Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Glycaemic Control Achieves Sustained Increases of Circulating Endothelial Progenitor Cells in Patients Hospitalized for Decompensated Diabetes: An Observational Study.

BACKGROUND AND AIM: Diabetes reduces the levels of circulating endothelial progenitor cells (EPCs), which contribute to vascular homeostasis. In turn, low EPCs levels predict progression of chronic complications. Several studies have shown that hyperglycaemia exerts detrimental effects on EPCs. Improvement in glucose control with glucose-lowering medications is associated with an increase of EPCs, but only after a long time of good glycaemic control. In the present study, we examined the effect of a rapid glycaemic amelioration on EPC levels in subjects hospitalized for decompensated diabetes. METHODS: We used flow cytometry to quantify EPCs (CD34+/CD133+KDR+) in patients hospitalized for/with decompensated diabetes at admission, at discharge, and 2 months after the discharge. During hospitalization, all patients received intensive insulin therapy. RESULTS: Thirty-nine patients with type 1 or type 2 diabetes were enrolled. Average (± SEM) fasting glucose decreased from 409.2 ± 25.9 mg/dl at admission to 190.4 ± 12.0 mg/dl at discharge and to 169.0 ± 10.3 at 2 months (both p < 0.001). EPCs (per million blood cells) significantly increased from hospital admission (13.1 ± 1.4) to discharge (16.4 ± 1.1; p = 0.022) and remained stable after 2 months (15.5 ± 1.7; p = 0.023 versus baseline). EPCs increased significantly more in participants with newly-diagnosed diabetes than in those with pre-existing diabetes. The increase in EPCs was significant in type 1 but not in type 2 diabetes and in those without chronic complications. CONCLUSION: In individuals hospitalized for decompensated diabetes, insulin therapy rapidly increases EPC levels for up to 2 months. EPC defect, reflecting impaired vascular repair capacity, may be reversible in the early diabetes stages.

Hematopoietic and Nonhematopoietic p66Shc Differentially Regulates Stem Cell Traffic and Vascular Response to Ischemia in Diabetes.

Aims: Peripheral artery disease (PAD) is a severe complication of diabetes, characterized by defective traffic of hematopoietic stem/progenitor cells (HSPCs). We examined the hematopoietic versus nonhematopoietic role of p66Shc in regulating HSPC traffic and blood flow recovery after ischemia in diabetic mice. Results: Using streptozotocin-induced diabetes, chimeric mice with green fluorescent protein (GFP)+ bone marrow (BM), and the hind limb ischemia model, we found that the physiologic mobilization and homing of HSPCs were abolished by diabetes, along with impaired vascular recovery. Hematopoietic deletion of p66Shc, obtained by transplanting p66Shc-/- BM cells into wild-type (Wt) recipients, but not nonhematopoietic deletion, constrained hyperglycemia-induced myelopoiesis, rescued postischemic HSPC mobilization, and improved blood flow recovery in diabetic mice. In Wt diabetic mice transplanted with BM cells from GFP+p66Shc-/- mice, the amount of HSPCs homed to ischemic muscles was greater than in mice transplanted with GFP+p66Shc+/+ cells, with recruited cells displaying higher expression of adhesion molecules and Vegf. In 40 patients with diabetes, p66Shc gene expression in mononuclear cells was correlated with myelopoiesis and elevated in the presence of PAD. In 13 patients with diabetes and PAD, p66Shc expression in HSPC-mobilized peripheral blood cells was inversely correlated with VEGF expression. Innovation: For the first time, we dissect the role of hematopoietic versus nonhematopoietic p66Shc in regulating HSPC traffic and ischemic responses. Conclusion: Hematopoietic deletion of p66Shc was sufficient to rescue HSPC mobilization and homing in diabetes after ischemia and improved blood flow recovery. Inhibiting p66Shc in blood cells may be a novel strategy to counter PAD in diabetes. Antioxid. Redox Signal. 36, 593-607. Clinical Trial No.: NCT02790957.

Inhibition of SGLT2 Rescues Bone Marrow Cell Traffic for Vascular Repair: Role of Glucose Control and Ketogenesis.

The mechanisms by which sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in people with diabetes are incompletely understood. Recent studies show that SGLT2i may increase the levels of circulating cells with vascular regenerative capacity, at least in part by lowering glycemia. In this study, we used mice with streptozotocin-induced diabetes treated with the SGLT2i dapagliflozin at a dose that reduced glucose levels by 20%. Dapagliflozin improved the diabetes-associated defect of hematopoietic stem cell mobilization after stimulation with granulocyte colony-stimulating factor. Dapagliflozin rescued the traffic of bone marrow (BM)-derived cells to injured carotid arteries and improved endothelial healing in diabetic mice. Defective homing of CD49d+ granulocytes was causally linked with impaired endothelial repair and was reversed by dapagliflozin. The effects of dapagliflozin were mimicked by a similar extent of glucose reduction achieved with insulin therapy and by a ketone drink that artificially elevated ß-hydroxybutyrate. Inhibition of endothelial repair by resident cells using the CXCR4 antagonist AMD3100 did not abolish the vascular effect of dapagliflozin, indirectly supporting that endothelial healing by dapagliflozin was mediated by recruitment of circulating cells. In summary, we show that dapagliflozin improved the traffic of BM-derived hematopoietic cells to the site of vascular injury, providing a hitherto unappreciated mechanism of vascular protection.

Diabetes mellitus impairs circulating proangiogenic granulocytes.

AIMS/HYPOTHESIS: Cardiovascular risk in diabetes is at least in part attributable to defective angiogenesis. Since diabetes negatively affects blood cells involved in angiogenesis, we herein evaluated whether diabetes impairs proangiogenic granulocytes (PAGs). METHODS: We characterised and quantified PAGs as CD49d+ granulocytes in peripheral blood of participants with type 2 or type 1 diabetes and in non-diabetic control participants. We evaluated PAG antigenic profile and assessed in vitro functional properties of CD49d+ granulocytes using 2D and 3D angiogenesis assays. We also quantified PAGs before and after glucose control with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin. In parallel, we measured Ly6G+CD49d+ PAGs in streptozotocin-induced type 1-like diabetic mice vs non-diabetic control mice. RESULTS: PAGs were composed of eosinophils (>80%) and neutrophils (<20%). Within both populations, CD49d identified CXCR4high/VEGFR1high cells. CD49d+ granulocytes supported in vitro angiogenesis by endothelial cells significantly more than CD49d- control granulocytes, and physically interacted with endothelial cells. Granulocytes from type 2 diabetic participants had a profoundly impaired capacity to stimulate endothelial cell tubule formation compared with those from non-diabetic control participants. CD49d+ PAGs were reduced by 30-40% and were functionally impaired in diabetic vs control individuals. PAG levels inversely correlated with plasma glucose (r = -0.25; p = 0.025) and significantly increased 1.8-times after glucose control with dapagliflozin, which reduced HbA1c by 1.0% (11 mmol/mol). Levels of Ly6G+CD49d+ PAGs were also significantly reduced also in type 1 diabetic mice vs control mice. CONCLUSIONS/INTERPRETATION: We illustrate a significant impairment of PAGs in diabetes and provide evidence for a direct role of hyperglycaemia. These findings add mechanistic information to explain the defective angiogenesis in diabetes. Graphical abstract.

Pharmacologic PPAR-γ Activation Reprograms Bone Marrow Macrophages and Partially Rescues HSPC Mobilization in Human and Murine Diabetes.

Mobilization of hematopoietic stem/progenitor cells (HSPC) from the bone marrow (BM) is impaired in diabetes. Excess oncostatin M (OSM) produced by M1 macrophages in the diabetic BM signals through p66Shc to induce Cxcl12 in stromal cells and retain HSPC. BM adipocytes are another source of CXCL12 that blunts mobilization. We tested a strategy of pharmacologic macrophage reprogramming to rescue HSPC mobilization. In vitro, PPAR-γ activation with pioglitazone switched macrophages from M1 to M2, reduced Osm expression, and prevented transcellular induction of Cxcl12 In diabetic mice, pioglitazone treatment downregulated Osm, p66Shc, and Cxcl12 in the hematopoietic BM, restored the effects of granulocyte-colony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. Osm deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization. In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate Cxcl12 in BM adipocytes. In patients with diabetes on pioglitazone therapy, HSPC mobilization after G-CSF was partially rescued. In summary, pioglitazone reprogrammed BM macrophages and suppressed OSM signaling, but sustained Cxcl12 expression by BM adipocytes could limit full recovery of HSPC mobilization.

Diabetes-Associated Myelopoiesis Drives Stem Cell Mobilopathy Through an OSM-p66Shc Signaling Pathway.

Diabetes impairs the mobilization of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow (BM), which can worsen the outcomes of HSPC transplantation and of diabetic complications. In this study, we examined the oncostatin M (OSM)-p66Shc pathway as a mechanistic link between HSPC mobilopathy and excessive myelopoiesis. We found that streptozotocin-induced diabetes in mice skewed hematopoiesis toward the myeloid lineage via hematopoietic-intrinsic p66Shc. The overexpression of Osm resulting from myelopoiesis prevented HSPC mobilization after granulocyte colony-stimulating factor (G-CSF) stimulation. The intimate link between myelopoiesis and impaired HSPC mobilization after G-CSF stimulation was confirmed in human diabetes. Using cross-transplantation experiments, we found that deletion of p66Shc in the hematopoietic or nonhematopoietic system partially rescued defective HSPC mobilization in diabetes. Additionally, p66Shc mediated the diabetes-induced BM microvasculature remodeling. Ubiquitous or hematopoietic restricted Osm deletion phenocopied p66Shc deletion in preventing diabetes-associated myelopoiesis and mobilopathy. Mechanistically, we discovered that OSM couples myelopoiesis to mobilopathy by inducing Cxcl12 in BM stromal cells via nonmitochondrial p66Shc. Altogether, these data indicate that cell-autonomous activation of the OSM-p66Shc pathway leads to diabetes-associated myelopoiesis, whereas its transcellular hematostromal activation links myelopoiesis to mobilopathy. Targeting the OSM-p66Shc pathway is a novel strategy to disconnect mobilopathy from myelopoiesis and restore normal HSPC mobilization.

Effects of Hypoglycemia on Circulating Stem and Progenitor Cells in Diabetic Patients.

Context: Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes. Objective: To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs). Design: We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2). Setting: Tertiary referral inpatient clinic. Patients and Other Participants: Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group). Interventions: Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared. Main Outcome Measure: Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR). Results: In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls. Conclusions: In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.

Shift of monocyte subsets along their continuum predicts cardiovascular outcomes.

BACKGROUND AND AIMS: Distribution of monocyte subsets has been shown to predict cardiovascular outcomes. However, monocytes form a continuum and categorization into discrete subsets may be an oversimplification. We herein aimed at establishing whether distribution of monocytes based on CD14 and CD16 fluorescence intensity provides incremental and complementary information on cardiovascular outcomes beyond enumeration of traditional subsets. METHODS: A cohort of 227 patients at high cardiovascular risk was characterized at baseline and followed for a median of 4 years. We quantified monocytes subsets by flow cytometry based on CD14 and CD16 expression and evaluated the continuous distribution of CD14 and CD16 fluorescence within each subset. RESULTS: A consistent shift toward higher CD16 fluorescence intensity within each monocyte subset was observed in patients with type 2 diabetes, despite no change in their frequencies. Patients with coronary artery disease (CAD) at baseline showed a doubling of CD14++CD16+ intermediate monocytes and a shift of non-classical and classical monocytes towards intermediates ones. During follow-up, cardiovascular death or cardiovascular events occurred in 26 patients, who showed monocyte skewing similar to those of patients with baseline CAD. In fully adjusted Cox proportional hazard regression models, higher CD16 expression on classical monocytes, but not the level of intermediate monocytes or other subsets, independently predicted adverse cardiovascular outcomes. CONCLUSIONS: Shift of monocyte subsets along the CD14/CD16 continuum, more than their frequencies, predicted adverse cardiovascular outcomes. This finding illustrates how the concept of monocyte continuum can be used to model the cardiovascular risk.

Plerixafor improves the endothelial health balance. The effect of diabetes analysed by polychromatic flow cytometry.

BACKGROUND AND AIMS: Diabetes damages the endothelium and reduces the availability of bone marrow (BM)-derived endothelial progenitor cells (EPCs). The mobilization of hematopoietic stem cells (HSCs) and EPCs in response to G-CSF is impaired by diabetes, owing to CXCL12 dysregulation. We have previously shown that the CXCR4/CXCL12 disruptor plerixafor rescues HSC and EPC mobilization in diabetes. We herein explored the effects of plerixafor on HSCs, EPCs, and circulating endothelial cells (CECs) in patients with and without diabetes. METHODS: We re-analysed data gathered in the NCT02056210 trial, wherein patients with (n = 10) and without diabetes (n = 10) received plerixafor to test stem/progenitor cell mobilization. We applied a novel and very specific polychromatic flow cytometry (PFC) approach to identify and quantify HSCs, EPCs, and CECs. RESULTS: We found that 7-AAD(-)Syto16(+)CD34(+)CD45(dim) HSC levels determined by PFC strongly correlated to the traditional enumeration of CD34(+) cells, whereas 7-AAD(-)Syto16(+)CD34(+)CD45(neg)KDR(+) EPCs were unrelated to the traditional enumeration of CD34(+)KDR(+) cells. Using PFC, we confirmed that plerixafor induces rapid mobilization of HSCs and EPCs in both groups, with a marginally significant defect in patients with diabetes. Plerixafor reduced live (7-AAD(-)) and dead (7-AAD(+)) Syto16(+)CD34(bright)CD45(neg)CD146(+) CECs more in patients without than in those with diabetes. The EPC/CEC ratio, a measure of the vascular health balance, was increased by plerixafor, but less prominently in patients with that in those without diabetes. CONCLUSIONS: In addition to rescuing defective mobilization associated with diabetes, plerixafor improves the balance between EPCs and CECs, but the latter effect is blunted in patients with diabetes.