. The study was conducted on 54 exposed workers and 51 matched controls. They were subjected to questionnaire, neurological examination and a cognitive test battery, Addenbrooke's Cognitive Examination - Revised (ACE-R). Serum Al, APP and CD enzyme activity were measured. A significant increase of serum Al was found in the exposed workers with an associated increase in serum APP and decrement in CD activity. The exposed workers displayed poor performance on the ACE-R test. No significant correlation was detected between ACE-R test total score and either APP or CD activity. We concluded that occupational exposure to Al is associated with cognitive impairment. The effect of occupational Al exposure on the serum levels of APP and CD activity may be regarded as a possible mechanism of Al in amyloidogenesis. However, our findings do not support the utility of serum APP and CD activity as screening markers for early or preclinical cognitive impairment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: As preclinical Alzheimer's disease becomes a target for therapeutic intervention, the overlap between imaging abnormalities associated with typical ageing and those associated with Alzheimer's disease needs to be recognised. We aimed to characterise how typical ageing and preclinical Alzheimer's disease overlap in terms of β-amyloidosis and neurodegeneration., Methods: We measured age-specific frequencies of amyloidosis and neurodegeneration in individuals with normal cognitive function aged 50-89 years. Potential participants were randomly selected from the Olmsted County (MN, USA) population-based study of cognitive ageing and invited to participate in cognitive and imaging assessments. To be eligible for inclusion, individuals must have been judged clinically to have no cognitive impairment and have undergone amyloid PET, (18)F-fluorodeoxyglucose ((18)F-FDG) PET, and MRI. Imaging results were obtained from March 28, 2006, to Dec 3, 2013. Amyloid status (positive [A(+)] or negative [A(-)]) was determined by amyloid PET with (11)C Pittsburgh compound B. Neurodegeneration status (positive [N(+)] or negative [N(-)]) was determined by an Alzheimer's disease signature (18)F-FDG PET or hippocampal volume on MRI. We determined age-specific frequencies of the four groups (amyloid negative and neurodegeneration negative [A(-)N(-)], amyloid positive and neurodegeneration negative [A(+)N(-)], amyloid negative and neurodegeneration positive [A(-)N(+)], or amyloid positive and neurodegeneration positive [A(+)N(+)]) cross-sectionally using multinomial regression models. We also investigated associations of group frequencies with APOE ɛ4 status (assessed with DNA extracted from blood) and sex by including these covariates in the multinomial models., Findings: The study population consisted of 985 eligible participants. The population frequency of A(-)N(-) was 100% (n=985) at age 50 years and fell to 17% (95% CI 11-24) by age 89 years. The frequency of A(+)N(-) increased to 28% (24-32) at age 74 years, then decreased to 17% (11-25) by age 89 years. The frequency of A(-)N(+) increased from age 60 years, reaching 24% (16-34) by age 89 years. The frequency of A(+)N(+) increased from age 65 years, reaching 42% (31-52) by age 89 years. The results from our multinomial models suggest that A(+)N(-) and A(+)N(+) were more frequent in APOE ɛ4 carriers than in non-carriers and that A(+)N(+) was more, and A(+)N(-) less frequent in men than in women., Interpretation: Accumulation of amyloid and neurodegeneration are nearly inevitable by old age, but many people are able to maintain normal cognitive function despite these imaging abnormalities. Changes in the frequency of amyloidosis and neurodegeneration with age, which seem to be modified by APOE ɛ4 and sex, suggest that pathophysiological sequences might differ between individuals., Funding: US National Institute on Aging and Alexander Family Professorship of Alzheimer's Disease Research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late-onset Alzheimer's disease (AD). Studies have shown that the binding between apoE and amyloid-β (Aβ) peptides occurs at residues 244-272 of apoE and residues 12-28 of Aβ. ApoE4 has been implicated in promoting Aβ deposition and impairing clearance of Aβ. We hypothesized that blocking the apoE/Aβ interaction would serve as an effective new approach to AD therapy. We have previously shown that treatment with Aβ12-28P can reduce amyloid plaques in APP/PS1 transgenic (Tg) mice and vascular amyloid in TgSwDI mice with congophilic amyloid angiopathy. In the present study, we investigated whether the Aβ12-28P elicits a therapeutic effect on tau-related pathology in addition to amyloid pathology using old triple transgenic AD mice (3xTg, with PS1M146V , APPSwe and tauP30IL transgenes) with established pathology from the ages of 21 to 26 months. We show that treatment with Aβ12-28P substantially reduces tau pathology both immunohistochemically and biochemically, as well as reducing the amyloid burden and suppressing the activation of astrocytes and microglia. These affects correlate with a behavioral amelioration in the treated Tg mice., (© 2013 International Society for Neurochemistry.)

Background: Amyloidosis is a rare disease group. AL amyloidosis represents the most common type of systemic amyloidosis and cardiac involvement determines prognosis. Although some studies have revealed that amyloidosis patients present high levels of depression, few data are available about depression-contributing factors. No investigations have been conducted about the coping strategies that AL amyloidosis patients use to face the disease and there is little research on patients with cardiac symptoms that are strongly related to the prognosis., Objectives: to examine coping strategies (avoidance, social support seeking and problem-solving) as potential mediator in the relationship between cardiac symptom severity (independent variable) and depressive symptoms (dependent variable) in AL cardiologic patients., Method: Thirty-four AL patients with cardiac-related symptoms were administered the Coping Strategy Indicator and the Centre for Epidemiological Study-Depression Scale. Clinical variables such as months since cardiac symptom onset and cardiac symptom severity were collected., Results: According to questionnaire normative values, all patients presented clinical depression. Moreover, out of the coping strategies, avoidance and social support seeking mediated the link between cardiac symptom severity and depressive symptoms. No mediational effect was found for problem-solving., Discussion: As cardiac symptoms have low severity, AL patients can avoid the disease. However, as cardiac symptoms proceed and interfere with daily activities, they can no longer ignore their signs thus perceiving the severity of their medical condition. This status makes individuals prone to seek less social support and thus to prefer social isolation. Results suggest the need for early psychological support on coping strategies for AL cardiologic patients.

Background: Hematopoietic stem cell transplantation (HSCT) is an intensive cancer therapy entailing numerous physical, emotional, cognitive, and practical challenges. Patients' ability to adjust and cope with such challenges may depend on their ability to exert control over cognitive, emotional, and behavioral processes, that is, ability to self-regulate. Self-regulatory capacity is a limited resource that can be depleted or fatigued (i.e., "self-regulatory fatigue"), particularly in the context of stressful life events such as cancer diagnosis and treatment., Purpose: This is one of the first studies to examine self-regulatory fatigue in a cancer population. The current study aimed to (1) extract items for a specific scale of self-regulatory capacity and (2) examine the impact of such capacity on adaptation in patients with hematologic malignancies preparing for HSCT., Methods: Factor analysis of four existing scales gauging psychological adjustment and well-being in 314 patients preparing for HSCT (63% male and 89% Caucasian) identified 23 items (α = 0.85) related to self-regulatory control or fatigue. This measure was then examined using existing clinical data obtained from 178 patients (57% male and 91% Caucasian) undergoing treatment for hematologic malignancies in relationship to quality of life, coping, and self-reported adherence to physicians' recommendations., Results: Controlling for pain severity, physical fatigue, and depression, self-regulatory fatigue scores were incrementally associated with decreased quality of life, use of avoidance coping strategies, and decreased adherence to physicians' recommendations., Conclusion: These results emphasize the potential role of self-regulatory capacity in coping with and adjusting to hematologic cancers and future research is warranted.

Alzheimer's disease is nowadays the leading cause of dementia. It affects more than a third of people over 85 years old. The gold standard diagnostic proof is currently based upon pathology examination. It seems rather crucial to find methodologies that make an early and accurate in vivo diagnosis so as to offer the patient the most suitable treatment. We hereby go over several available neuro-imaging techniques used in nuclear medicine that increase the diagnostic accuracy of Alzheimer's disease.

Alzheimer's disease, responsible for the vast majority of dementia cases in the elderly population, is caused by accumulation of toxic levels of amyloid beta peptide (A beta) in the brain. Neprilysin is a major enzyme responsible for the degradation of A beta in vivo. We have previously shown that elevation of neprilysin levels in the brain delays the deposition of A beta-plaques in a mouse model of amyloidosis and that lack of neprilysin leads to increased A beta generation and to signs of incipient neurodegeneration in mouse brains. This study was designed to test whether low brain levels of neprilysin affect the amyloid pathology or perturb the learning and memory performance of mice. Double-mutated mice carrying a targeted depletion of one allele of Mme, the gene encoding neprilysin, and over-expressing human amyloid precursor protein (APP), exhibited a reinforced amyloid pathology in comparison with their APP transgenic littermates. Moreover, in contrast to their parental lines, these mice were impaired in the Morris water maze learning and memory paradigm and showed facilitated extinction in the conditioned taste aversion test. These data suggest that even a partial neprilysin deficiency, as is found during aging, exacerbates amyloid pathology and may impair cognitive functions.

Alzheimer's disease research is beginning to yield promising treatments and prevention strategies. Current Alzheimer's disease treatments benefit symptoms, but do not appreciably alter the basic disease process. The new generation of Alzheimer's disease medications, however, will likely include disease-modifying treatments, which will slow disease progression or stop it entirely. These new treatments pursue four points of intervention: increasing the clearance of amyloid-beta42 (Abeta42) proteins in the brain, blocking Abeta42 production, decreasing Abeta42 production, and decreasing Abeta42 aggregation. Neurogenerative therapies are being explored as well, suggesting future treatments may not only stop disease progression but also reverse it. Risk factors for developing Alzheimer's disease and factors associated with a lower risk of Alzheimer's disease have been identified. Future Alzheimer's disease management may come to resemble routine cardiovascular disease prevention and management, which involves the control of modifiable risk factors and the use of medications that decrease or stop underlying pathology. The hope is that such management will arrest the disease process before cognitive symptoms have begun. Like other neurologic illnesses, Alzheimer's disease has a profound impact on creativity. Alzheimer's disease attacks the right posterior part of the brain, which enables people to retrieve internal imagery and copy images. Alzheimer's disease patients may lose the ability to copy images entirely. However, people with Alzheimer's disease can continue to produce art by using their remaining strengths, such as color or composition instead of shapes or realism. Studying art and dementia is a model for identifying the strengths of psychiatric patients. Remarkably, art emerges in some patients even in the face of degenerative disease. In this expert roundtable supplement, Jeffrey L. Cummings, MD, offers an overview of recent advances in Alzheimer's disease research. Bruce L. Miller, MD, discusses creativity in patients with neurologic illnesses. Daniel D. Christensen, MD, discusses emerging Alzheimer's disease therapies. Debra Cherry, PhD, discusses the advocacy needs of Alzheimer's disease patients and their caregivers. In addition, Patricia Utermohlen, MA, provides a testimonial of the impact of Alzheimer's disease on an accomplished artist.

Intracerebral amyloid-beta (Abeta) peptide deposition is considered to play a key role in Alzheimer's disease and is designated as a principal therapeutic target. The relationship between brain Abeta levels and clinical deficits remains, however, unclear, both in human patients and in animal models of the disease. The purpose of the present study was to investigate, in a transgenic mouse model of brain amyloidosis, the consequences of Abeta deposition on basic neurological functions using a longitudinal approach. Animals were phenotyped at different ages corresponding to graded neuropathological stages (from no extracellular Abeta deposition to high amyloid loads). Sensory functions were evaluated by assessing visual and olfactory abilities and did not show any effects of the amyloid precursor protein (APP) transgene. Motor functions were assessed using multiple experimental paradigms. Results showed that motor strength was considerably reduced in APP transgenic mice compared with control animals. No deficit was noted in a motor coordination test although APP transgenic mice displayed decreased locomotion on a stationary beam. Hypolocomotion was also observed in the standard open-field test. Measures of anxiety obtained in the elevated plus-maze show some evidence of hyperanxiety in 15-month-old transgenic mice. Some of the neurological impairments showed by APP mice had an early onset and worsened with progressive aging, in parallel to gradual accumulation of Abeta in brain parenchyma. Relationships between neuropathologically assessed amyloid loads and behavioral deficits were further explored, and it was observed that motor strength deficits were correlated with cortical amyloid burden.

Familial amyloidotic polyneuropathy is an autosomal dominant neurodegenerative disorder caused by accumulation of mutated transthyretin (TTR) amyloid fibrils in different organs and prevalently around peripheral nerves. We have constructed transgenic flies, expressing the clinical amyloidogenic variant TTRL55P and the engineered variant TTR-A (TTRV14N/V16E) as well as the wild-type protein, all in secreted form. Within a few weeks, both mutants but not the wild-type TTR demonstrated a time-dependent aggregation of misfolded molecules. This was associated with neurodegeneration, change in wing posture, attenuation of locomotor activity including compromised flying ability and shortened life span. In contrast, expression of wild-type TTR had no discernible effect on either longevity or behavior. These results suggest that Drosophila can be used as a disease-model to study TTR amyloid formation, and to screen for pharmacological agents and modifying genes.

We present a case of obstructive jaundice due to duodenal amyloidosis presenting as a bulbar pseudotumor (amyloidoma). The duodenal and biliary obstruction were treated by double bypass, hepatojejunostomy and gastroenterostomy. Our case suggests that surgical palliative treatment may be effective, and that anastomosis is probably safe, allowing the patient a good quality of life.

Most of the transgenic mice generated to model Alzheimer's disease express human amyloid precursor protein (APP) mutants alone or in conjunction with presenilin mutants. We have generated a mouse model by overexpressing human BACE and human APP with the V717F mutation. The combination of a mutation at the gamma-secretase cleavage site of APP and of increased beta-secretase activity should favour the production of amyloid peptides. We analysed double BACE/APPIn and single APPIn transgenic mice at 16-18 months for amyloid load, brain histopathology and behavioural deficits. We show that overexpression of BACE induces an increase in APP CTFbeta and total brain Abeta peptides. Brain histopathology shows clearly enhanced amyloid deposits in the cortex, hippocampus and in brain vasculature when compared to single APPIn transgenic mice. Amyloid deposits are mostly diffuse and predominantly composed of Abeta(42). A strong inflammatory reaction is evidenced by the presence of microglial cells around the most mature amyloid deposits and astrocytosis over the entire cerebral cortex. At the same age, the APPIn single-transgenic mice show only very limited pathology. When assessed for their cognitive performance at 12 months, BACE/APPIn mice show impaired spatial acquisition in the Morris water maze test. However, these deficits are not greater than those observed in the APPIn single-transgenic animals.

Current evidence supports the notion that beta-amyloid deposits or Abeta intermediates may be responsible for the pathogenesis in Alzheimer's disease (AD) patients. In the present work, we have assessed the neuroprotective effect of the chronic intraperitoneal administration of a five-amino-acid beta-sheet breaker peptide (iAbeta5p) on the rat behavioral deficit induced by the intrahippocampal Abeta-fibrils injection. At 1 month after the injection, animals showed a partial reduction of the amyloid deposits formed and a decreased astrocytic response around the injection site. More importantly, we report that following the iAbeta5p treatment, hippocampal-dependent spatial learning paradigms, including the standard Morris water maze and a working memory analysis, showed a significant prevention from impairments induced by Abeta deposits in the dorsal hippocampus. Thus, it is possible that a noninvasive treatment such as the one presented here with beta-sheet breaker peptides may be used as a potential therapy for AD patients.

Background: High-dose therapy with autologous stem cell transplantation (HDT/ASCT) is a commonly used treatment for hematologic malignancies. The procedure causes significant psychological distress and no interventions have been demonstrated to improve mood in these patients. Music therapy has been shown to improve anxiety in a variety of acute medical settings. In the current study, the authors determined the effects of music therapy compared with standard care on mood during inpatient stays for HDT/ASCT., Methods: Patients with hematologic malignancy admitted for HDT/ASCT at two sites (Memorial Sloan-Kettering Cancer Center and Ireland Cancer Center in Cleveland, Ohio) were randomized to receive music therapy given by trained music therapists or standard care. Outcome was assessed at baseline and every 3 days after randomization using the Profile of Mood States., Results: Of 69 patients registered in the study, follow-up data were available for 62 (90%). During their inpatient stay, patients in the music therapy group scored 28% lower on the combined Anxiety/Depression scale (P = 0.065) and 37% lower (P = 0.01) on the total mood disturbance score compared with controls., Conclusions: Music therapy is a noninvasive and inexpensive intervention that appears to reduce mood disturbance in patients undergoing HDT/ASCT., (Copyright 2003 American Cancer Society.)

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

Point mutations within the beta-amyloid precusor protein (beta-APP) gene known to segregate with Alzheimer's disease in certain families were introduced into human beta-APP cDNAs and expressed under the control of a neuron-specific enolase (NSE) promoter in mice. The transgenic animals exhibited transgene expression predominantly in neocortex and hippocampus where the levels were maximally 1.3-fold of those of wild-type mouse beta-APP. Quantitative immunoblot analysis in homozygous mice carrying different missense mutations showed slightly increased alpha-secretory processing. In V7171 mice compared to nontransgenic mice there was more alpha-secretory beta-APP (beta-APPsec) in cortex/hippocampus, less in cerebellum, and no difference in midbrain/brain stem. In none of the transgenic animals tested was a 4 kDa amyloid fragment detected by Western blotting of brain extracts, immunohistochemistry, or by 125I-A beta-binding onto brain sections. No glial reaction was observed. Behavioral analysis of mice carrying the V7171 mutation showed no appreciable deficit in comparison to wild-type mice. Together, these data suggest that low levels of expression of mutated beta-APP in 10-12-month-old transgenic mouse brains result in slightly more beta-APPsec, and are insufficient to induce amyloidogenic processing and AD-like pathology.

Background: Sporadic observations suggest a possible taste impairment in AL amyloidosis, but the frequency and intensity of this sensory anomaly are not known., Materials and Methods: We submitted 21 AL amyloidotic patients, drawn from subjects referred to the Amyloidosis Study Center of the Department of Internal Medicine and Medical Therapy, University of Pavia, to suprathreshold scaling analysis., Results: Taste acuity was reduced in most of them. Every taste showed independent behavior, and 90% of these patients were hypogeusic. True ageusia for one or two tastes was observed in 35% of patients. No patient was aware of reduced taste acuity. Macroglossia did not seem to play a prominent role in dulling tastes., Conclusions: Impairment of taste perception suggests that gustative neuropathy is a frequently unnoticed expression of sensory involvement in AL amyloidosis.

We report a 32-year-old man with a 4-year history of headaches, seizures, and dementia secondary to multifocal amyloidomas in the white matter. Immunohistochemical and electron microscopic analyses suggest that the amyloidomas resulted from processing of plasma-cell-derived amyloidogenic protein by microglial cells.

Sixteen patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type were examined neuropsychologically. Abnormalities were found in all patients, and dementia was present in 12 of them. Three patients were tested twice at an interval of some years. All three exhibited a progressive intellectual deterioration and memory disturbance; in two of them there was no evidence of intercurrent strokes. Cerebral amyloid angiopathy can lead to dementia because it produces multiple focal cerebral lesions, but a chronic ischemic or metabolic effect on brain parenchyma may play a contributing role.

Physiatrists are rarely presented with a case of amyloidosis. Its unrelenting course must be appreciated in order to speed the process of rehabilitation and help in setting appropriate and rapidly achievable goals. These rehabilitation challenges are discussed with respect to a patient with amyloidosis and a right cerebrovascular accident. The need for medical management of the systemic symptoms of amyloidosis is also addressed. It is felt that the addition of such a progressive terminal disease to the diagnosis of stroke leads to unique interactions among the rehabilitation staff, the patient, and the patient's family, and the need for an aggressive approach to goal-setting and discharge planning.