Interactions of comorbid neuropsychiatric subsyndromes with neurodegenerative and cerebrovascular pathologies on cognition.

Comorbid neuropsychiatric symptoms are commonly found in individuals with dementia and is likely influenced by a combination of neurodegenerative and cerebrovascular pathophysiology. We evaluated the associations of a validated composite MRI-based quantitative measure of both neurodegeneration (hippocampus volume and cortical thickness of AD-specific regions) and cerebrovascular disease (CeVD; white matter hyperintensities and infarcts) with neuropsychiatric subsyndromes, and their interactions on cognition in a community-based sample across the disease spectrum (N = 773). Lower composite MRI scores corresponding to greater comorbid neurodegeneration and CeVD burden were associated with hyperactivity (OR = 1.48) and apathy (OR = 1.90) subsyndromes. Lower MRI scores with concomitant hyperactivity was associated with greater cognitive impairment, especially in patients who were at least moderately impaired, while the interaction with apathy was not dependent on disease stage. These MRI scores interaction models resulted in a better fit than models consisting of neurodegeneration or CeVD alone. Integrating multiple biomarkers with specific, disease stage-dependent neuropsychiatric subsyndromes may provide a more holistic risk profile to facilitate the identification of individuals at the highest risk of disease progression.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

Socio-emotional and motor engagement during musical activities in older adults with major neurocognitive impairment.

Although music therapy may engender clinical benefits in patients with neurodegenerative disease, the impacts of social and musical factors of such activities on socio-emotional and motor engagements are poorly understood. To address this issue, non-verbal behaviors of 97 patients with or without major cognitive impairment (CI) were assessed when listening to music or a metronome in front of a musician who was present physically (live) or virtually (video). Socio-emotional engagement was quantified as emotional facial expression production and gaze direction. Motor engagement was quantified as overall body motion and the production of rhythmic movements. In both groups, positive facial expressions were more frequent and rhythmic motor activities lasted longer with music than with a metronome, and during a live performance rather than a video performance. Relative to patients without CI, patients with CI moved less with music, expressed fewer emotions, and spent less time looking at the musician in the video condition and in the metronome condition. The relative reductions in motor and socio-emotional engagements in patients with CI might be markers of disease progression. However, the presence of a live partner induces older adults to engage emotionally and physically in musical activities emphasizing the relevance of using live performance as motivational levers during music therapy.

Therapeutic potential of mangiferin in the treatment of various neuropsychiatric and neurodegenerative disorders.

Xanthones are important chemical class of bioactive products that confers therapeutic benefits. Of several xanthones, mangiferin is known to be distributed widely across several fruits, vegetables and medicinal plants. Mangiferin has been shown to exert neuroprotective effects in both in-vitro and in-vivo models. Mangiferin attenuates cerebral infarction, cerebral edema, lipid peroxidation (MDA), neuronal damage, etc. Mangiferin further potentiate levels of endogenous antioxidants to confer protection against the oxidative stress inside the neurons. Mangiferin is involved in the regulation of various signaling pathways that influences the production and levels of proinflammatory cytokines in brain. Mangiferin cosunteracted the neurotoxic effect of amyloid-beta, MPTP, rotenone, 6-OHDA etc and confer protection to neurons. These evidence suggested that the mangiferin may be a potential therapeutic strategy for the treatment of various neurological disorders. The present review demonstrated the pharmacodynamics-pharmacokinetics of mangiferin and neurotherapeutic potential in several neurological disorders with underlying mechanisms.

Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease.

The objective of this study was to investigate whether juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease (NAFLD), cholestasis, and gut dysbiosis would develop histological and metabolic markers of neurodegeneration in the frontal cortex (FC) and whether supplementing probiotics would influence the response to the diet. Twenty-eight juvenile Iberian pigs were fed for 10 wk either a control (CON) or high-fructose high-fat (HFF) diet with or without a commercial probiotic mixture. Compared with CON, HFF-fed pigs had a decreased number of neurons and an increase in reactive astrocytes in FC tissue. There was also a decrease in one-carbon metabolites choline and betaine and a marked accumulation of bile acids, cholesteryl esters, and polyol pathway intermediates in FC of HFF-fed pigs, which were associated with markers of neurodegeneration and accentuated with the severity of NAFLD. Betaine depletion in FC tissue was negatively correlated with choline-derived phospholipids in colon content, whereas primary conjugated bile acids in FC were associated with cholestasis. Plasma kynurenine-to-tryptophan quotient, as a marker of indoleamine 2,3-dioxygenase activity, and intestinal dysbiosis were also correlated with neuronal loss and astrogliosis. Recognition memory test and FC levels of amyloid-ß and phosphorylated Tau did not differ between diets, whereas probiotics increased amyloid-ß and memory loss in HFF-fed pigs. In conclusion, our results show evidence of neurodegeneration in FC of juvenile Iberian pigs and establish a novel pediatric model to investigate the role of gut-liver-brain axis in diet-induced NAFLD.

"Slowed Down but Not Stopped": A Spiritual Life Review Intervention in Patients with Neurodegenerative Disease.

Spiritual health is important in managing and coping with chronic and debilitating illnesses, such as neurodegenerative diseases. However, few spiritual interventions have addressed this population. This article quantitatively and qualitatively evaluates outcomes of a spiritual life review in neurodegenerative diseases patients. The majority of participants improved or maintained quality of life and spiritual/emotional well-being following the intervention. Spiritual life review may be an important intervention in the comprehensive care of patients with neurodegenerative diseases.

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.

Age-related defects in short-term plasticity are reversed by acetyl-L-carnitine at the mouse calyx of Held.

Hearing acuity and sound localization are affected by aging and may contribute to cognitive dementias. Although loss of sensorineural conduction is well documented to occur with age, little is known regarding short-term synaptic plasticity in central auditory nuclei. Age-related changes in synaptic transmission properties were evaluated at the mouse calyx of Held, a sign-inverting relay synapse in the circuit for sound localization, in juvenile adults (1 month old) and late middle-aged (18-21 months old) mice. Synaptic timing and short-term plasticity were severely disrupted in older mice. Surprisingly, acetyl-l-carnitine (ALCAR), an anti-inflammatory agent that facilitates mitochondrial function, fully reversed synaptic transmission delays and defects in short-term plasticity in aged mice to reflect transmission similar to that seen in juvenile adults. These findings support ALCAR supplementation as an adjuvant to improve short-term plasticity and potentially central nervous system performance in animals compromised by age and/or neurodegenerative disease.

Tangeretin inhibits neurodegeneration and attenuates inflammatory responses and behavioural deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease dementia in rats.

Our aim was to investigate whether tangeretin, a citrus flavonoid, was able to prevent neuroinflammation and improve dementia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rodent model of Parkinson's disease (PD). MPTP-HCl was infused into the substantia nigra pars compacta of male Sprague-Dawley rats. Tangeretin (50, 100 or 200 mg/kg body weight) was administered orally starting 3 days prior to MPTP injection and was continued for 20 days following injection. MPTP-lesioned rats revealed motor dysfunction in bar test and rota rod tests. Deficits in working memory and object recognition function were also observed following MPTP induction. Tangeretin treatment significantly attenuated the memory deficits and improved motor functions and cognition. Immunohistochemical analysis reveals the protective effects of tangeretin against MPTP lesion-induced dopaminergic degeneration and hippocampal neuronal loss. Tangeretin reduced expression of inflammatory mediators-COX-2, iNOS-as well reduced the levels of cytokines-interleukins (IL)-IL-1ß, IL-6 and IL-2. The experimental data suggest tangeretin as an effective candidate drug with potential for prevention and treatment of neuroinflammation and dementia associated with PD.

Postischemic fish oil treatment confers task-dependent memory recovery.

A series of our previous studies demonstrated that fish oil (FO), equivalent to 300mg/kg docosahexahenoic acid (DHA), facilitates memory recovery after transient, global cerebral ischemia (TGCI) in the aversive radial maze (AvRM). The present study sought to address two main issues: (i) whether the memory-protective effect of FO that has been observed in the AvRM can be replicated in the passive avoidance test (PAT) and object location test (OLT) and (ii) whether FO at doses that are lower than those used previously can also prevent TGCI-induced memory loss. In Experiment 1, naive rats were trained in the PAT, subjected to TGCI (4-vessel occlusion model), and tested for retrograde memory performance 8 and 15days after ischemia. Fish oil (300mg/kg/day DHA) was given orally for 8days. The first dose was delivered 4h postischemia. In Experiment 2, the rats were subjected to TGCI, treated with the same FO regimen, and then trained and tested in the OLT. In Experiment 3, the rats were trained in the AvRM, subjected to TGCI, administered FO (100, 200, and 300mg/kg DHA), and tested for memory performance up to 3weeks after TGCI. At the end of the behavioral tests, the brains were examined for neurodegeneration and neuroblast proliferation. All of the behavioral tests (PAT, OLT, and AvRM) were sensitive to ischemia, but only the AvRM was able to detect the memory-protective effect of FO. Ischemia-induced neurodegeneration and neuroblast proliferation were unaffected by FO treatment. These results suggest that (i) the beneficial effect of FO on memory recovery after TGCI is task-dependent, (ii) doses of FO<300mg/kg DHA can protect memory function in the radial maze, and (iii) cognitive recovery occurs in the absence of neuronal rescue and/or hippocampal neurogenesis.

Exposure to short photoperiod regime reduces ventral subicular lesion-induced anxiety-like behavior in Wistar rats.

Neurodegeneration of hippocampal structures is implicated in Alzheimer's disease (AD). Patients with AD exhibit 'sundown syndrome' featuring mood swings and anxiety. Although there are studies demonstrating circadian rhythm disruption associated with sundown phenomenon, the mechanisms underlying the emotional disturbances remain elusive. In the present study, we examined the relationship between subiculum (a key hippocampal output structure) and anxiety. Our study demonstrates that bilateral ventral subicular lesion (VSL) leads to anxiogenic behavior. In the elevated plus maze test, VSL rats made less number of entries into the open arms and spent significantly more time in the closed arms. Similarly, in the light-dark exploration test, VSL rats spent significantly more time in the dark chamber and made fewer entries into the light chamber. VSL also produced significant neurodegeneration in the paraventricular, suprachiasmatic and dorsomedial nuclei of the hypothalamus. Exposing VSL rats to a short photoperiod regime (SPR; 06/18h light-dark cycle) for 21days ameliorated the anxiety-like behavior. VSL rats on SPR also exhibited increased food consumption and higher core body temperature. Our study supports the hypothesis that the ventral subiculum regulates anxiety-like behavior and that SPR helps in the alleviation of such behavior. Even though the mechanisms underlying anxiolytic effects of light-dark cycle manipulation are yet to be elucidated, such non-pharmacological strategies can help to mitigate anxiety-like behavior. A proper understanding of the effectiveness of photoperiod manipulation will help in developing strategies in the management of emotional disturbances associated with affective and neurodegenerative disorders including AD.

Postischemic fish oil treatment restores long-term retrograde memory and dendritic density: An analysis of the time window of efficacy.

We reported that fish oil (FO) prevented the loss of spatial memory caused by transient, global cerebral ischemia (TGCI), provided the treatment covered the first days prior to and after ischemia. Continuing these studies, trained rats were subjected to TGCI, and FO was administered for 10days, with a time window of efficacy (TWE) of 4, 8 or 12h post-ischemia. Retrograde memory was assessed up to 43days after TGCI. In another experiment, ischemic rats received FO with a 4- or 12-h TWE, and dendritic density was assessed in the hippocampus and cerebral cortex. The brain lipid profile was evaluated in sham-operated and ischemic rats that were treated with FO or vehicle with a 4-h TWE. Ischemia-induced retrograde amnesia was prevented by FO administration that was initiated with either a 4- or 8-h TWE. Fish oil was ineffective after a 12-h TWE. Independent of the TWE, FO did not prevent ischemic neuronal death. In the hippocampus, but not cerebral cortex, TGCI-induced dendritic loss was prevented by FO with a 4-h TWE but not 12-h TWE. The level of docosahexaenoic acid almost doubled in the hippocampus in ischemic, FO-treated rats (4-h TWE). The data indicate that (i) the anti-amnesic effect of FO can be observed with a TWE of up to 8h, (ii) the stimulation of dendritic neuroplasticity may have contributed to this effect, and (iii) DHA in FO may be the main active constituent in FO that mediates the cognitive and neuroplasticity effects on TGCI.

[Dignity and Ethics of Care in the Neurodegenerative Diseases]. / Dignidad y Ética del Cuidar en las Enfermedades Neurodegenerativas.

In the context of neurodegenerative diseases the doctor is called more than in other areas to respond not only to the simple question of health, but also to the need of assistance, which implicates the necessity of relationship, too. The scheme of symptom diagnosis treatment healing is to be replaced in these cases with a treatment based on an open system of uncertain length and results. It is a model called ″medicine of incurable″, which aims to combat the discomfort of the disease rather than the fight against the disease. In this perspective, the commitment to ensure a quality of life to the sick in itself means attention to his dignity, which is expressed in acting towards him treating him always as a person, that is protagonist of his life, and then to recognize his right to be assisted in physical, psychological and spiritual dimensions. In this model it becomes particularly important to converse with the patient, even if affected by cognitive pathologies, as well as to stimulate hope, with the belief that human being, if properly supported, is still able, even in extremely critical situations, to make out of his personal experience a chance to grow, thanks to the construction of new balances, however weak they may be.

Striatal contributions to sensory timing: Voxel-based lesion mapping of electrophysiological markers.

To achieve precise timing, the brain needs to establish a representation of the temporal structure of sensory input and use this information to generate timely responses. These operations engage the basal ganglia. Current research in this direction is limited by reliance on animal models, motor and/or offline tasks, small sample sizes, the low temporal resolution of functional magnetic resonance imaging, and the study of progressive neurodegeneration. Here, we combine the excellent temporal resolution of electrophysiological potentials with the high spatial resolution of structural neuroimaging to investigate basal ganglia contributions to sensory timing. Chronic-stage lesion patients and healthy controls listened to pure-tone sequences differing exclusively in temporal regularity. Event-related potentials (ERPs) indicate a selective indifference against this manipulation in patients, attributable to the striatal part of the basal ganglia on the basis of a lesion-mapping approach. These findings provide evidence for a crucial contribution of the basal ganglia to basic sensory functioning.

[Psychotic disorder induced by Fahr's syndrome: a case report]. / Trouble psychotique secondaire à un syndrome de Fahr: à propos d'une observation.

UNLABELLED: Fahr's syndrome is a rare disorder characterized by abnormal deposits of calcium in areas of the brain that control movement, including the basal ganglia and the cerebral cortex associated with many neurological and psychiatric abnormalities such as a rigid hypokinetic syndrome, mood disorders and cognitive impairment. Fahr's syndrome is secondary to some disorders, such as hypoparathyroidism. CASE REPORT: We report the case of a 56 year-old man, with a history of cataract, who was admitted to our psychiatric hospital for the first time in his life because of psychotic symptoms associated with irritability and aggressiveness. Since the age of 38 the patient had become nervous, 10 years later he developed tonic-clonic seizures. Two months ago, he began expressing delusions of persecution against his wife and sons and making fugues. According to his family during this period, he was agitated, aggressive, and suffered from insomnia and anorexia. The general and psychiatric examination showed an upright and bronzed patient with neglected hygiene. He was indifferent to his environment and expressed poor mimics and gestures. He was anxious, suspicious and not very talkative. He was conscious but his attention was slightly decreased. Moreover, he was not aware of his problems. The neurological examination showed extrapyramidal syndrome with postural tremor and cerebellar ataxia. A cranial computed tomography brain scan found bilateral, symmetric basal ganglia calcifications, in favour of Fahr's syndrome. Phosphocalcic investigations revealed low concentration of serum calcium at 1.01mmol/L (normal 2.15 to 2.57mmol/L) and hyperphosphoremia at 2.69mmol/L (normal 0.81 to 1.55mmol/L). He also had low concentrations of 25-OH vitamin as well as decreased urinary levels of phosphate and calcium. The blood level of parathyroid hormone was 0ng/L. The diagnosis of Fahr's syndrome, revealing a hypoparathyroidism was posed. He was supplemented with calcium and alpha cholecalciferol and treated with clozapine (100mg per day). After four weeks, psychotic symptoms responded well to this treatment without expressing any side effects, notably seizures. DISCUSSION: Psychotic symptoms seen in Fahr's disease include auditory and visual hallucinations, complex perceptual distortions, delusions, and fugue state. Some of them were manifest in this patient. It is likely that the psychosis in both Fahr's disease and schizophrenia share a similar pathology. Positive psychotic symptoms, hallucinations, and paranoia are not necessarily generated by the classical hypothesis of dopamine-mediated attachment of salience to internally generated stimuli. Still, there is some evidence that disruption of the cortex involved in the pathophysiology of schizophrenia is also seen in Fahr's disease, particularly in areas of the limbic system. CONCLUSION: Psychiatrists should consider Fahr's syndrome as a differential diagnosis in the evaluation of psychosis associated with seizures. This case, along with others in the literature, further emphasizes the importance of the role of neuro-imaging and the search for disrupted phosphocalcic metabolism in patients with atypical psychotic symptoms. Moreover, further research should focus on pharmacologic interventions. The efficacy and risks of neuropharmacologic and psychopharmacologic interventions in Fahr's syndrome, and correlates of good and poor outcome with these interventions remain to be defined.

Caffeoylquinic acid-rich purple sweet potato extract, with or without anthocyanin, imparts neuroprotection and contributes to the improvement of spatial learning and memory of SAMP8 mouse.

The effects of caffeoylquinic acid (CQA)-rich purple sweet potato (PSP) extract, with (PSPEa) or without (PSPEb) anthocyanin, on the improvement of spatial learning and memory of senescence-accelerated prone mouse strain (SAMP) 8 was determined. SAMP8 was treated with 20 mg/kg/day of PSPEa or PSPEb for 30 days. The effect on spatial learning and memory and the molecular mechanism of this effect were determined in vivo (SAMP8) and in vitro (SH-SY5Y cells). PSPEa or PSPEb reduced the escape latency time of SAMP8 by 17.0 ± 8.0 and 14.2 ± 5.8 s (P < 0.01), respectively. PSPEa administration induced an overexpression of antioxidant-, energy metabolism-, and neuronal plasticity-related proteins in the brain of SAMP8. Additionally, PSPEa and PSPEb increased the cell viability by 141.6 and 133% as compared to Aß1-42-treated cells. These findings suggest that PSP rich in CQA derivatives with or without anthocyanidine had a neuroprotective effect on mouse brain and can improve the spatial learning and memory of SAMP8.

Prevention of age-associated neurodegeneration and promotion of healthy brain ageing in female Wistar rats by long term use of bacosides.

Bacopa monnieri (L.), popularly known as Brahmi, is a revered Ayurvedic medicinal plant used as nerve tonic since time immemorial. The present study aims to investigate the neuroprotective effect of bacosides, the active saponins of Bacopa monnieri (L.) against age associated neurodegeneration and its impact over the prevention of Senile Dementia of Alzheimer's Type (SDAT). The optimum dose of bacosides with no adverse effect was selected by screening its dose dependant activity on ageing biomarker lipofuscin and SDAT biomarker neurotransmitter acetylcholine in the aged female Wistar rat brain. The selected therapeutic dose of bacosides (200 mg/kg) was orally administered for 3 months in middle aged and aged rats and further investigated for its protective action against age associated alterations in neurotransmission system, behavioral paradigms, hippocampal neuronal loss and oxidative stress markers. The results of the present study suggest that bacosides may act as a potential therapeutic intervention in forestalling the deleterious effects of ageing and preventing the age associated pathologies like SDAT.

Visuo-spatial imagery impairment in posterior cortical atrophy: a cognitive and SPECT study.

This study investigated the cognitive profile and the cerebral perfusion pattern in a highly educated 70 year old gentleman with posterior cortical atrophy (PCA). Visuo-perceptual abilities, spatial memory, spatial representation and navigation, visuo-spatial mental imagery, semantic and episodic-autobiographical memory were assessed. Regional cerebral blood flow (rCBF) was imaged with SPECT. Cognitive testing showed visual-perceptual impairment, apperceptive visual and landmark agnosia, topographical disorientation with way-finding deficits, impaired map learning and poor mental image generation. Semantic memory was normal, while episodic-autobiographical memory was impaired. Reduced rCBF was found mainly in the right hemisphere, in the precentral gyrus, posterior cingulate and middle temporal gyri, cuneus and precuneus, in the left superior temporal and lingual gyri and in the parahippocampus bilaterally. Hypoperfusion in occipito-parietal regions was associated with visuo-spatial deficits, whereas deficits in visuo-spatial mental imagery might reflect dysfunction related to hypoperfusion in the parahippocampus and precuneus, structures which are responsible for spatial and imagery processing. Dissociating performance between preserved semantic memory and poor episodic-autobiographical recall is consistent with a pattern of normal perfusion in frontal and anterior temporal regions but abnormal rCBF in the parahippocampi. The present findings indicate that PCA involves visuo-spatial imagery deficits and provide further validation to current neuro-cognitive models of spatial representation and topographical disorientation.

Nonpharmacological therapies in Alzheimer's disease: a systematic review of efficacy.

INTRODUCTION: Nonpharmacological therapies (NPTs) can improve the quality of life (QoL) of people with Alzheimer's disease (AD) and their carers. The objective of this study was to evaluate the best evidence on the effects of NPTs in AD and related disorders (ADRD) by performing a systematic review and meta-analysis of the entire field. METHODS: Existing reviews and major electronic databases were searched for randomized controlled trials (RCTs). The deadline for study inclusion was September 15, 2008. Intervention categories and outcome domains were predefined by consensus. Two researchers working together detected 1,313 candidate studies of which 179 RCTs belonging to 26 intervention categories were selected. Cognitive deterioration had to be documented in all participants, and degenerative etiology (indicating dementia) had to be present or presumed in at least 80% of the subjects. Evidence tables, meta-analysis and summaries of results were elaborated by the first author and reviewed by author subgroups. Methods for rating level of evidence and grading practice recommendations were adapted from the Oxford Center for Evidence-Based Medicine. RESULTS: Grade A treatment recommendation was achieved for institutionalization delay (multicomponent interventions for the caregiver, CG). Grade B recommendation was reached for the person with dementia (PWD) for: improvement in cognition (cognitive training, cognitive stimulation, multicomponent interventions for the PWD); activities of daily living (ADL) (ADL training, multicomponent interventions for the PWD); behavior (cognitive stimulation, multicomponent interventions for the PWD, behavioral interventions, professional CG training); mood (multicomponent interventions for the PWD); QoL (multicomponent interventions for PWD and CG) and restraint prevention (professional CG training); for the CG, grade B was also reached for: CG mood (CG education, CG support, multicomponent interventions for the CG); CG psychological well-being (cognitive stimulation, multicomponent interventions for the CG); CG QoL (multicomponent interventions for PWD and CG). CONCLUSION: NPTs emerge as a useful, versatile and potentially cost-effective approach to improve outcomes and QoL in ADRD for both the PWD and CG.