diabete e demenze - grg · diabete e demenze davide lauro [email protected] . the...
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The pathophysiology of Type 2 Diabetes
Metabolic activity
Glucose Regulation
Years from Type 2 Diabetes diagnosis –10 –5 0 5 10 15 20 25 30
–10 –5 0 5 10 15 20 25 30
Modified from Ferrannini E. Presentazione al 65° ADA meeting Washington, DC, 2006.
NGT → Insulin Resistance → IGT/ IFG → Type 2 Diabetes
Post prandial glycaemia
Fasting glycaemia
Insulin Resistance
Pancreatic beta cell function
Insulin concentration
Timing of beta cells destruction
Alzheimer’s & Dementia 9 (2013) 63–7510
Murray CJL et al. NEJM 2013: 369:5; 448-457
Murray CJL et al. NEJM 2013: 369:5; 448-457
Anders A. F. Sima, Acta Diabetol, 2010
Projected increases in the prevalence of diabetes (a) and dementia (b) the next 30 years
Demenza: compromissione
intellettiva acquisita e persistente
con alterazione di molteplici
funzioni cognitive (memoria,
linguaggio, capacità visuo-
spaziali)
Taken from: Reijmer et al, Diabetes/Metab Res Rev. 26:507-519, 2010
Decrements Are More Predominant in Older Adults with T2DM
Miles WR, Root HF, Arch Intern Med , 30:767–777, 1922
PRIMARIE (Neurodegenerative ) senza segni motori prevalenti - Malattia di Alzheimer -Demenze Fr.Temp. con segni motori prevalenti Malattia di Parkinson Mal. a corpi di Lewy diffusi Malattia di Huntington
SECONDARIE (Non Neurodegenerative) • VASCOLARI (multinfartuale, Malattia di Binswanger) • DEMIELINIZZANTI • TRAUMATICHE (Ematoma subdurale, Demenza del pugile) • NEOPLASTICHE (Meningioma) • IDROCEFALO • METABOLICHE (Encefalopatia uremica, epatica, disendocrinopatie, deficit di vit. B12 e folati) • TOSSICHE (Alcool, abuso di droghe, farmaci, metalli) • INFETTIVE (Neurolue, AIDS, malattia da prioni) • PSICHIATRICHE: DEPRESSIONE (Pseudodemenza)
CLASSIFICAZIONE EZIOLOGICA
Demenza Vascolare (VaD): secondaria a danno vascolare cerebrale ischemico e/o emorragica e/o ipossico
• Demenza da patologia dei grandi vasi: Demenza multinfartuale (da infarti estesi, >> corticali; possono coesistere ischemie sottocorticali, stati lacunari, alt. sost bianca sottocorticale) Demenza da infarti strategici (il danno ischemico interessa specifiche aree critiche: giro angolare, ippocampo, talamo, ecc) • Demenza da patologia dei piccoli vasi: Demenza vascolare ischemica sottocorticale ( >> la sost.bianca sottocorticale, n. della base, tronco encefalo; con infarti completi, lacunari o microinfarti >> vasi del microcircolo cerebrale con deg.Ialina da ipoperfusione cronica – con Infarti incompleti: lesioni della sostanza bianca identificati come “malattia di Binswanger” • Demenza da ipoperfusione, emorragica, vascolare ereditaria, mista(AD + VaD)
Lancet Neurology, 2002
Risk of dementia in Type 2 Diabetes: the Rotterdam Study, 1999
Age & sex
adjusted
RR (95% CI)
Total dementia 1.9 (1.3-2.8)
VaD 2.0 (0.7-5.6)
AD 1.9 (1.2-3.1)
AD without CVD 1.8 (1.1-3.0)
• 6,370 subjects aged 55+, dementia-free at baseline, followed up for an average 2.1.y
• Data obtained using a 3-step screening and comprehensive diagnostic work-up and examination of medical files
• Mean age of cohort 69y, n = 692 with diabetes
• Patients on insulin were at highest risk for dementia (RR of 4.3 95%CI 1.7-10.5)
• Population attributable risk of diabetes to incident dementia was 8.8%
Ott et al. Neurology 1999; 58: 1937-41
van den Berg E, Reijmer YD, de Bresser J, et al. A 4 year follow-up study of cognitive functioning in patients with type 2 diabetes mellitus. Diabetologia 2010; 53: 58–65.
68 38
Ding J, Strachan MWJ, Reynolds RM, et al. Diabetic retinopathy and cognitive decline in older people with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetes 2010; 59: 2883–89.
Estimated mean (2 SE) of general factor (g) scores of men and women according to severity of DR.
1,046 men and women aged 60–75 years with type 2 diabetes underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests
DCCT/EDIC Study Research Grouop NEJM 2007 356:18
DCCT/EDIC Study Research Grouop NEJM 2007 356:18
1. Problem Solving 2. Learning 3. Immediate memory 4. Delay recall 5. Spatial information 6. Attention 7. Psychomotor efficiency 8. Motor Speed
Impact of glycaemic control on cognition
• 20% of patients found to have undetected cognitive impairment at baseline
• No difference in DSST score (or any other cognitive tests) at 40 mths.
• Greater mean total brain volume on MRI on intensive than standard treatment (p=0.0007)
ACCORD-MIND - Memory in Diabetes Sub-study of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial 2977 patients aged 55-80 (mean 62y) with type 2 diabetes, treated with standard care or intensive glycaemic control.
Launer et al. Lancet Neurol 2011;10:969-77
PUNTHAKEE Z. et al. DIABETES CARE, VOLUME 35, APRIL 2012
Launer et al. Lancet Neurol 2011;10:969-77
Rachel A. Whitmer, JAMA. 2009;301(15):1565-1572
Frequency of Hypoglycemic Episodes by Dementia Status
Those with at least 1 hypoglycemic event were also more likely to be diagnosed with dementia The attributable risk of dementia for pa-tients with 1 or more hypoglycemic episodes compared with those with no episodes was 2.39% per year
16 667 patients with a mean age of 65 years
The recognition of the clinical manifestations of hypoglycaemia is difficult in patients presenting with dementia….. In fact, agitation, increased confusion or other behavioural disorders may be associated with the dementia and lead to the initiation of inappropriate psychotropic drug treatment.
B. Bauduceau, Diabetes & Metabolism, 2010
Survival probability curves derived from Kaplan–Meier analysis of proportions of patients remaining free of severe hypoglycaemia defined by cognitive status at study entry.
Dementia promotes hypoglycaemic incidents in diabetics
D. G. Bruce, Diabetologia, 2009
the Fremantle Diabetes Study
Normal
MCI
Dementia
Glucose Levels and Risk of Dementia
Crane PK et al. NEJM 369:6 540- 548
Risk of incident dementia associated with diabetes and APOE ε4: the HAAS
Rita Peila, Diabetes, 51:1256–1262, 2002
Type 2 Diabetes, APOE Gene, and the Risk for Dementia and Related Pathologies. The Honolulu-Asia Aging Study
Potential mediators of cognitive impairment in patients with type 2 diabetes mellitus
Strachan, M. W. J. et al. (2011) Cognitive function, dementia and type 2 diabetes mellitus in the elderly Nat. Rev. Endocrinol. doi:10.1038/nrendo.2010.228
. Filippi BM, Mighiu PI. and Lam TKT 2012 Diabetes 61: 773:775
Lin Li, , Christian Hölscher, Brain Research Reviews, 2007
Common pathological processes in Alzheimer disease and type 2 diabetes: A review
Sonia.C. Correia et al. / Ageing Research Reviews 10 (2011) 264–273
Insulin-resistance-mediated amyloid- (A) peptide deposition via a mechanism involving insulin-degrading enzyme (IDE).
la stimolazione di insulina accelera il traffico di AβPP-Aβ dal network trans-Golgi, in cui viene generata, alla membrana plasmatica; l’insulina stimola secrezione extracellulare AβPP-Aβ e ne inibisce l'accumulo intracellulare favorendo la clearance da parte dell’enzima degradante l’insulina (IDE)
anomalie funzionali del segnale insulinico compromettono sia la processazione che la clearance di AβPP-Aβ. L’oligomero si accumula ed entra in competizione con l'insulina, riducendone l’espressione cellulare per il proprio recettore e l'affinità di legame
Fernanda G. De Felice JCI 123(2):531:539
Talbot K et al. JCI 122:4 1316:1338
Nisticò R, Lauro D, Mercuri NB, D'Amelio M. Neuromolecular Med. 2012;14(4):262-9.
Mechanisms Underlying Inflammation
in Neurodegeneration
Christopher K. Glass, Cell, 2010
Fernanda G. De Felice JCI 123(2):531:539
- Associazione tra AD, IR cerebrale e
deficit di insulina (ridotti livelli nel SNC e
CSF), con o senza insulino-resistenza
sistemica e T2DM
- I diabetici anziani trattati hanno minore
densità di “lesioni AD” vs i non-diabetici
- I diabetici ben controllati con terapia
insulinica o ADO significativi
miglioramenti nella memoria e
rallentamento della progressione AD
potenziali cerebrali evocati
e la funzione neurotrasmettitore
La terapia insulinica
può non essere efficace
nel facilitare la memoria
se i livelli di AβPP-Aβ42
nel CSF sono
marcatamente elevati a
causa di insulino-
resistenza.
Terapia antidiabetica e Malattia di Alzheimer
S. de la Monte, Drugs 2012; 72 (1): 49-66
Leah R Hanson1 BMC Neuroscience 2008
Tendenza verso la
terapia insulinica
intranasale per AD
il trattamento è
vantaggioso, sicuro
ed efficace per
aumentare
i livelli di insulina nel
cervello, per il
miglioramento della
memoria, l'attenzione
e ridurre AβPP-
Aβ42 che è
neurotossico
Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease
S. Craft, Arch Neurol. 2012 January ; 69(1): 29–38.
Abstract Objective—To examine the effects of intranasal insulin administration on cognition function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with MCI or AD. Design—Randomized, double-blind, placebo-controlled trial. Participants—The intent-to-treat sample consisted of 104 adults with MCI (n = 64) or mild to moderate AD (n = 40). Intervention—Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Main Outcome Measures: Delayed story recall score and the Dementia Severity Rating Scale score, ADAS-cog score and ADCS-ADL scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Results— Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < 0.05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein–to–Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions
Intranasal Insulin Therapy for Alzheimer Disease and AmnesticMild Cognitive Impairment
Areas of hypometabolism
S. Craft, Arch Neurol. 2012 January ; 69(1): 29–38.
Intranasal Insulin Therapy for Alzheimer Disease and AmnesticMild Cognitive Impairment
-GLP-1R expression -has been observed in
specific cellular subtypes which are crucial
for memory and learning functions, including pyramidal neurons of CA region
and granule cells of dentate gyrus in
hippocampus, and in large
neocortical neurons.
-Other authors have observed
GLP-1R expression
also on glial cells
(microglia and astrocytes), Proposing a role for them as
modulators of CNS inflammation.
E. Mossello, Experimental Diabetes Research , 2011, Hölscher C, Vitam Horm. 2010;84:331-54. The role of GLP-1 in neuronal activity and neurodegeneration.
Exenatide and the treatment of patients with PD
Aviles-Olmos I. et al. JCI 2013 123:6 2730-2736
Exenatide and the treatment of patients with PD
Aviles-Olmos I. et al. JCI 2013 123:6 2730-2736
Exenatide and the treatment of patients with PD
Aviles-Olmos I. et al. JCI 2013 123:6 2730-2736
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