CSF ferritin in the clinicopathological progression of Alzheimer's disease and associations with APOE and inflammation biomarkers.

BACKGROUND: A putative role for iron in driving Alzheimer's disease (AD) progression is complicated by previously reported associations with neuroinflammation, apolipoprotein E and AD proteinopathy. To establish how iron interacts with clinicopathological features of AD and at what disease stage iron influences cognitive outcomes, we investigated the association of cerebrospinal fluid (CSF) biomarkers of iron (ferritin), inflammation (acute phase response proteins) and apolipoproteins with pathological biomarkers (CSF Aß42/t-tau, p-tau181), clinical staging and longitudinal cognitive deterioration in subjects from the BioFINDER cohort, with replication of key results in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. METHODS: Ferritin, acute phase response proteins (n=9) and apolipoproteins (n=6) were measured in CSF samples from BioFINDER (n=1239; 4 years cognitive follow-up) participants stratified by cognitive status (cognitively unimpaired, mild cognitive impairment, AD) and for the presence of amyloid and tangle pathology using CSF Aß42/t-tau (A+) and p-tau181 (T+). The ferritin and apolipoprotein E associations were replicated in the ADNI (n=264) cohort. RESULTS: In both cohorts, ferritin and apoE were elevated in A-T+ and A+T+ subjects (16%-40%), but not clinical diagnosis. Other apolipoproteins and acute phase response proteins increased with clinical diagnosis, not pathology. CSF ferritin was positively associated with p-tau181, which was mediated by apolipoprotein E. An optimised threshold of ferritin predicted cognitive deterioration in mild cognitive impairment subjects in the BioFINDER cohort, especially those people classified as A-T- and A+T-. CONCLUSIONS: CSF markers of iron and neuroinflammation have distinct associations with disease stages, while iron may be more intimately associated with apolipoprotein E and tau pathology.

Evidence that iron accelerates Alzheimer's pathology: a CSF biomarker study.

OBJECTIVE: To investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF ß-amyloid (Aß) and tau. METHODS: Mixed-effects models of CSF Aß1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aß1-42 for up to 5 years. RESULTS: In subjects with biomarker-confirmed Alzheimer's pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aß1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aß1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aß deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aß from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aß over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aß levels to the average level of Alzheimer's subjects from 18.8 to 10.8 years. CONCLUSIONS: Iron might facilitate Aß deposition in Alzheimer's and accelerate the disease process.

What can predict and prevent the long-term use of benzodiazepines?

Although benzodiazepines (BZDs) are commonly prescribed for insomnia or anxiety, long-term use of BZDs causes serious adverse effects such as daytime drowsiness and cognitive decline. In the current study, we evaluated the predictors and preventers of long-term usage of BZDs from a retrospective survey by utilizing the 12-year prescription record of a university hospital. From the prescription data of 92,005 people, users of BZDs (n = 3,470, male = 39.2%, mean age = 60 ± 17.5) were analyzed. During this period, both the number of prescriptions (2722 in 2004 to 1019 in 2016) and the number of BZDs (1.73 in 2004 to 1.36 in 2016) gradually decreased, although more than half of the patients continued to take BZDs for over three years. High risk factors for long-term use of BZDs include elderly patients (>65 years old), high dosage (>5 mg diazepam per day), psychiatrist-prescribers, and users with polytherapy. Discontinuation is significantly found in users of hypnotic BZDs and alternative psychotropic medical drugs (including antipsychotics, serotonergic drugs, or newer types of sleep medicine). Future studies should focus on elucidating interventions that are more effective against long-term usage of BZDs.

Involvement of hippocampal excitability in amyloid ß-induced behavioral and psychological symptoms of dementia.

In patients with Alzheimer's disease, in addition to the core symptoms, i.e., cognitive dysfunction, behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety, and hallucinations are known to occur frequently. Because various environmental factors influence the onset and progression of Alzheimer's disease, in the present study, BPSD-like behavioral abnormality of Amyloid ß (Aß)1-42-injected mice was assessed under social isolation, which induces behavioral abnormality. Aß protein (500 pmol) was injected into the lateral ventricle of mice, which were individually housed. Two and three weeks after injection into adult mice, the rate of mice that exhibited aggressive behavior, i.e., biting attacks and wrestling, to the total mice, was markedly increased by Aß injection. Aß-injected adult mice also showed anxiety-like behavior, in addition to cognitive decline. Serum corticosterone level was markedly increased by Aß injection. When excitability of hippocampal neurons was checked using hippocampal slices, KCl-induced presynaptic activity was enhanced in hippocampal slices prepared from Aß-injected mice. These results suggest that social isolation housing of Aß1-42-injected adult mice induces BPSD-like behavioral abnormality in addition to cognitive decline. It is likely that behavioral abnormality of Aß1-42-injected adult mice is associated with excitability of hippocampal glutamatergic neurons, which is associated with the elevated corticosterone level.

Metal chaperones: a holistic approach to the treatment of Alzheimer's disease.

As evidence for the role of metal ion dysregulation in the pathogenesis of multiple CNS disorders grows, it has become important to more precisely identify and differentiate the biological effects of various pharmacological modulators of metal ion homeostasis. This is particularly evident in disorders such as Alzheimer's disease (AD), where the use of metal chaperones (that transport metals), as opposed to chelators (which exclude metals from biological interactions), may prove to be the first truly disease modifying approach for this condition. The purpose of this mini-review is to highlight the emerging notion that metal chaperones, such as PBT2 (Prana Biotechnology), modulate a variety of critical pathways affecting key aspects of the AD cascade to provide a more "holistic" approach to the treatment of this disease.