Parkinson e decadimento cognitivo. Stelvio Sestini

Parkinson e decadimento cognitivo Stelvio Sestini

Patients with PD can develop a spectrum of cognitive symptoms Heterogeneity of cognitive deficits The cognitive symptoms can evolve to dementia (Mov Disorder 2010) Cognitive impairment is still present in early disease Common, over a third of patients have deficits at the time of diagnosis (PD de NOVO) (Brain 2004) Cognitive deficits that are severe and thus easily to recognize in dementia can be subtle and thus difficult to detect in early disease 20% - 40% of early PD patients have cognitive deficits (Neurology 2009, 2010) Not all, but only some PD patients with cognitive deficits may evolve into dementia 62% of patients with early cognitive deficits develop dementia in a mean time of 10 y. Prevalence for dementia is 15-38% at 4-5 y fu and 50-78% at 8-10 y fu. Incidence rate for dementia is four - sixfold higher than in general population (J Neurol Sci 2009, Lancet Neurol 2010, Nature 2013) There are two main subgroups of PD patients with cognitive deficits, eg. a subgroup with cognitive deficits associated with an increased risk for conversion to dementia and a subgroup with cognitive deficits not associated to the risk of conversion

Heterogeneity of cognitive deficits Cognitive deficits that are severe and thus easily to recognize in dementia can be subtle and thus difficult to detect in early disease It includes 3 cognitive domains (Nature 2013) (1) Memory and (2) Visuospatial impairments - visual working memory - storage component of working memory - semantic and spatial memory [ ] (3) Executive/attention impairment - ability to plan ahead and sentence processing - develop strategies for a goal-directed outcomes - initiate and inhibit actions - make alterations to behaviour based on feed-back These non motor features largely contribute: There are two main subgroups of PD patients with cognitive deficits, eg. a subgroup with cognitive deficits associated with an increased risk for conversion to dementia and a subgroup with cognitive deficits not associated to the risk of conversion to increase disability associated with motor symptoms of PD, to increase mortality to increase the impact on patient management/caregiver distress The key priority is : early recognition of cognitive impairment and identification of PD subgroup at risk for dementia in order to introduce disease modifying treatments

Heterogeneity of cognitive deficits Cognitive deficits that are severe and thus easily to recognize in dementia can be subtle and thus difficult to detect in early disease The recognition of cognitive symptoms in PD has led to the recent development of clinical criteria for PD-Dementia (PDD) and mild cognitive impairment (PD-MCI) These formalized criteria aim to facilitate the earlier detection and better characterization of cognitive impairment MCI: on the basis of formal neuropsychological testing, the criteria allow subtyping according to the involvement of: a single domain (PD- MCI SD) multiple domain (PD- MCI MD) There are two main subgroups of PD patients with cognitive deficits, eg. a subgroup with cognitive deficits associated with an increased risk for conversion to dementia and a subgroup with cognitive deficits not associated to the risk of conversion PDD: on the basis of presence/absence of less typical PDD cognitive domain (eg. language or pure amnestic symptoms) or confounding factors (es. cerebrovascular co-morbidity) possible PDD probable PDD Mov Disorder 2012, Neurol Publ Corp 2013

The recognition of cognitive symptoms in PD has led to the recent development of clinical criteria for PD-Dementia (PDD) and mild cognitive impairment (MCI) (PD-MCI) These formalized criteria aim to facilitate the earlier detection and better characterization of cognitive impairment and comparative studies On the basis of formal neuropsychological testing, the criteria allow subtyping according to the involvement of: a single domain (PD-MCI SD) multiple domain (PD-MCI MD) On the basis of presence/absence of less typical PDD cognitive domain (eg. language or pure amnestic symptoms) or confounding factors (es. cerebrovascular co-morbidity) possible PDD probable PDD J Neurol Neurosurg Psy 2013, Brain 2014 Neurology Research Int 2013 Mov Disorder 2012, Neurol Publ Corp 2013 Prevalence of impairment in 3 cognitive domains Cognitive domain Mean % Prevalence (1,346 PD patients) Memory 13.3 Visuospatial 11.0 Attention/executive 10.1 Prevalence of single (SD) vs multiple domain (MD) SD/MD Domain SD-MCI MD-MCI Mean % Prevalence (559 PD patients) Prevalence of cognitive domain in SD MCI SD-MCI subtype SD-MCI amnestic SD-MCI non amnestic -visuospatial -executive 68.6 31.4 Mean % Prevalence SD- MCI group 31,6 68.4

Heterogeneity of cognitive deficits There is evidence that PD patients presenting a deficit in more posterior cortical abilities, such as visuospatial and memory functions, are associated with an increased risk for conversion to dementia Cognitive deficits that are severe and thus easily to recognize in dementia can be subtle and thus difficult to detect in early disease PD de NOVO/PD MCI SD PD de NOVO/PD MCI MD + common - common MCI amnestic - common SD-MCI memory MCI nonamnestic + common Executive Memory Visuosp. There are two main subgroups of PD patients with cognitive deficits, eg. a subgroup with cognitive deficits associated with an increased risk for conversion to dementia and a subgroup with cognitive deficits not associated to the risk of conversion Mov Disorder 2012, 2013, Neurol Publ Corp 2013 SD-MCI visuosp. SD-MCI executive PDD To notice

There are two main subgroups of PD patients with cognitive deficits, eg. a subgroup with cognitive deficits associated with an increased risk for conversion to dementia and a subgroup with cognitive deficits not associated to the risk of conversion PDD To notice Risk factors for conversion beside MCI Clinical DD between AD and PDD - Age - Male sex - Low education - Visual hallucinations - Prominent axial rigidity - Severe olfactory dysfunction, greater autonomic impairment - Severity of sleep disturbance Mov Disorder 2012, 2013, Brain 2012 There is some similarity between the cognitive symptoms of PDD and AD but DD can be made due to the presence in PDD of hallucinations, cognitive fluctuations, depression, sleep disturbance. Clinical DD between DLB and PDD By contrast, the cognitive features of PDD are similar to and often indistinguishable from the clinical syndrome of DLB, whose diagnosis is made on the onset of dementia (< 1y )

There is evidence that PD patients presenting a deficit in more posterior cortical abilities, such as visuospatial and memory functions, are associated with an increased risk for conversion to dementia PD de NOVO/PD MCI SD PD de NOVO/PD MCI MD It has been suggested that two distinct MCI syndromes exist, each carrying a different prognosis: + common - common MCI amnestic MCI nonamnestic 1 - the executive syndrome - common SD-MCI memory + common Executive Memory Visuosp. 2 - the visuospatial/memory syndrome SD-MCI visuosp. SD-MCI executive PDD To notice Mov Disorder 2012, Cols Spring Harb Perspect Med 2012

The executive syndrome is an early phenomenon of altered dopaminergic tone in the frontal cortex It has been suggested that two distinct MCI syndromes exist, each carrying a different prognosis: FRONTAL CORTEX OFC VLPFC ACC DLPFC SMA PMC THALAMUS VA MD VL 1 - the executive syndrome GPi PALLIDUM SNr 2 - the visuospatial/memory syndrome Mov Disorder 2012, Cols Spring Harb Perspect Med 2012 TINS 2013 J Neuroscience 2003 ventral putamen - n. accumbens dorsal tier STRIATUM Substantia nigra dorsal putamen - tail caudate ventral tier Degeneration of SN cells in most severe in the ventral midbrain. Thus, in unmedicated patients, cognitive tasks depending on dorsal striatum and its cortical connection are impaired alongside motor control and they are improved by DA replacement medications. On the other hand, DA medications cause impairments of corticoventral striatal loop and related cognitive executive tasks due to dopaminergic overdose of these circuits that are less affected by disease.

The visuospatial/memory syndrome is a late phenomenon of altered cholinergic tone in the parietal inferior, temporal, and associative occipital cortex It has been suggested that two distinct MCI syndromes exist, each carrying a different prognosis: 1 - the executive syndrome 2 - the visuospatial/memory syndrome (Nature 2013) TINS 2013 Impairment of temporal and posterior cortical regions has been related to deafferentation of cholinergic projections fibers of the basal forebrain potentially as a result of increased Lewy Body load in this region

Neuropathology underlying PDD The main neuropathological features of PDD include severe borden of Lewy bodies (asterisks) and Lewy neurities (arrows) [image from ACC] The second neuropathological feature of PDD includes extensive diffuse amyloid plaque pathology (asterisks) [image from superior temporal cortex] Nature 2013 Acta Neuropathol 2010 J Alzheimers Dis Parkinsonism 2014 The third neuropathological feature of PDD includes moderate tau diffuse threads (arrows) and neurofibrillary tangles (asterisks) [image from ACC]

TINS 2012 Mov Disorders 2009 The main neuropathological features of PDD include severe borden of Lewy bodies (asterisks) and Lewy neurities (arrows) [image from ACC] S. Nigra A In early stage, α-syn misfolding and aggregation within DA SNc neurons result in neuron loss and both the clinical motor and executive cognitive syndromes of PDi B The second neuropathological feature of PDD includes extensive diffuse amyloid plaque pathology (asterisks) [image from superior temporal cortex] The third neuropathological feature of PDD includes moderate tau diffuse threads (arrows) and neurofibrillary tangles (asterisks) [image from ACC] Panel 1 A Under pathological conditions, the native protein a-syn undergoes misfolding into pathogenic and toxic species (dimers, trimers, oligomers) that further aggregate into higher order structures (eg. amyloid fibrils) which are the building blocks for the a-syn pathological inclusions eg. LB and Lewy neurites. B Normal quality control systems that prevent, reverse or eliminate misfolded proteins are overwhelmed C Pathogenic a-syn can transfer between cells leading to neurodegeneration C

Basal forebrain In the later stages, caudal rostral ascending progression of a- syn pathology from brainstem into limbic and neocortical regions passing through the basal forebrain cholinergic nuclei leads to the visuospatial/memory syndrome and PDD B C D E Panel 2 D Braak model reveals a caudal- rostral ascending progression of a-syn. LB spread from brainstem structures in early stage of disease to limbic and neocortical areas in the later stages E Ascending progression of a-syn pathology into limbic and neocortical regions is associated with transition in basal forebrain cholinergic nuclei. The loss of cholinergic neurons has been shown to impairment in visuospatial/memory cognition

Overall The current data support the existence of two phenomena that affect disease progression, one associated with DA cell loss as disease progresses and the other associated with an increase in the abnormal accumulation of Lewy bodies, especially in patients with late onset disease Panel 3 F Patient who develops symptoms at 55y of age vs G a patient who develops symptoms at 70 y. The severity of dopamine cell loss is related to the duration of symptoms, thus it is higher in the patient of 55 y old (represented by progressively darker color). The infiltration of Lewy bodies appears more marked in the late onset disease eg in the 70y patient, and in many instances it is accompanied by additional age related pathologies eg. cortical plaques. Indeed, dementia, as indicated in the lower bar, occurs earlier in the disease in older-onset patients, consistent with the greater pathology observed.

Aβ plaques - NFT The main neuropathological features of PDD include severe borden of Lewy bodies (asterisks) and Lewy neurities (arrows) [image from ACC] The second neuropathological feature of PDD includes extensive diffuse amyloid plaque pathology (asterisks) [image from superior temporal cortex] The third neuropathological feature of PDD includes moderate tau diffuse threads (arrows) and neurofibrillary tangles (asterisks) [image from ACC] Patients with PDD tend to have higher cortical Aβ plaques burden and to lesser degree a higher NFT burden than patients without PDD Patients with PDD tend to have higher striatal Aβ plaques burden than patients without PDD Up to 50% PDD patients present with levels of Aβ plaques and NFT sufficient high to meet the threshold for a second diagnosis, that is PDD + AD. Increased severity of cortical Aβ plaques and NFT burden is associated with increased cortical a-syn pathology density, suggesting a potential synergy between a-syn and Aβ pathology

Influence of addictive effect of Aβ plaques NFT on prognosis The addictive effect if a-syn pathology, Aβ plaques and NFT could influence the clinical features of PDD Thus, AD pathology appears to have an important role in the pathogenesis of PDD for a significant proportion of patients PDD + AD is associated with shorter disease duration PDD + AD is associated with shortened survival possibly because of an older age of PD onset Overall, the presence of AD neuropathology in patients with PD could lead to an Older Age - of- onset PD subtype that has a more malignant course

The role of functional and molecular neuroimaging Functional Neuroimaging Radioligand Target [f] -> loss of SINAPTIC FUNCTION f (time/space) by measuring the reduction of GLU metabolism in astrocytes 18-FDG PET All transmission neural systems Molecular Neuroimaging Radioligand Target [f] -> loss of specific function of a neural transmission system or accumulation of misfolding protein in the brain f (time/space) by measuring a peculiar process of neural transmission or [C] of the pathological protein 123I FPCIT, 18F-DOPA Amiloid radioligands Cholinergic radioligands [ ] Aβ Specific transmission neural systems or Accumulation of misfolding proteins QJNM 2012

The role of functional and molecular neuroimaging Functional Neuroimaging with 18-FDG in PD-MCI and PDD Drug naive patients with PD (PD de Novo) with MCI (SD or MD) exhibit an early hypometabolism independent of therapy or motor disability in the superior and inferior parietal, and associative occipital, prefrontal cortices, and an early subcortical hypometabolism in striatum (relative to controls and to a lesser extent to PD nmci) [Pappata S, Neurology 2011] This pattern is shared by patients with advanced PD-MCI and PDD Thus, this pattern may represent an early marker of prodromal dementia

The role of functional and molecular neuroimaging Functional Neuroimaging with 18-FDG in PD-MCI and PDD PD patients with MCI (SD or MD) exhibit an early hypometabolism in the associative parietal, occipital and less extensive in localized areas of frontal and temporal cortices (relative to controls), which is present more extensive in PDD patients (relative to PD MCI patients) [Garcia-Garcia D, EJNMMI 2012].

The role of functional and molecular neuroimaging Functional Neuroimaging with 18-FDG in PD-MCI and PDD Covariance analysis showed that executive/language syndromes were related to hypometabolism in frontal lobes, memory with hypometabolism in temporoparietal lobes and visuospatial function with occipitoparietal/temporal lobes. [Garcia-Garcia D, 2012]. Thus, the occipitoparietal pattern may represent an reliable marker of PDD

The role of functional and molecular neuroimaging Functional Neuroimaging with 18-FDG in PD-MCI and PDD Results of 2 y follow-up study have shown that PD MCI patients converter to PDD are characterized by decreased metabolism in the visual association cortex and particularly in the precuneus and cuneus [BA 18] (related to controls). Hypometabolism was also present in posterior cingulate cortex, temporal and parietal lobes, mesiofrontal lobe, and mild in caudate/ thalamus. [Bohnen NI, JNM 2011]. Thus, the occipitoparietal pattern [BA18] may represent an reliable marker of PDD

The role of functional and molecular neuroimaging A window on other neuroimaging technologies Mild cognitive impairment is linked with faster rate of cortical thinning in patients with PD longitudinally. [Hanganu A, Brain 2014]. Morphological longitudinal (20 months) MRI study A higher rate of cortical thinning was found in occipital (especially medial) and temporal (especially amigdala) cortices and n. accumbens related to results of Montreal Cognitive Assessment

The role of functional and molecular neuroimaging A window on other neuroimaging technologies A three dimensional anatomical view of oscillatory resting state activity and functional connectivity in PD related to dementia: a MEG study using atlas-based beamforming. [Ponsen MM 2013]. MEG study in delta theta alpha beta and gamma frequency bands PD Connectivity PD PDD Deficit in neural activity in PDD vs. PD vs. Connectivity PDD PDD patients had a slowing in neural activity (less alpha and beta power and less connectivity in parietal, temporal, occipital and to less extent in frontal areas (related to PD)

The role of functional and molecular neuroimaging A window on other neuroimaging technologies Parkinson disease, movement disorders and dementia [Tessitore A 2012]. Resting state fmri study of Default Mode Network (DMN) connectivity in PD with dementia PDD PDD patients may present an altered deactivation of posterior cortical areas and mpfc during different cognitive tasks e.g. visuospatial and executive respectively, suggesting a perturbation of DMN.

The role of functional and molecular neuroimaging Overview of studies performed at subcortical level PD de NOVO: decrease of [DAT] in the caudate contra-lateral to the more affected side is associated and predictive for the progressive decline of executive functions Overview of studies performed at cortical level Molecular n. imaging with DA tracers PD early: decrease of [DOPA] in the lateral frontal c. PDD: decrease of [DOPA] in the frontal cortex is extended to the medial frontal cortex and ACC PD early: endogenous release of DA [Raclopride] is reduced in the caudate but not in the frontal medial cortex and ACC Overall Brain 2002 J Neuroimaging 2008 According to the model, in the early PD and later on in PDD performance of executive function is sustained by integrity of nigro-striatal network in the caudate nucleus and related frontal cortical-striatal pathway rather than function of medial frontal cortex

The role of functional and molecular neuroimaging Overview of studies According to the model, PD de NOVO/early PD, PDD exhibit a cholinergic degeneration across the entire cortex but most notably in posterior regions, related to visuospatial, and less significant, executive skills (Klein JC, Neurology 2010) Molecular n. imaging with cholinergic tracers for acetylcholinesterase (AChE) [11C-MP4A or PMP] PD-MCI vs controls PDD vs controls PD-MCI vs PDD

The role of functional and molecular neuroimaging Overview of studies Patients with PD-MCI and mild PDD exhibit a progressive increase in PIB binding in frontal, temporal and posterior cingulate cortex, related to global cognitive and WAIS score (Petru M, Neurology 2012) Molecular n. imaging with amyloid (PIB)

The role of functional and molecular neuroimaging Molecular n. imaging with amyloid (PIB) Overview of studies At baseline measurements, amyloid burden does not distinguish between cognitively impaired and unimpaired subjects with PD without dementia (Gomperts SN Neurology 2008). It has been suggested that low level of PIB retention could be used to differentiate PDD to DLB and AD

The role of functional and molecular neuroimaging Overview of studies Amyloid contributes to cognitive, but not motor, decline over time. Higher PiB retention predicted a greater hazard of conversion to a more severe diagnosis (Gomperts SN Neurology 2012). Molecular n. imaging with amyloid (PIB)

The role of functional and molecular neuroimaging Molecular n. imaging with amyloid (PIB) Overview of studies Different β-amyloid binding patterns in AD and PD diseases: It's the network! (Heidelberg D. Neurology 2013) PiB binding in PD is lower than AD, with a pattern similar to normal and different from AD (Campbell M Neurology 2013)

Summary

Summary PD MCI 18FDG PDD

Future Directions The Future is called Molecular Medicine with Disease Biomarkers (tissue, serum, urine, imaging) Early and Specific detection of Disease Predictive, Prognostic and driven Personalized Medicine Personalized Medicine in the 21st century is delivering the right care to the right patient at the right time, with measurable improvements in outcome and potentially great reductions in costs

Future Directions The use of Disease Biomarkers is the great challenge of 21st century. By using the biomarkers, we will be able to visualize and measure with high reproducibility the presence of a specific disease without imaging it from indirect signs. Grazie per l attenzione.

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