The dentate gyrus of the hippocampus is one of the few areas of the adult brain that undergoes neurogenesis. In the present study, cells capable of proliferation and neurogenesis were isolated and cultured from the adult rat hippocampus. In defined medium containing basic fibroblast growth factor (FGF-2), cells can survive, proliferate, and express neuronal and glial markers. Cells have been maintained in culture for 1 year through multiple passages. These cultured adult cells were labeled in vitro with bromodeoxyuridine and adenovirus expressing ,i-galactosidase and were transplanted to the adult rat hippocampus. Surviving cells were evident through 3 months postimplantation with no evidence of tumor formation. Within 2 months postgrafting, labeled cells were found in the dentate gyrus, where they differentiated into neurons only in the intact region of the granule cell layer. Our results indicate that FGF-2 responsive progenitors can be isolated from the adult hippocampus and that these cells retain the capacity to generate mature neurons when grafted into the adult rat brain.Most neurons in the adult central nervous system are terminally differentiated, exist through the life of the organism, and are not replaced when they die. However, evidence exists that small populations of neurons continue to be born in the adult ventricular zone (1-3), olfactory system (4-6), and hippocampus (7-10). In the adult hippocampus, newly born neurons originate from putative stem cells that exist in the subgranular zone of the dentate gyrus. Progeny of these putative stem cells differentiate into neurons in the granule cell layer within a month of the cells' birth, and this late neurogenesis continues throughout the adult life of the rodent (11-15). Paralleling these in vivo findings, in vitro studies have shown that the precursor cells isolated from adult mouse ventricular zone and forebrain have the capacity for in vitro neurogenesis when stimulated with epidermal growth factor (16) or basic fibroblast growth factor (FGF-2) (17), respectively. FGF-2 is a potent mitogen for fetal cells isolated from different areas of the brain (18)(19)(20)(21)(22). This proliferative property of FGF-2 has allowed the isolation and culturing of fetal hippocampal cells for over a year through multiple passages (21), some of which expressed neuronal phenotypes in vitro. These studies have raised the question whether the FGF-2 responsive cells can be isolated and cultured from the adult brain, particularly in the hippocampus, where neurogenesis occurs even in adulthood. In the present study we report that a population of FGF-2 responsive progenitor cells can be isolated and cultured from the adult rat hippocampus. Cells in culture express precursor, glial, and neuronal cell markers. Upon implantation into the adult rat hippocampus, cells migrate and differentiate into mature neurons or glia, depending on the terminal site of migration. Such a progenitor population will be valuable forThe publication costs of this article were defrayed in ...
Neurogenesis continues throughout adulthood in discrete regions. Proliferative zones include the subependymal zone, from where progenitors migrate along the rostral migratory pathway to differentiate into neurons in the olfactory bulb, and the hippocampal subgranular zone, where they migrate and differentiate into granule neurons. Progenitors isolated from adult subependymal zone exhibit in vitro neurogenesis when stimulated with epidermal or fibroblast growth factor. Cultured adult rat hippocampal progenitors (AHPs) grafted to adult rat hippocampus show site-specific neuronal differentiation. Here we investigate determinants of multipotentiality in the adult central nervous system, by grafting AHPs into homotypic (hippocampus) or heterotypic (the rostral migratory pathway) neurogenic sites or a heterotypic, non-neurogenic site (the cerebellum). We found that grafts into neurogenic, but not nonneurogenic sites, showed neuronal differentiation. Furthermore, AHPs grafted in the rostral migratory pathway migrated into the olfactory bulb, differentiating into tyrosine-hydroxylase-positive neurons, a non-hippocampus phenotype. These results reveal that AHP populations can respond to persistent neuronal differentiation cues in the adult central nervous system.
NPS are common even in the early stages of AD. NPS were significantly associated with caregiver assessment of the patient's QoL but not with patients' self-assessed QoL. Depression decreases QoL, but may remain unrecognized in AD patients, emphasizing the need for careful and structured assessment of NPS before deciding on the appropriate treatment.
Objective: To examine the association between neuropsychiatric symptoms (NPS) with self-and caregiver-rated Quality of Life (QoL) for patients with Alzheimer's disease (AD) during a 5-year follow-up. Methods: The ALSOVA 5-year follow-up study included, at baseline, 236 patients with either very mild (Clinical Dementia Rating Scale (CDR) 0.5), or mild (CDR 1) AD, together with their caregivers from three Finnish hospital districts. QoL was evaluated using patient self-reported, and caregiver-rated, QoL in AD (QoL-AD) scores. NPS were assessed using the Neuropsychiatric Inventory (NPI), and AD severity was evaluated using the CDR, with cognition tested by the mini-mental state examination. The performance of daily activities was assessed using the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory. Results: Over the 5-year follow-up period, patient self-reported QoL-AD scores did not change significantly (p = 0.245), despite increases in their NPS. However, caregiver-rated patient QoL-AD scores declined significantly (p ≤ 0.001), as total NPI scores increased during follow-up. No NPS at baseline, and only apathy at follow-up, correlated significantly (p = 0.007) with patient self-rated QoL-AD scores. Caregiver-rated patient QoL-AD scores correlated significantly with most NPS, especially (p ≤ 0.001) apathy, agitation, anxiety, irritability, depression, and delusions at baseline, and delusions, hallucinations, apathy, appetite disturbances, and anxiety during follow-up. Conclusions: Patient rated QoL-AD scores are an unreliable tool with which to evaluate the success of therapy for NPS. Instead, caregiver-rated scores for patients correlated well with NPI scores, and health care professionals in the clinic should preferentially use these.
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