biomarkers and the neuropsychology of the ageing-brain cognitive diseases

1
outpatient clinics that provide a full range of services going from the initial evaluation and diagnostic visits, to subsequent counseling and referral to community services, educational, and caregiverssupport services. The more complex, usually older, patients who suffer from multiple comorbidity and geriatric syndromes can also benet from case management by interdisci- plinary teams that combine the expertise of professionals from the medical (neurology, geriatrics, and old age psychiatry), nursing, physical and occu- pational therapy, as well as social work elds. Keywords. Collaborative care; Case management; Dementia care OLEUROPEIN AGLYCON COUNTERACTS AD-LIKE PATHOLOGY AND COGNITIVE IMPAIRMENTS: AN IN VIVO PRECLINICAL STUDY Fiorella Casamenti. University of Florence, Florence, Italy. E-mail: orella.casamenti@uni.it Alzheimers disease (AD) is the most common form of dementia, patholog- ically characterized by intracellular accumulation of neurobrillary tangles and by extracellular plaques of amyloid-b (Ab). In the amyloid hypothesis, Ab deposits initiate a cascade of events of progressive neurodegeneration. Despite the importance of plaques to AD, oligomers are considered to be the principal toxic forms of Ab and pyroglutamate (pE)-modied Ab peptides at amino acid position 3 (Ab 3pE-42 ), generated by the enzyme glutaminyl cyclase (QC), were identied as a highly toxic Ab species and have been proposed as initiators of AD pathogenesis. Among lifestyle factors, mounting evidence supports that greater adherence to the Mediterranean diet is associated with a reduced risk of AD. Here, we report that 8 weeks dietary supplementation of oleuropein aglycone (OLE) (50 mg/kg of diet, 10 g/day per mouse), the major phenol present in the extra virgin olive oil, signi- cantly reduces de novo Ab deposition and favors preformed plaque disassembly, which appeared reduced in size and compactness displaying ribbon-like and uffymorphologies, in the TgCRND8 mouse model of Ab deposition, at the early, intermediate and late stages of Ab deposits. The treatment fully counteracts the transgene-induced behavioural impair- ments in the young/middle-aged transgenic animals and results in an astonishingly strong autophagic reaction in the cortex, as shown by an intense bright and punctate autophagic marker immunoreactivities and of lysosomal activity. Interestingly OLE-fed TgCRND8 mice show a signicant reduction of Ab3pE-42 load, both as total plaque area and plaque number, in somatosensory/parietal and piriform/entorhinal cortices and hippocampus, as compared to untreated age-matched transgenic mice. These studies suggest that dietary supplementation with OLE, both as a nutraceutical or as a food integrator, may prevent/delay the occurrence of AD and reduce the severity of its symptoms. Keywords. AD-like pathology, Ab toxicity, Oleuropein aglycone polyphenol EARLY AND LATE INFLAMMATION IN ALZHEIMERS PATHOLOGY A. Claudio Cuello. McGill University, Montreal, QC, Canada. E-mail: [email protected] Sparked by observations of reduced prevalence of Alzheimers disease (AD) in patients with rheumatoid arthritis, numerous studies would indicate that anti-inammatory treatments might delay or prevent symptom onset. These ndings, along with recognition that inammation is an important compo- nent of the AD neuropathology, have provoked several randomized trials using NSAIDs and other anti-inammatory treatments. But the results have been disappointing. These seemingly contradictory ndings raise funda- mental questions about the role(s) of inammation and effects of anti-in- ammatory treatments, at different stages of AD pathogenesis. We will discuss the proposition that inammatory processes may have very different roles in the evolution of the AD pathology. Hence, suppression of these in- ammatory processes at different stages of the disease might have drastically different consequences. We will summarize relevant studies supporting this idea and will present recent demonstrations of important roles of inam- matory process early in the development of AD-like pathology as revealed in rat and mouse transgenic models. Such transgenic models suggest important inammatory changes well before the appearance of amyloid plaques. These processes appear to be characterized by intermediateactivation of microglia and their recruitment towards Ab-burdened neurons in the hippocampus and cortex. The McGill-R-Thy1-APP rat transgenic model also shows early activation of both, astrocytes and microglia The McGill rat transgenic model in addition, display a marked up-regulation of Il-1b, COX2, TNF-a and fractalkine (CX3CL1) well before the formation of extracellular amyloid plaques. These early inammatory events may well represent dis- ease-aggravating processes, so that anti-inammatory processes at this juncture might attenuate or delay pathogenesis. By contrast, the later occurrence of inammation with fully activated microglia and monocyte inltration might have a signicant role in removal of toxic amyloid material. Suppression of inammation at these later stages could therefore bring limited benet, or even harm. Keywords. Alzheimers Disease, Early pathology and Inammation BIOMARKERS AND THE NEUROPSYCHOLOGY OF THE AGEING- BRAIN COGNITIVE DISEASES Jean-François Démonet. Leenaards Memory Centre, CHUV, Lausanne, Switzerland. E-mail: [email protected] The traditional clinical concept of dementiashas evolved to the current conceptualization of age-related, chronic brain diseases with a long lasting, clinically silent stage followed by a prodromal stage involving initially subtle cognitive and behavioural disorders. Formerly named dementias,these diseases are here referred to as ageing-brain cognitive diseases (ABCDs). The increasing inuence of biomarkers in this eld challenges neuropsychology which used to be the only diagnosis method available aside from clinical assessment. One may wonder about the input of cognitive assessment to diagnosis and follow up of patients who will progressively benet from the discovery of a variety of imaging and biological markers to more and di- agnose and appraise the severity of these brain diseases. Perspectives will be proposed for a renewed neuropsychological approach to ABCDs, an approach whose methodology depends on the specic aims of researchers and prac- titioners, e.g. screening of potentially at-risk subjects, the specic diagnosis of a given disease or follow up of a new treatment. Keywords. Neuropsychology, Dementia, Biomarkers D2 AGONIST ADMINISTRATION RESTORES ALTERED CORTICAL PLASTICITY IN ALZHEIMERS DISEASE PATIENTS Francesco Di Lorenzo 1 , A. Martorana 2 , V. Giacobbe 1 , S. Bonnì 1 , G. Koch 1 . 1 Fondazione Santa Lucia, Rome, Italy; 2 DIpartimento di Neuroscienze, Università di Tor Vergata, Rome, Italy. E-mail: [email protected] In animal models of AD, amyloid-beta fragments interfere with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). Accordingly, recent evidence showed that in AD patients LTP-like cortical plasticity is impaired, while LTD seems to be preserved. Despite its major role in synaptic plasticity mechanisms, the involvement of dopamine in controlling cortical plasticity mechanisms in AD is still debated. A crucial role for dopaminergic networks in cognitive and motor processes has been well established but largely unexplored in AD. Here we aimed at investigating whether administration of a D2 agonist could modulate cortical plasticity in AD patients, as measured by standard theta burst stimulation (TBS) protocols applied over the primary motor cortex. Three groups of mild AD patients were tested before and after four weeks of treatment with rotigotine, rivastigmine or placebo. Each patient was evaluated for plasticity induction of LTP/LTD-like effects using respectively intermittent TBS (iTBS) or continuous TBS (cTBS). Central cholinergic activity was also evaluated by means of the short latency afferent inhibition (SLAI) protocol. Neuropsy- chological evaluations were performed to assess memory, executive func- tions and visuo-spatial abilities. At baseline AD patients showed the previously described pattern of impaired LTP-like cortical plasticity as assessed by iTBS. After four weeks of D2 agonist administration we observed a remarkable change in the iTBS protocol effects, revealing that LTP-like plasticity was strikingly enhanced. No effects were seen in rivastigmine and in placebo group. LTD-like cortical plasticity wasnt modulated in any con- dition. Cholinergic activity was slightly increased by both rotigotine and rivastigmine groups. Neuropsychological testing showed improvement in Abstracts / Neurobiology of Aging 35 (2014) S1eS27 S5

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Page 1: Biomarkers and the neuropsychology of the ageing-brain cognitive diseases

Abstracts / Neurobiology of Aging 35 (2014) S1eS27 S5

outpatient clinics that provide a full range of services going from the initialevaluation and diagnostic visits, to subsequent counseling and referral tocommunity services, educational, and caregivers’ support services. The morecomplex, usually older, patients who suffer from multiple comorbidity andgeriatric syndromes can also benefit from case management by interdisci-plinary teams that combine the expertise of professionals from the medical(neurology, geriatrics, and old age psychiatry), nursing, physical and occu-pational therapy, as well as social work fields.

Keywords. Collaborative care; Case management; Dementia care

OLEUROPEIN AGLYCON COUNTERACTS AD-LIKE PATHOLOGYAND COGNITIVE IMPAIRMENTS: AN IN VIVO PRECLINICAL STUDY

Fiorella Casamenti. University of Florence, Florence, Italy.E-mail: [email protected]

Alzheimer’s disease (AD) is the most common form of dementia, patholog-ically characterized by intracellular accumulation of neurofibrillary tanglesand byextracellular plaques of amyloid-b (Ab). In the amyloid hypothesis, Abdeposits initiate a cascade of events of progressive neurodegeneration.Despite the importance of plaques to AD, oligomers are considered to be theprincipal toxic forms of Ab and pyroglutamate (pE)-modified Ab peptides atamino acid position 3 (Ab3pE-42), generated by the enzyme glutaminylcyclase (QC), were identified as a highly toxic Ab species and have beenproposed as initiators of AD pathogenesis. Among lifestyle factors,mountingevidence supports that greater adherence to the Mediterranean diet isassociated with a reduced risk of AD. Here, we report that 8 weeks dietarysupplementation of oleuropein aglycone (OLE) (50 mg/kg of diet, 10 g/dayper mouse), the major phenol present in the extra virgin olive oil, signifi-cantly reduces de novo Ab deposition and favors preformed plaquedisassembly, which appeared reduced in size and compactness displayingribbon-like and “fluffy” morphologies, in the TgCRND8 mouse model of Abdeposition, at the early, intermediate and late stages of Ab deposits. Thetreatment fully counteracts the transgene-induced behavioural impair-ments in the young/middle-aged transgenic animals and results in anastonishingly strong autophagic reaction in the cortex, as shown by anintense bright and punctate autophagic marker immunoreactivities and oflysosomal activity. Interestingly OLE-fed TgCRND8 mice show a significantreduction of Ab3pE-42 load, both as total plaque area and plaque number, insomatosensory/parietal and piriform/entorhinal cortices and hippocampus,as compared to untreated age-matched transgenic mice. These studiessuggest that dietary supplementationwith OLE, both as a nutraceutical or asa food integrator, may prevent/delay the occurrence of AD and reduce theseverity of its symptoms.

Keywords. AD-like pathology, Ab toxicity, Oleuropein aglycone polyphenol

EARLY AND LATE INFLAMMATION IN ALZHEIMER’S PATHOLOGY

A. Claudio Cuello. McGill University, Montreal, QC, Canada.E-mail: [email protected]

Sparked by observations of reduced prevalence of Alzheimer’s disease (AD)in patients with rheumatoid arthritis, numerous studies would indicate thatanti-inflammatory treatments might delay or prevent symptom onset. Thesefindings, along with recognition that inflammation is an important compo-nent of the AD neuropathology, have provoked several randomized trialsusing NSAIDs and other anti-inflammatory treatments. But the results havebeen disappointing. These seemingly contradictory findings raise funda-mental questions about the role(s) of inflammation and effects of anti-in-flammatory treatments, at different stages of AD pathogenesis. We willdiscuss the proposition that inflammatory processes may have very differentroles in the evolution of the AD pathology. Hence, suppression of these in-flammatory processes at different stages of the diseasemight have drasticallydifferent consequences. We will summarize relevant studies supporting thisidea and will present recent demonstrations of important roles of inflam-matory process early in the development of AD-like pathology as revealed inrat and mouse transgenic models. Such transgenic models suggest importantinflammatory changes well before the appearance of amyloid plaques.These processes appear to be characterized by “intermediate” activation ofmicroglia and their recruitment towards Ab-burdened neurons in the

hippocampus and cortex. The McGill-R-Thy1-APP rat transgenic model alsoshows early activation of both, astrocytes and microglia The McGill rattransgenic model in addition, display a marked up-regulation of Il-1b, COX2,TNF-a and fractalkine (CX3CL1) well before the formation of extracellularamyloid plaques. These early inflammatory events may well represent dis-ease-aggravating processes, so that anti-inflammatory processes at thisjuncture might attenuate or delay pathogenesis. By contrast, the lateroccurrence of inflammation with fully activated microglia and monocyteinfiltration might have a significant role in removal of toxic amyloid material.Suppression of inflammation at these later stages could therefore bringlimited benefit, or even harm.

Keywords. Alzheimer’s Disease, Early pathology and Inflammation

BIOMARKERS AND THE NEUROPSYCHOLOGY OF THE AGEING-BRAIN COGNITIVE DISEASES

Jean-François Démonet. Leenaards Memory Centre, CHUV, Lausanne,Switzerland.E-mail: [email protected]

The traditional clinical concept of “dementias” has evolved to the currentconceptualization of age-related, chronic brain diseases with a long lasting,clinically silent stage followed by a prodromal stage involving initially subtlecognitive and behavioural disorders. Formerly named “dementias,” thesediseases are here referred to as ageing-brain cognitive diseases (ABCDs). Theincreasing influence of biomarkers in this field challenges neuropsychologywhich used to be the only diagnosis method available aside from clinicalassessment. One may wonder about the input of cognitive assessment todiagnosis and follow up of patients who will progressively benefit from thediscovery of a variety of imaging and biological markers to more and di-agnose and appraise the severity of these brain diseases. Perspectives will beproposed for a renewed neuropsychological approach to ABCDs, an approachwhose methodology depends on the specific aims of researchers and prac-titioners, e.g. screening of potentially at-risk subjects, the specific diagnosisof a given disease or follow up of a new treatment.

Keywords. Neuropsychology, Dementia, Biomarkers

D2 AGONIST ADMINISTRATION RESTORES ALTERED CORTICALPLASTICITY IN ALZHEIMER’S DISEASE PATIENTS

Francesco Di Lorenzo1, A. Martorana2, V. Giacobbe1, S. Bonnì1, G. Koch1.1 Fondazione Santa Lucia, Rome, Italy; 2DIpartimento di Neuroscienze,Università di Tor Vergata, Rome, Italy.E-mail: [email protected]

In animal models of AD, amyloid-beta fragments interfere with mechanismsof cortical plasticity such as long-term potentiation (LTP) and long-termdepression (LTD). Accordingly, recent evidence showed that in AD patientsLTP-like cortical plasticity is impaired, while LTD seems to be preserved.Despite its major role in synaptic plasticity mechanisms, the involvement ofdopamine in controlling cortical plasticity mechanisms in AD is still debated.A crucial role for dopaminergic networks in cognitive and motor processeshas been well established but largely unexplored in AD. Here we aimed atinvestigating whether administration of a D2 agonist couldmodulate corticalplasticity in AD patients, as measured by standard theta burst stimulation(TBS) protocols applied over the primary motor cortex. Three groups of mildAD patients were tested before and after four weeks of treatment withrotigotine, rivastigmine or placebo. Each patient was evaluated for plasticityinduction of LTP/LTD-like effects using respectively intermittent TBS (iTBS) orcontinuous TBS (cTBS). Central cholinergic activity was also evaluated bymeans of the short latency afferent inhibition (SLAI) protocol. Neuropsy-chological evaluations were performed to assess memory, executive func-tions and visuo-spatial abilities. At baseline AD patients showed thepreviously described pattern of impaired LTP-like cortical plasticity asassessed by iTBS. After four weeks of D2 agonist administrationwe observeda remarkable change in the iTBS protocol effects, revealing that LTP-likeplasticity was strikingly enhanced. No effects were seen in rivastigmine andin placebo group. LTD-like cortical plasticity wasn’t modulated in any con-dition. Cholinergic activity was slightly increased by both rotigotine andrivastigmine groups. Neuropsychological testing showed improvement in