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Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.In this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p0·0001) and in people with Down syndrome (n=32; r=-0·801; p0·0001). There was no difference in global PET amyloid burden between asymptomatic people with Down syndrome (mean 18·80 centiloids [SD 28·33]) versus asymptomatic mutation carriers (24·61 centiloids [30·27]; p=0·11) and between symptomatic people with Down syndrome (77·25 centiloids [41·76]) versus symptomatic mutation carriers (69·15 centiloids [51·10]; p=0·34). APOE ɛ4 status and sex had no effect on global amyloid PET deposition. Amyloid deposition was elevated significantly earlier in mutation carriers than in participants with Down syndrome (estimated years to symptom onset -23·0 vs -17·5; p=0·0002). PSEN1 mutations primarily drove this difference. Early amyloid accumulation occurred in striatal and cortical regions for both mutation carriers (n=265) and people with Down syndrome (n=128). Although mutation carriers had widespread amyloid accumulation in all cortical regions, the medial occipital regions were spared in people with Down syndrome.Despite minor differences, amyloid PET changes were similar between people with autosomal dominant Alzheimer's disease versus Down syndrome and strongly supported early amyloid dysregulation in individuals with Down syndrome. Individuals with Down syndrome aged at least 35 years might benefit from early intervention and warrant future inclusion in clinical trials, particularly given the relatively high incidence of Down syndrome.The National Institute on Aging, Riney and Brennan Funds, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the German Center for Neurodegenerative Diseases, and the Japan Agency for Medical Research and Development.

Background Because of battery depletion, an implantable cardioverter-defibrillator (ICD) generator requires surgical replacement every 5 to 7 years. Routine replacement is the norm without discussion with patients about whether or not to proceed. Objective The aim of this study was to develop a patient decision aid (PDA) for patients facing ICD replacement and plan for its implementation. Methods An embedded mixed-methods study was conducted using questionnaires and semistructured interviews focused on current ICD replacement practices; PDA acceptability, usability, and content; and PDA implementation. Transcripts were analyzed using constant comparative analysis. Results Eighteen PDA end users in 16 interviews characterized the current ICD replacement approach as automatic without consideration for patient preferences. The PDA was positively received, and the content was iteratively revised 4 times during the interviews. Changes were related to missing and excess information, language, and wording. The PDA was identified as a means to support a shared decision-making (SDM) process, not to be used as a standalone instrument. To shift current practices to an SDM process, participants identified that an invitation to discuss the option of ICD replacement is required-whether initiated by the patient or the clinician. Conclusion Currently, the option of ICD replacement is rarely offered, and patient preferences are seldom elicited. Participants believed the PDA to be a useful intervention that could help facilitate an SDM process for patients facing ICD replacement. Preparing for implementation during the development phase will allow us to strategize effectively to overcome perceived barriers and capitalize on perceived facilitators during actual implementation.

Rapid eye movement sleep behavior disorder occurs with idiopathic Parkinson's disease (PD) and often precedes PD. Its frequency in LRRK2-PD and utility as a preclinical marker has not been established.One hundred forty-four idiopathic PD, 142 LRRK2 G2019S mutation PD, 117 non-manifesting carriers, 93 related noncarriers, and 40 healthy controls completed the Rapid eye movement sleep Behavior Disorder Screening Questionnaire.Cut scores were met by 30.6% idiopathic PD, 19.7% LRRK2-PD, 6% nonmanifesting carriers, 20.4% related noncarriers, and 15% controls. The likelihood of abnormal scores was decreased in LRRK2-PD versus idiopathic PD (odds ratio = 0.55, P = 0.03), nonmanifesting carriers versus related noncarriers (OR = 0.25, P0.01), and PD of less than 3 years' duration, 1 of 19 LRRK2-PD versus 14 of 41 idiopathic PD (P0.05).A lower frequency of abnormal questionnaire scores is seen in LRRK2-PD, especially in early LRRK2-PD, and in nonmanifesting carriers. Therefore, the Rapid eye movement sleep Behavior Disorder Questionnaire is unlikely to serve as a preclinical marker for phenoconversion to PD.

The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n = 97) and non-carriers (n = 391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P 0.001), were more likely to be women (51.5% vs. 37.9%; P = 0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P 0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P 0.001), postural instability and gait difficulty (PIGD) (P = 0.043), and a persistent levodopa response for5 years (P = 0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.

Temporal and seasonal trends in Campylobacter genotypes causing human gastroenteritis were investigated in a 6-year study of 3,300 recent isolates from Oxfordshire, United Kingdom. Genotypes (sequence types [ST]) were defined using multilocus sequence typing and assigned to a clonal complex (a cluster of related strains that share four or more identical alleles with a previously defined central genotype). A previously undescribed clonal complex (ST-464) was identified which, together with ST-42, ST-45, and ST-52 complexes, showed increasing incidence. Concurrently, the incidence of ST-574, ST-607, and ST-658 complexes declined. The relative frequencies of three clonal complexes (ST-45, ST-283, and ST-42) peaked during summer and those of two (ST-353 and ST-403) peaked during winter. Nine clonal complexes (ST-22, ST-45, ST-48, ST-61, ST-257, ST-283, ST-403, ST-658, and ST-677) were significantly associated with ciprofloxacin sensitivity ( P < 0.05). Seven clonal complexes (ST-49, ST-206, ST-354, ST-446, ST-460, ST-464, and ST-607) were associated with ciprofloxacin resistance ( P < 0.05). Clonal complexes exhibited changing incidence and differences in seasonality and antibiotic resistance phenotype. These data also demonstrated that detailed surveillance at a single site captures information which reflects that observed nationally.