***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective : To determine the spatiotemporal mapping of neurofibrillary degeneration ( NFD ) in normal aging and the different stages of AD . Background : The pathophysiologic significance of AD lesions , namely amyloid plaques and neurofibrillary tangles , is still unclear , especially their interrelationship and their link with cognitive impairment . Methods : The study included 130 patients of various ages and different cognitive statuses , from nondemented control subjects ( n = 60 , prospect i ve study ) to patients with severe definite AD .  Paired helical filaments (PHF)-tau and Aβ were used as biochemical and histologic markers of NFD and amyloid plaques , respectively . Results : NFD with PHF-tau was systematic ally present in variable amounts in the hippocampal region of nondemented patients age > 75 years . When NFD was found in other brain areas , it was always along a stereotyped , sequential , hierarchical pathway . The progression was categorized into 10 stages according to the brain regions affected : transentorhinal cortex ( S1 ) , entorhinal ( S2 ) , hippocampus ( S3 ) , anterior temporal cortex ( S4 ) , inferior temporal cortex ( S5 ) , medium temporal cortex ( S6 ) , polymodal association areas ( prefrontal , parietal inferior , temporal superior ) ( S7 ) , unimodal areas ( S8 ) , primary motor ( S9a ) or sensory ( S9b , S9c ) areas , and all neocortical areas ( S10 ) . Up to stage 6 , the disease could be asymptomatic . In all cases studied here , stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired . Conclusions : The relationship between NFD and Alzheimer-type dementia , and the criteria for a biochemical diagnosis of AD , are documented , and an association between AD and the extent of NFD in defined brain areas is shown In this prospect i ve study 37 % of 239 patients developed a post-lumbar puncture headache ( PPH ) after a diagnostic lumbar puncture .  PPH was more prevalent in females than males ( 46 % vs. 21 % ; P = 0.0003 ) as were the severest form of PPH ( 64 % vs. 23 % ; P = 0.02 ) and nausea ( 74 % vs. 39 % ; P = 0.01 ) in those who developed PPH . Females scored their pain in the upright position more severe on a 100-mm visual analogue scale than males ( median 60 mm vs. 47.5 mm ; P = 0.02 ) . The frequency of PPH was higher with the use of a 20-gauge compared with a 22-gauge needle in all patients ( 50 % vs. 26 % ; P = 0.0002 ) and in females ( 57 % vs. 36 % ; P = 0.02 ) and males ( 38 % vs. 10 % ; P = 0.004 ) , separately . Neither age , weight , height , nor body mass index ( BMI ) , influenced the prevalence of PPH , but tinnitus was more prevalent in tall compared with smaller patients ( 53 % vs. 17 % ; P = 0.02 ) . Old age was associated with a long median pain delay upon rising , and also , small patients tended to report a longer median pain delay than tall patients . The pain intensity changed more slowly upon rising and reclining in patients with a high BMI than in those with a lower BMI ( median 60 s vs. 12 s ; P = 0.02 ) . The results concerning height , BMI and needle size might be anticipated according to the leakage theory . In a multivariate analysis sex ( P = 0.0003 ) and needle size ( P = 0.0002 ) were related to the development of PPH on a statistically significant level . Furthermore , the pain severity was positively related to female sex ( P = 0.03 ) and young age ( P = 0.03 ) . The pain delay increased with age ( P = 0.008 ) and the pain decrease time increased with an increasing BMI ( P = 0.04 ) IMPORTANCE This study assesses factors associated with the most common adverse event following  lumbar puncture .  OBJECTIVE To identify factors associated with the risk , onset , and persistence of  post-dural puncture headache ( PDPH ) .  DESIGN , SETTING , AND PARTICIPANTS We performed univariate and multivariable analyses of  338 lumbar punctures in the Dominantly Inherited Alzheimer Network observational study using linear mixed models , adjusting for participant-level and family-level r and om effects . MAIN OUTCOMES AND MEASURES We directly evaluated associations of 3 post-lumbar puncture outcomes ( immediate postprocedural headache , PDPH at 24-hour follow-up , and PDPH receiving a therapeutic blood patch ) with participant age and sex , positioning , collection method , needle size , needle insertion site , and cerebrospinal fluid ( CSF ) volume collected . RESULTS The incidence of adverse events included 73 immediate postprocedural headaches ( 21.6 % ) , 59 PDPHs at 24-hour follow-up ( 17.5 % ) , and 15 PDPHs receiving a therapeutic blood patch ( 4.4 % ) . Greater volume of CSF collected was associated with increased risk of immediate postprocedural headache , largely owing to a nonlinear increase in risk on collection of volumes above 30 mL ( odds ratio , 3.73 for > 30 mL and 0.98 for < 17 mL ) . In contrast , collection of higher volumes showed a protective effect in decreasing rates of PDPH at 24-hour follow-up and rates of PDPH receiving a therapeutic blood patch ( odds ratio , 0.35 per 10 mL ) . Although differences in needle size did not reach statistical significance , no participant in the 24 G needle group received a therapeutic blood patch compared to 8 of 253 for the larger 22 G needles . CONCLUSIONS AND RELEVANCE Factors that acutely lower CSF pressure ( eg , seated positioning or extracting very high volumes of CSF ) may be associated with transient post-lumbar puncture headache , without increasing rates of persistent PDPH or therapeutic blood patch . Collection of up to 30 mL of CSF appears to be well tolerated and safe OBJECTIVE To identify plasma biomarkers for the diagnosis of Alzheimer disease ( AD ) . DESIGN Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data . SETTING General community-based , prospect i ve , longitudinal study of aging . PARTICIPANTS A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study ( AIBL ) cohort with identified biomarkers that were vali date d in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative ( ADNI ) cohort . RESULTS A biomarker panel was identified that included markers significantly increased ( cortisol , pancreatic polypeptide , insulinlike growth factor binding protein 2 , β(2 ) microglobulin , vascular cell adhesion molecule 1 , carcinoembryonic antigen , matrix metalloprotein 2 , CD40 , macrophage inflammatory protein 1α , superoxide dismutase , and homocysteine ) and decreased ( apolipoprotein E , epidermal growth factor receptor , hemoglobin , calcium , zinc , interleukin 17 , and albumin ) in AD . Cross-vali date d accuracy measures from the AIBL cohort reached a mean ( SD ) of 85 % ( 3.0 % ) for sensitivity and specificity and 93 % ( 3.0 ) for the area under the receiver operating characteristic curve . A second validation using the ADNI cohort attained accuracy measures of 80 % ( 3.0 % ) for sensitivity and specificity and 85 % ( 3.0 ) for area under the receiver operating characteristic curve . CONCLUSIONS This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity . Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis Background : Acute and chronic systemic inflammation are characterized by the systemic production of the proinflammatory cytokine tumor necrosis factor α ( TNF-α ) that plays a role in immune to brain communication . Previous pre clinical research shows that acute systemic inflammation contributes to an exacerbation of neurodegeneration by activation of primed microglial cells . Objective : To determine whether acute episodes of systemic inflammation associated with increased TNF-α would be associated with long-term cognitive decline in a prospect i ve cohort study of subjects with Alzheimer disease . Methods : Three hundred community-dwelling subjects with mild to severe Alzheimer disease were cognitively assessed , and a blood sample was taken for systemic inflammatory markers . Each subject ’s main caregiver was interviewed to assess the presence of incident systemic inflammatory events . Assessment s of both patient and caregiver were repeated at 2 , 4 , and 6 months . Results : Acute systemic inflammatory events , found in around half of all subjects , were associated with an increase in the serum levels of proinflammatory cytokine TNF-α and a 2-fold increase in the rate of cognitive decline over a 6-month period . High baseline levels of TNF-α were associated with a 4-fold increase in the rate of cognitive decline . Subjects who had low levels of serum TNF-α throughout the study showed no cognitive decline over the 6-month period . Conclusions : Both acute and chronic systemic inflammation , associated with increases in serum tumor necrosis factor α , is associated with an increase in cognitive decline in Alzheimer disease There is no consensus for a blood-based test for the early diagnosis of Alzheimer ’s disease ( AD ) . Expression profiling of small non-coding RNA ’s , microRNA ( miRNA ) , has revealed diagnostic potential in human diseases . Circulating miRNA are found in small vesicles known as exosomes within biological fluids such as human serum . The aim of this work was to determine a set of differential exosomal miRNA biomarkers between healthy and AD patients , which may aid in diagnosis . Using next-generation deep sequencing , we profiled exosomal miRNA from  serum ( N=49 ) collected from the Australian Imaging , Biomarkers and Lifestyle Flagship Study ( AIBL ) . Sequencing results were vali date d using quantitative reverse transcription PCR ( qRT-PCR ; N=60 ) , with predictions performed using the R and om Forest method . Additional risk factors collected during the 4.5-year AIBL Study including clinical , medical and cognitive assessment s , and amyloid neuroimaging with positron emission tomography were assessed . An AD-specific 16-miRNA signature was selected and adding established risk factors including age , sex and apolipoprotein ɛ4 ( APOE ɛ4 ) allele status to the panel of deregulated miRNA result ed in a sensitivity and specificity of 87 % and 77 % , respectively , for predicting AD . Furthermore , amyloid neuroimaging information for those healthy control subjects incorrectly classified with AD-suggested progression in these participants towards AD . These data suggest that an exosomal miRNA signature may have potential to be developed as a suitable peripheral screening tool for AD Olfactory dysfunction in general , and impaired odor identification in particular , have been reported in Alzheimer 's disease ( AD ) . Olfactory testing may be a useful diagnostic aid for AD , but the types of odor most commonly affected need to be identified . This study aim ed to determine pattern and types of odor affected in AD with the goal of improving clinical applicability . 54 out patients with mild to moderate AD and 40 age and gender-matched non-demented controls ( NDC ) were tested using British version of University of Pennsylvania Smell Identification Test ( UPSIT ; Sensonics , Inc. , Haddon Heights , NJ ) and data analyzed to identify an optimal subset of UPSIT to best differentiate AD patients from controls . AD subjects had significantly lower UPSIT total scores than NDC . R and om Forest with backward elimination identified 12 UPSIT items which accurately differentiated AD patients compared to controls ( sensitivity , 0.89 and specificity , 0.83 , positive predictive value of 0.889 , and negative predictive value of 0.833 ) . The 12 smell items found to be most affected in AD subjects reflects important attributes such as safety and food , known to be affected in people with AD and that has the potential to impair activities of daily living . The 12 items of British UPSIT most affected in AD subjects provides a potential brief scale for early detection of AD in clinical setting s. Independent replication is needed to vali date these findings Immunocytochemistry for choline acetyltransferase ( ChAT ) and the vesicular acetylcholine transporter ( VAChT ) was used to examine the expression of these linked cholinergic markers in human basal forebrain , including cases with early stages of Alzheimer 's disease ( AD ) . Previous neurochemical studies have measured decreased ChAT activity in terminal fields , but little change or even increased levels of VAChT. To determine total cholinergic neuron numbers in the nucleus basalis of Meynert ( nbM ) , stereologic methods were applied to tissue derived from three groups of individuals with varying levels of cognition : no cognitive impair 
    Output:
    
After network analysis of the 10 miRNAs , they were found to be associated with the immune system , cell cycle , gene expression , cellular response to stress , neuron growth factor signalling , wnt signalling , cellular senescence , and Rho GTPases