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Background: Behavioral and psychological symptoms of dementia (BPSD) affect 60-90% of patients with Alzheimer's disease (AD). Objective: To determine if environmental therapy is an effective strategy to reduce BPSD, we tested 163 patients with AD with Neuropsychiatric Inventory (NPI) before and after 6 months of an indoor therapeutic garden (TG) or standard environment. Methods: A single-blind randomized controlled trial on AD patients with BPSD. Participants were randomized to an indoor TG (N = 82), or standard environment (control, N = 81) for 6 months. Primary outcome: change in the NPI score from baseline (T0) to end of treatment (T1). Secondary outcomes: change in use of quetiapine, cognition, activities of daily living, salivary cortisol, blood pressure from T0 to T1. Results: NPI score significantly ameliorated (TG versus control: -31.8 points), quetiapine dosage (-150 mg), blood pressure (-2.6 mm Hg), and salivary cortisol (-6.4 to -2.1 Nmol/l) were significantly reduced, the Mini-Mental State Examination significantly improved (1.8 points) in the TG versus control arm at T1 (p < 0.001). No adverse events were reported. Conclusion:The indoor TG seems safe and may reduce BPSD, medication intake, and cortisol levels in AD.

Cognitive and physical activity treatments (CT and PT) are two non-pharmacological approaches frequently used in patients with Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD). The aim of this study was to compare CT and PT in these diseases. Eighty-seven patients were randomly assigned to CT (n=30), PT (n=27) or control group (CTRL; n=30) for 6 months. The global cognitive function was measured by Mini Mental State Examination (MMSE). Specific neuropsychological tests explored attention, memory, executive functions, behavioral disorders. Cardiovascular risk factors (CVD) were collected. All measures were performed before (T0), after treatments (T1), and at three-months follow-up (T2). MMSE did not change from T0 to T1 and T2 in patients assigned to PT and CT, while CTRL patients showed a decline MCI: -11.8%, AD: -16.2%). Between group differences (MCI vs AD) were not found at T1 and T2. Significant worsening was found for CTRL in MCI (T0- T1: P =.039; T0-T2: P <.001) and AD (T0-T1: P <.001; T0-T2: P <.001), and amelioration was found for CT in AD (T0-T2: P <.001). Attention, executive functions and behavioral disorders were unaffected by either PT or CT. Memory was increased in patients with MCI assigned to PT (+6.9%) and CT (+8.5%).. CVD were ameliorated in the PT group. CTRL patients of both groups, revealed significant decline in all functions and no between groups differences were detected. PT appear to ameliorate CVD. Although between groups differences were not found, results suggest a major retention in MCI compared with AD, suggesting that the latter might benefit better of constant rather than periodic treatments. This study confirms the positive effects of CT and PT in mitigating the cognitive decline in MCI and AD patients, and it is the first to demonstrate their similar effectiveness on maintaining cognitive function.

The association of lysosomal dysfunction and neurodegeneration has been documented in several neurodegenerative diseases, including Alzheimer’s Disease (AD). Herein, we investigate the association of lysosomal enzymes with AD at different stages of progression of the disease (mild and severe) or with mild cognitive impairment (MCI). We conducted a screening of two classes of lysosomal enzymes: glycohydrolases (β-Hexosaminidase, β-Galctosidase, β-Galactosylcerebrosidase, β-Glucuronidase) and proteases (Cathepsins S, D, B, L) in peripheral blood samples (blood plasma and PBMCs) from mild AD, severe AD, MCI and healthy control subjects. We confirmed the lysosomal dysfunction in severe AD patients and added new findings enhancing the association of abnormal levels of specific lysosomal enzymes with the mild AD or severe AD, and highlighting the difference of AD from MCI. Herein, we showed for the first time the specific alteration of β-Galctosidase (Gal), β-Galactosylcerebrosidase (GALC) in MCI patients. It is notable that in above peripheral biological samples the lysosomes are more sensitive to AD cellular metabolic alteration when compared to levels of Aβ-peptide or Tau proteins, similar in both AD groups analyzed. Collectively, our findings support the role of lysosomal enzymes as potential peripheral molecules that vary with the progression of AD, and make them useful for monitoring regenerative medicine approaches for AD.

Advanced aging, vascular dysfunction, and nitric oxide (NO) bioavailability are recognized risk factors for Alzheimer's disease (AD). However, the contribution of AD, per se, to this putative pathophysiological mechanism is still unclear. To better answer this point, we quantified cortical perfusion with arterial spin labeling (PVC-CBF), measured ultrasound internal carotid (ICA), and femoral (FA) artery blood flow in a group of patients with similar age (~78 years) but different cognitive impairment (i.e., mild cognitive impairment MCI, mild AD-AD1, moderate AD-AD2, and severe AD-AD3) and compared them to young and healthy old (aged-matched) controls. NO-metabolites and passive leg-movement (PLM) induced hyperemia were used to assess systemic vascular function. Ninety-eight individuals were recruited for this study. PVC-CBF, ICA, and FA blood flow were markedly (range of 9–17%) and significantly (all p < 0.05) reduced across the spectrum from YG to OLD, MCI, AD1, AD2, AD3 subjects. Similarly, plasma level of nitrates and the values of PLM were significantly reduced (range of 8–26%; p < 0.05) among the six groups. Significant correlations were retrieved between plasma nitrates, PLM and PVC-CBF, CA, and FA blood flow. This integrative and comprehensive approach to vascular changes in aging and AD showed progressive changes in NO bioavailability and cortical, extracranial, and peripheral circulation in patients with AD and suggested that they are directly associated with AD and not to aging. Moreover, these results suggest that AD-related impairments of circulation are progressive and not confined to the brain. The link between cardiovascular and the central nervous systems degenerative processes in patients at different severity of AD is likely related to the depletion of NO.