Neuroimaging of Vessel Amyloid in Alzheimer's Disease a , b

Despite extensive recent advances in understanding Alzheimer's disease (AD) we are unable to noninvasively establish a definite diagnosis during life and cannot monitor the cerebral deposition of amyloid Β protein (A/Β) in living patients. We evaluated the use of 10H3, a monoclonal antibody Fab targeting AΒ protein 1-28 labeled with Tc-99m. Six subjects with probable AD were studied using single-photon emission computed tomography (SPECT) at times from 0–24 hours following injection. Curves of radioactivity in blood demonstrate a half-life of the injected Fab of 2–3 hours. Images show uptake around the head in the scalp or bone marrow in all subjects. There is no evidence of cerebral uptake of the antibody. Scalp biopsies in all six patients demonstrate diffuse staining with 10H3 of the scalp, a pattern indistinguishable from that found in controls. Evidence of amyloid deposition in the scalp in AD is not seen with other anti-AΒ antibodies, suggesting that 10H3 is cross-reacting with another protein. Further studies with anti-AΒ antibodies will require longer-lived radionuclides to detect cerebral uptake at later tunes after injection to allow for complete clearance from the blood. Afternately, imaging using labeled AΒ itself may provide a means for noninvasive targeting of cerebral amyloid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73674/1/j.1749-6632.1997.tb48475.x.pd

Behavioral Variant Frontotemporal Lobar Degeneration with Amyotrophic Lateral Sclerosis with a Chromosome 9p21 Hexanucleotide Repeat

To determine the genetic basis of familial frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS) we performed a clinical and genetic analysis of an affected family. A 51-year-old man with behavioral variant FTLD with ALS had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD. Five others unaffected from the family were negative (all had less than 11 repeats). Because of the clinical and pathological overlap between FTLD and AD we performed a larger genome-wide association study and did not find association of single nucleotide polymorphisms (SNPs) in the C9ORF72 gene with Alzheimer’s disease (AD) risk. Bioinformatic analysis of C9ORF72 using the Gene Expression Omnibus database showed expression differences in patients with muscular dystrophy, neural tube defects, and schizophrenia. We also report analysis of gene expression in brain regions using the Allen Human Brain Atlas. Defects in this recently reported gene are now believed to be the most common cause of inherited ALS and an important cause of inherited FTLD. Our work suggests that the gene may also be important in other neurological and psychiatric conditions

Lack of association between angiotensin-converting enzyme and dementia of the Alzheimer’s type in an elderly Arab population in Wadi Ara, Israel

The angiotensin-converting enzyme (ACE), a protease involved in blood pressure regulation, has been implicated as an important candidate gene for Alzheimer’s disease (AD). This study investigated whether the ACE gene insertion–deletion (ID) polymorphism is associated with risk of developing dementia of Alzheimer’s type (DAT) in an Arab–Israeli community, a unique genetic isolate where there is a high prevalence of DAT. In contrast to several other studies, we found no evidence of an association between this polymorphism and either DAT or age-related cognitive decline (ARCD)

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer's, and Parkinson's Diseases.

Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain

Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review.

BACKGROUND: Deposition of amyloid-beta (Abeta) in vessel walls of the brain as cerebral amyloid angiopathy (CAA) could be a major factor in the pathogenesis of dementia. Here we investigate the relationship between dementia and the prevalence of CAA in older populations. We searched the literature for prospective population-based epidemiological clinicopathological studies, free of the biases of other sampling techniques, which were used as a comparison. METHODS: To identify population-based studies assessing CAA and dementia, a previous systematic review of population-based clinicopathological studies of ageing and dementia was employed. To identify selected-sample studies, PsychInfo (1806-April Week 3 2008), OVID MEDLINE (1950-April Week 2 2008) and Pubmed (searched 21 April 2008) databases were searched using the term "amyloid angiopathy". These databases were also employed to search for any population-based studies not included in the previous systematic review. Studies were included if they reported the prevalence of CAA relative to a dementia classification (clinical or neuropathological). RESULTS: Four population-based studies were identified. They showed that on average 55-59% of those with dementia displayed CAA (of any severity) compared to 28-38% of the non-demented. 37-43% of the demented displayed severe CAA in contrast to 7-24% of the non-demented. There was no overlap in the range of these averages and they were less variable and lower than those reported in 38 selected sample studies (demented v non-demented: 32-100 v 0-77% regardless of severity; 0-50 v 0-11% for severe only). CONCLUSION: CAA prevalence in populations is consistently higher in the demented as compared to the non-demented. This supports a significant role for CAA in the pathogenesis of dementia

Alzheimer\u27s disease and vascular dementia in developing countries: prevalence, management, and risk factors

Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (≥5%) in certain Asian and Latin American countries, but consistently low (1–3%) in India and sub-Saharan Africa; Alzheimer\u27s disease accounts for 60% whereas vascular dementia accounts for ∼30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE ε4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions

Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation.

The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer's disease (AD) and Down's syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects (p < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported via macrophages and the majority of the vesicular hepcidin enters the brain via a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation

Hepcidin Increases Cytokines in Alzheimer's Disease and Down's Syndrome Dementia: Implication of Impaired Iron Homeostasis in Neuroinflammation.

The liver-derived hormone hepcidin, a member of the defensin family of antimicrobial peptides, plays an important role in host defense and innate immunity due to its broad antibacterial and antiviral properties. Ferritin, an iron storage protein is often associated with iron deficiency, hypoferritinemia, hypoxia, and immune complications, which are all significant concerns for systemic infection in Alzheimer's disease (AD) and Down's syndrome (DS) dementia. Serum and post-mortem brain samples were collected from AD, DS and age-matched control subjects. Serum samples were analyzed with ELISA for ferritin, hepcidin and IL-6. Additionally, post-mortem brain sections were assessed by immunohistochemistry for iron-related and inflammatory proteins. A significant increase in serum hepcidin levels was found in DS, compared to controls and AD subjects (p < 0.0001). Hepcidin protein was visible in the epithelial cells of choroid plexus, meningeal macrophages and in the astrocytes close to the endothelium of blood vessels. Hepcidin co-localized with IL-6, indicating its anti-inflammatory properties. We found significant correlation between hypoferritinemia and elevated levels of serum hepcidin in AD and DS. Hepcidin can be transported via macrophages and the majority of the vesicular hepcidin enters the brain via a compromised blood brain barrier (BBB). Our findings provide further insight into the molecular implications of the altered iron metabolism in acute inflammation, and can aid towards the development of preventive strategies and novel treatments in the fight against neuroinflammation

Rationing tests for drug-resistant tuberculosis - who are we prepared to miss?

BACKGROUND: Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss. METHODS: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB. RESULTS: Overall, 147/1,545 (9.5%) subjects had culture-positive TB, of which 32 (21.8%) had DR-TB (MDR, 13.6%; isoniazid mono-resistant, 7.5%; rifampicin mono-resistant, 0.7%). A total of 553 subjects (35.8%) reported one or more MDR-TB risk factors; of these, 506 (91.5%; 95% CI, 88.9-93.7%) did not have TB, 32/553 (5.8%; 95% CI, 3.4-8.1%) had drug-susceptible TB, and only 15/553 (2.7%; 95% CI, 1.5-4.4%) had DR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2%; 95% CI, 34.7-70.9). CONCLUSIONS: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority

Neuroprotective Effect of TREM-2 in Aging and Alzheimer's Disease Model.

Neuroinflammation and activation of innate immunity are early events in neurodegenerative diseases including Alzheimer's disease (AD). Recently, a rare mutation in the gene Triggering receptor expressed on myeloid cells 2 (TREM2) has been associated with a substantial increase in the risk of developing late onset AD. To uncover the molecular mechanisms underlying this association, we investigated the RNA and protein expression of TREM2 in APP/PS1 transgenic mice. Our findings suggest that TREM2 not only plays a critical role in inflammation, but is also involved in neuronal cell survival and in neurogenesis. We have shown that TREM2 is a soluble protein transported by macrophages through ventricle walls and choroid plexus, and then enters the brain parenchyma via radial glial cells. TREM2 protein is essential for neuroplasticity and myelination. During the late stages of life, a lack of TREM2 protein may accelerate aging processes and neuronal cell loss and reduce microglial activity, ultimately leading to neuroinflammation. As inflammation plays a major role in neurodegenerative diseases, a lack of TREM2 could be a missing link between immunomodulation and neuroprotection.Medical Research Council (Grant ID: RNAG/254), National Institute of Health Research, The John Van Geest Foundation, Cambridgeshire and Peterborough Foundation NHS TrustThis is the author accepted manuscript. The final version is available from IOS Press via https://doi.org/10.3233/JAD-16066