Littérature scientifique sur le sujet « Dementia, metabolic imaging, neuropsychology »

Alzheimer’s disease (AD) is the most common form of dementia in old age, and is characterized by prominent impairment of episodic memory. Recent functional imaging studies in AD have demonstrated alterations in a distributed network of brain regions supporting memory function, including regions of the default mode network. Previous positron emission tomography studies of older individuals at risk for AD have revealed hypometabolism of association cortical regions similar to the metabolic abnormalities seen in AD patients. In recent functional magnetic resonance imaging (fMRI) studies of AD, corresponding brain default mode regions have also been found to demonstrate an abnormal fMRI task-induced deactivation response pattern. That is, the relative decreases in fMRI signal normally observed in the default mode regions in healthy subjects performing a cognitive task are not seen in AD patients, or may even be reversed to a paradoxical activation response. Our recent studies have revealed alterations in the pattern of deactivation also in elderly individuals at risk for AD by virtue of their APOE e4 genotype, or evidence of mild cognitive impairment (MCI). In agreement with recent reports from other groups, these studies demonstrate that the pattern of fMRI task-induced deactivation is progressively disrupted along the continuum from normal aging to MCI and to clinical AD and more impaired in e4 carriers compared to non-carriers. These findings will be discussed in the context of current literature regarding functional imaging of the default network in AD and at-risk populations.

Subcortical dementia refers to a clinical syndrome characterised by slowing of cognition, memory disturbances, difficulty with complex intellectual tasks such as strategy generation and problem solving, visuospatial abnormalities, and disturbances of mood and affect. The syndrome was first described by Kinnier Wilson, but further progress in development of the concept has occurred only within the past ten years. Subcortical dementia occurs in degenerative extrapyramidal disorders and has also been identified in inflammatory, infectious, and vascular conditions. Histologic, metabolic, and neurochemical investigations implicate dysfunction primarily of subcortical neurotransmitter systems and subcortical structures or subcortical-frontal connections in the genesis of the syndrome. Subcortical dementia contrasts neuropsychologically and anatomically with disorders such as dementia of the Alzheimer type that affect primarily the cerebral cortex. The clinical characteristics of subcortical dementia reflect the interruption of fundamental functions (motivation, mood, timing, arousal) mediated by phylogenetically and ontogenetically early maturing structures.

Dementia occurs in up to 30% of people with Parkinson's disease and is a major cause of disability. Pathologically, Parkinson's dementia, where dementia follows the onset of parkinsonism by at least one year, overlaps with dementia with Lewy bodies. We review the functional impact, definitions, neuropsychology, epidemiology and pathophysiology of Parkinson's dementia, dementia with Lewy bodies and their overlap. Associated psychiatric and imaging findings are also considered. Lastly, current and emerging approaches to assessment and treatment in patients with these Lewy body associated dementias are presented.

In vivo functional brain imaging provides an opportunity to quantify and localize functional deficits associated with Alzheimer's disease (AD), in relation to dementia severity and heterogeneous cognitive profiles. Such imaging also provides a basis for distinguishing AD from other causes of dementia and for making an early diagnosis of disease. One imaging modality that can elucidate AD is positron emission tomography (PET), which is used to measure regional cerebral metabolic rates for glucose (rCMRglc) and regional cerebral blood flow (rCBF). Resting-state measurements with PET, when related to cognitive profiles in longitudinal studies, indicate that specific cognitive defects are preceded and predicted by reductions in rCMRglc in regions subserving the cognitive functions tested. Metabolic reductions and right/left metabolic asymmetries can be used to convert a “possible” to a “probable” diagnosis of AD by the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Furthermore, discriminant analyses of PET metabolic patterns can identify patients at risk for AD with mild memory deficits as having probable AD. In the future, stimulation PET studies should augment the power of this discriminant analysis.

Parametric FDG-PET images offer the potential for automated identification of the different dementia syndromes. However, various existing image features and classifiers have their limitations in characterizing and differentiating the patterns of this disease. We reported a hybrid feature extraction, selection, and classification approach, namely, the GA-MKL algorithm, for separating patients with suspected Alzheimer’s disease and frontotemporal dementia from normal controls. In this approach, we extracted three groups of features to describe the average level, spatial variation, and asymmetry of glucose metabolic rates in 116 cortical volumes. An optimal combination of features, that is, capable of classifying dementia cases was identified by a genetic algorithm- (GA-) based method. The condition of each FDG-PET study was predicted by applying the selected features to a multikernel learning (MKL) machine, in which the weighting parameter of each kernel function can be automatically estimated. We compared our approach to two state-of-the-art dementia identification algorithms on a set of 129 clinical cases and improved the performance in separating the dementia types, achieving accuracy of 94.62%. There is a very good agreement between the proposed automated technique and the diagnosis made by clinicians.

In the last decade, the differential diagnosis of dementia has become very challenging. Different clinical syndromes can in fact be associated with the same underlying pathology and different pathologies can be associated with the same clinical phenotype, making it very difficult to distinguish them in vivo. In the present project we focused on the differential diagnosis of cognitive syndromes affecting, at onset, posterior cerebral networks with particular reference to PCA, CBD and LBD, respectively. We enrolled 70 consecutive patients, referred to the memory clinic of the Neurology Department of S. Gerardo Hospital, with a cognitive profile characterized primarily by impairment of posterior cognitive functions and a relative spare of language and memory functions. Each patient underwent, an extensive neuropsychological battery, a neurological examination and a [18F]FDG-PET in close proximity to the neuropsychological assessment. Applying Principal Components Analysis to all the tasks of posterior cognitive functions, we highlighted three cognitive sub-syndromes that we interpret as anatomical-based and label as “left parietal”, “left temporo-occipital” and “right parietal” and we classify patients on the basis of these three components. Cerebral metabolism measured with [18F]FDG-PET confirm this interpretation of the three sub-syndromes. We then compared empirical patients classification and the diagnoses made with the current diagnostic criteria for Posterior Cortical Atrophy (PCA), Corticobasal degeneration (CBD), Lewy body dementia (LBD) and Alzheimer’s disease (AD). One of the most important evidence was that all patients classified as “left temporo-occipital” were diagnosed as AD or PCA (only one of these patients met both criteria of PCA and CBD). Two additional quite interesting associations emerged, although less strong: the first between “left parietal” and CBD diagnosis and the second between “right parietal” and PCA diagnosis. Finally a large group of patients could not be classified only on the basis of their very specific posterior cognitive profile. In conclusion, this new empirical approach seems to be quite useful in the differential diagnosis of dementia syndromes.

The present thesis comprises three main parts: one theoretical and two experimental. The first part, composed of two chapters, will introduce the clinical and neuropathological features underlying parkinsonian disorders, namely in Parkinson’s disease (PD) as well as in atypical parkinsonisms — multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) (Chapter 1). In this regard, PD and MSA are defined as synucleinopathies due to the presence of synuclein aggregates; while PSP that is characterized by tau protein accumulations, is part of tauopathies. Further, Chapter 2 will provide an overview of the cognitive dysfunctions characterizing these disorders, as well as evidence on the biological mechanisms and structural changes underlying cognitive alterations. The second and third parts are composed by studies I conducted during my doctoral research. Namely, in Chapter 3, I report results of my studies on cognitive screening instruments most sensitive in detecting cognitive alterations in atypical parkinsonisms compared to PD. In the following study, I characterized the progression of cognitive decline in these disorders (Chapter 4). Finally, I investigated with magnetic resonance imaging the structural changes underlying cognitive alterations in PD (Chapter 5), and MSA (Chapter 6). I conclude this thesis by discussing the clinical consequences of these cognitive and imaging findings (Chapter 7). PART I - Theoretical background Chapter 1: Parkinsonian disorders Parkinsonian disorders are characterized by different underlying pathologies. In PD and MSA there are synuclein aggregates respectively in dopamine neurons or in glial cells, while PSP patients present pathological aggregation of the tau-protein, resulting in neurofibrillary tangles formation (Daniel, de Bruin, & Lees, 1995; Dickson, 1999). Clinical manifestations depend by the characteristics of protein aggregation and by the extent of disease spread to cortical and subcortical regions (Halliday, Holton, Revesz, & Dickson, 2011). Thus, the present chapter will overview the underlying pathology of PD, MSA and PSP; and it will describe the different clinical features; and lastly review the most recent diagnostic criteria (e.g., Gelb, Oliver, & Gilman, 1999; Gilman et al., 2008; Höglinger et al., 2017). Chapter 2: Cognitive features and their underlying mechanisms in parkinsonian disorders Non-motor symptoms represent a crucial part of the parkinsonian disorders spectrum; and cognitive dysfunctions, including dementia, are probably the most relevant, since they affect functional independence of patients, increase caregiver burden as well as wield a considerable socioeconomic impact (Keranen et al., 2003; McCrone et al., 2011; Vossius, Larsen, Janvin, & Aarsland, 2011). The first part of this chapter will provide an overview on cognitive dysfunctions in PD, MSA, and PSP. Moreover, the clinical criteria for the diagnosis of mild cognitive impairment and dementia in PD will be reported (Dubois et al., 2007; Emre et al., 2007; Litvan et al., 2012), while so far there are no available criteria to assess cognitive syndromes in PSP and MSA. Lastly, the second and third parts of this chapter will review the evidence on biological mechanisms and structural changes underlying cognitive alterations in these disorders. PART II - Studies on cognitive manifestations in parkinsonian disorders Chapter 3: Montreal Cognitive Assessment and Mini-Mental State Examination performance in progressive supranuclear palsy, multiple system atrophy and Parkinson’s disease There is general agreement that cognitive dysfunctions are common in PD as well as in other parkinsonian disorders (Aarsland et al., 2017; Brown et al., 2010; Gerstenecker, 2017). Brief screening cognitive scales can be adopted in routine care, to support the clinician in the diagnostic process (Marras, Troster, Kulisevsky, & Stebbins, 2014). The Mini-Mental State Examination (MMSE) is the most widely used (Folstein, Folstein, & McHugh, 1975) although MMSE is relatively insensitive in detecting cognitive deficits in parkinsonian disorders mainly because it does not investigate the fronto-executive domain (Hoops et al., 2009). Conversely, the Montreal Cognitive Assessment (MoCA), another brief cognitive screening tool widely used with PD patients (Nasreddine et al., 2005), showed high sensitivity and specificity in the assessment of cognitive dysfunctions in PD (Gill, Freshman, Blender, & Ravina, 2008; Hoops et al., 2009; Zadikoff et al., 2008), as well as also in several neurodegenerative conditions such as Alzheimer’s disease, dementia with Lewy bodies (DLB) and Huntington’s disease (Biundo et al., 2016b; Hoops et al., 2009; Nasreddine et al., 2005; Videnovic et al., 2010). However, MoCA has been poorly investigated in atypical parkinsonisms — especially in PSP and MSA (Kawahara et al., 2015). Thus, this study’s main aim was to determine if MoCA is more sensitive than the commonly used MMSE in detecting cognitive abnormalities in patients with probable PSP and MSA, compared to PD. In this multicenter study across three European institutions, MMSE and MoCA were administered to 130 patients: 35 MSA, 30 PSP and 65 age, and education and sex matched-PD. We assessed between-group differences for MMSE, MoCA, and their subitems and calculated receiver operating characteristic (ROC) curves. Our results show that the mean MMSE is higher than the mean MoCA score in each patient group: MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p<0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p<0.0001), and PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p<0.0001). Furthermore, MoCA total score as well as its letter fluency subitem differentiates PSP from MSA and PD with high specificity and moderate sensitivity. Namely, a cut-off score of seven words or less per minute would support a diagnosis of PSP (PSP vs. PD: 86% specificity, 70% sensitivity; PSP vs. MSA: 71% specificity, 70% sensitivity). On the contrary, MMSE presented a ceiling effect for most subitems, except for the ‘bisecting pentagons’, with PSP performing worse than MSA and PD patients. These findings suggest that PSP and MSA, similar to PD patients, may present normal performance on MMSE, but reduced performance on MoCA. To conclude, MoCA is more sensitive than MMSE in detecting cognitive dysfunctions in atypical parkinsonisms, and together with its verbal fluency subitem can be a valuable test to support PSP diagnosis. Chapter 4: Prospective assessment of cognitive dysfunctions in parkinsonian disorders Clinical and research evidence suggests cognitive impairments in parkinsonian disorders are progressive. However, there are only a few longitudinal studies in the literature that investigated cognitive progression in PSP and MSA compared to PD (Dubois & Pillon, 2005; Rittman et al., 2013; Soliveri, 2000). In addition, previous studies are based on brief cognitive screening scales or on neuropsychological assessments that do not extensively investigate the full spectrum of cognitive abilities across the five cognitive domains (i.e., attention/working-memory, executive, memory, visuospatial and language). Furthermore, even though clinical criteria for mild cognitive impairment (MCI) and dementia in PD have been formulated (Dubois et al., 2007; Litvan et al., 2012), it remains to be investigated whether similar criteria might be applied also for atypical parkinsonisms (Marras et al., 2014). Based on these observations, the aims of the present study were to: i) assess the severity of cognitive dysfunctions in PSP and MSA patients using PD-criteria for cognitive statuses (i.e., MCI or dementia); ii) investigate the sensitivity of two widely used cognitive screening instruments, the MMSE and MoCA, in differentiating MSA, PSP and PD global cognitive profile; iii) characterize the progression of cognitive decline on the five cognitive domains and behavioral features; and to compare the 15-month follow-up profile across the parkinsonian diseases. Our sample included 18 patients with PSP, 12 MSA; and 30 PD patients, matched for age, education and sex. They were evaluated at baseline and at a mean of 15-month follow-up. Demographic and clinical variables were collected. From the cognitive standpoint, I selected a comprehensive neuropsychological battery specifically designed to target cognitive deficits in PD, according to Level II criteria (Dubois et al., 2007; Litvan et al., 2012; Marras et al., 2014). Thus, I applied these criteria also to MSA and PSP since there are no published criteria for atypical parkinsonisms. Statistical non-parametric analyses were used. I found PSP patients had more severe cognitive decline compared to PD and MSA. Namely, after 15-month follow-up, we noted a marked decline in the executive and language domains in the PSP group. Baseline and follow-up evaluations agreed, showing that PSP had a worse performance than PD and MSA patients: especially, in the Stroop test, verbal fluencies (semantic and phonemic) and MoCA. Assessing the severity of cognitive deficits, I found different percentages of cognitive status (i.e., normal cognition vs. MCI vs. dementia) among the three groups. In particular, the percentage of patients with dementia was higher in PSP compared to MSA (33% vs. no patients with dementia) even if disease duration was similar. Among MSA and PSP patients with multidomain MCI at baseline only PSP converted to dementia at follow-up. Then, although the disease duration was longer for PD patients compared with PSP, the proportion of patients who converted to dementia was lower in the PD group compared to PSP (7% vs. 16%), despite both groups having had similar baseline severity of MCI. Overall, these results suggest more rapid and severe cognitive decline in PSP while MSA patients generally have milder deficits. MoCA showed higher sensitivity than MMSE in detecting cognitive changes, especially in PSP. But MoCA was less sensitive than MMSE in detecting cognitive decline at 15-month in PD, suggesting that MMSE is better if one wants to track cognitive changes in PD. Neuropsychiatric features are more common in PSP than PD patients, especially apathy with accompanying low levels of anxiety and depression. Lastly, analysis of subitems revealed that PSP patients had a ‘clinically significant’ worsening after 15-month in the attentive/executive subitems (Trial Making Test part B and Clock drawing). But it has been observed that some patients also improved in specific subtasks at the follow-up. This improvement could be related to their higher medication dose (although the dopaminergic treatment was not significantly different between the baseline and follow-up). However, noteworthy alterations in performance have been seen for subitems sensitive to motor conditions (such as drawing figures and linking circles with a pen), which could affect cognitive outcome, leading to higher performance at follow-up. These limits of MoCA and MMSE scale have already been reported in PD patients (Biundo et al., 2016b; Hu et al., 2014), and maybe are more pronounced in atypical parkinsonisms. Taken together, these findings show that PSP patients were markedly impaired in comparison to the other parkinsonian disorders (MSA and PD) and six years after first symptoms, 33 percent of patients have dementia. This severe progression is possibly associated with the distribution of tau pathology that involves also cortical structures. On the contrary, the pattern of cognitive impairment in MSA is less severe, possibly due to the predominance of subcortical pathology with cortical involvement occurring only secondary to these abnormalities. Thus, these findings recommend using cognitive assessment to help differential diagnosis in atypical parkinsonisms, and to monitor disease progression. PART III - Neuroimaging studies of synucleinopathies Chapter 5: Amyloid depositions affect cognitive and motor manifestations in Parkinson’s disease Cognitive deficits, particularly executive problems, can be observed early in PD (Aarsland, Bronnick, Larsen, Tysnes, & Alves, 2009). Dysfunction of the frontostriatal dopaminergic system may influence the presence of executive and attention problems (Bruck, Aalto, Nurmi, Bergman, & Rinne, 2005), but so far, evidence from dopamine transporter (DAT) imaging are inconsistent (Delgado-Alvarado, Gago, Navalpotro-Gomez, Jimenez-Urbieta, & Rodriguez-Oroz, 2016). In this regard, the neuropathology underlying cognitive impairment in PD is heterogeneous (Irwin, Lee, & Trojanowski, 2013; Kehagia, Barker, & Robbins, 2010) and amyloid deposit involvement with synuclein pathology remains poorly defined, particularly in the disease’s early stages. Thus, this study’s aims were to investigate the interplay between amyloid depositions in frontostriatal pathways, striatal dopaminergic deficit and brain atrophy rates; and their contribution to cognitive defects (i.e., fronto-executive functions) in early-PD. A multicenter cohort of 33 PD patients from the Parkinson's Progression Markers Initiative underwent [18F]florbetaben positron emission tomography (PET) amyloid, [123I]FP-CIT (see Abbreviations List) single-photon emission computed tomography (SPECT), structural magnetic resonance imaging (MRI), clinical and selective cognitive evaluations. Our results showed that high amyloid levels were associated with reduced dopaminergic deficits in the dorsal striatum (as compared to low amyloid levels), increased brain atrophy in frontal and occipital regions and a tendency to show more frequent cognitive impairment in global cognition (as assessed by MoCA) and fronto-executive tests. Of note, amyloid depositions in frontostriatal regions were inversely correlated with cognitive performance. Overall, our findings suggest that early-PD patients with amyloid burden have higher brain atrophy rates and may experience more cognitive dysfunctions (i.e., executive) and motor impairment as compared to amyloid negative subjects. In this regard, our results seem to be aligned with a recent neuropathological hypothesis that considers synaptic axonal damage and dysfunction as the PD key feature (Tagliaferro & Burke, 2016). Indeed, dopaminergic system neurons are particularly vulnerable to synuclein pathology due to their axonal characteristics — long, thin and unmyelinated. This is also confirmed by imaging studies with DAT-binding PET (Caminiti et al., 2017), suggesting that synuclein aggregations in PD can affect synaptic function, and thus signal transmission from the disease’s very early stages. Our findings suggested a possible interaction between synuclein and the coincident amyloid pathology, wherein amyloid burden may facilitate the spread of synuclein (i.e., Lewy bodies) (Toledo et al., 2016), and we speculate that this interaction can further contribute to axonal vulnerability. Thus, consistently with this hypothesis, we conclude that possibly amyloid depositions act synergistically with synuclein pathology and affect PD clinical manifestations. Chapter 6: Brain structural profile of multiple system atrophy patients with cognitive impairment In contrast to other synucleinopathies (e.g., PD and DLB), presence of dementia is considered a non-supporting feature for MSA diagnosis (Gilman et al., 2008), however there is growing evidence that MSA patients can experience cognitive impairment ranging from executive dysfunctions to multiple-domain cognitive deficits, and in a few cases, also dementia (Gerstenecker, 2017). MMSE is a commonly used global cognitive scale and recently a large multicenter study has suggested using a cutoff score below 27 to increase the MMSE sensitivity in identifying cognitive dysfunctions in MSA (Auzou et al., 2015). Underlying mechanisms of cognitive impairment in MSA are still not understood, and in this regard evidence from MRI studies suggested a discrete cortical and subcortical contribution to explain cognitive deficits (Kim et al., 2015; Lee et al., 2016a), even though these findings were based on a relatively small number of patients at various disease stages as well as being single-center. Thus, the aim of our multicenter study was to better characterize the anatomical changes associated with cognitive impairment in MSA and to further investigate the cortical and subcortical structural differences in comparison to a sample of healthy subjects. We examined retrospectively 72 probable MSA patients and based on the MMSE threshold below 27, we defined 50 MSA as cognitively normal (MSA-NC) and 22 with cognitive impairment (MSA-CI). We directly compared the MSA subgroup, and further compared them to 36 healthy subjects using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to healthy subjects, MSA patients showed widespread cortical (i.e., bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white matter alterations. However, the direct comparison MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These findings suggest only a marginal contribution of cortical pathology to cognitive deficits in MSA. Hence, we suggest that cognitive alterations are driven by focal frontostriatal degeneration that is in line with the concept of ‘subcortical cognitive impairment’.
La presente tesi è formata da tre parti principali: la prima teorica mentre le due seguenti sono sperimentali. La prima parte, composta di due capitoli, introdurrà le caratteristiche cliniche e neuropatologiche sottostanti ai disturbi parkinsoniani, in particolare nella malattia di Parkinson (PD) e nei parkinsonismi atipici — atrofia multisistemica (MSA) e paralisi progressiva sopranucleare (PSP) (Capitolo 1). Nello specifico, PD ed MSA sono definite come sinucleinopatie per la presenza di aggregati di sinucleina, mentre la PSP che è caratterizzata dall’accumulo di proteina tau rientra a far parte delle tauopatie. Invece, il Capitolo 2 fornirà una panoramica delle disfunzioni cognitive che caratterizzano questi disturbi e fornirà inoltre evidenze circa i meccanismi biologici e i cambiamenti strutturali che sono alla base delle alterazioni cognitive. Nella seconda e la terza parte sono riportati alcuni studi che ho condotto durante il dottorato di ricerca. In particolare, nel Capitolo 3 riporto i risultati dei miei studi sugli strumenti di screening cognitivo più sensibili nel rilevare alterazioni cognitive nei parkinsonismi atipici rispetto ai pazienti con PD. Nel successivo studio invece ho investigato la progressione del declino cognitivo in questi disturbi (Capitolo 4). Infine, ho investigato con studi di risonanza magnetica i cambiamenti strutturali che sottendono le alterazioni cognitive nel PD (Capitolo 5) e nella MSA (Capitolo 6). Seguiranno le conclusioni generali, in cui discuto le conseguenze cliniche dei risultati ottenuti negli studi cognitivi e di imaging (Capitolo 7). PARTE I – Background teorico Capitolo 1: I disturbi parkinsoniani I disturbi parkinsoniani sono caratterizzati da una diversa patologia sottostante. Nel PD ed MSA ci sono aggregati di sinucleina rispettivamente nei neuroni dopaminergici o nelle cellule gliali, mentre i pazienti con PSP presentano delle aggregazioni di proteina tau che determina la formazione di ammassi neurofibrillari (Daniel, de Bruin, & Lees, 1995; Dickson, 1999). Le manifestazioni cliniche dipendono dalle caratteristiche di aggregati proteici e dall’entità di diffusione della malattia nelle regioni corticali e sottocorticali (Halliday, Holton, Revesz, & Dickson, 2011). Quindi, il presente capitolo illustrerà la patologia sottostante nel PD, MSA e PSP, saranno poi descritte le diverse caratteristiche cliniche ed infine, saranno presentati i più recenti criteri diagnostici di questi disturbi (e.g., Gelb, Oliver, & Gilman, 1999; Gilman et al., 2008; Höglinger et al., 2017). Capitolo 2: Caratteristiche cognitive e i sottostanti meccanismi nei disturbi parkinsoniani I sintomi non-motori rappresentano una parte cruciale dello spettro dei disturbi parkinsoniani, in particolare le disfunzioni cognitive, inclusa la demenza, sono probabilmente tra i sintomi non-motori più rilevanti, in quanto influenzano l'autonomia funzionale dei pazienti, incrementano il carico di gestione del caregiver ed hanno un notevole impatto socioeconomico (Keranen et al., 2003; McCrone et al., 2011; Vossius, Larsen, Janvin, & Aarsland, 2011). La prima parte di questo capitolo fornirà una panoramica sulle disfunzioni cognitive nel PD, MSA e PSP. Saranno inoltre riportati i criteri clinici per la diagnosi di declino cognitivo lieve e di demenza nel PD (Dubois et al., 2007; Emre et al., 2007; Litvan et al., 2012), al contrario invece non esistono al momento criteri disponibili per valutare le sindromi cognitive in PSP e MSA. Infine, la seconda e la terza parte di questo capitolo forniranno evidenze sui meccanismi biologici e sui cambiamenti strutturali sottostanti alle alterazioni cognitive in questi disturbi. PARTE II - Studi sulle manifestazioni cognitive nei disturbi parkinsoniani Capitolo 3: Performance al Montreal Cognitive Assessment e Mini-Mental State Examination nella paralisi sopranucleare progresiva, atrofia multisistemica e malattia di Parkinson Vi è un generale consenso nel riconoscere che le alterazioni cognitive siano frequenti nei PD e negli altri disturbi parkinsoniani (Aarsland et al., 2017; Brown et al., 2010; Gerstenecker, 2017). Pertanto, nella pratica clinica possono essere adottate delle scale brevi di screening cognitivo, per supportare il clinico nel processo diagnostico (Marras, Troster, Kulisevsky, & Stebbins, 2014). Il Mini-Mental State Examination (MMSE) è la scala più utilizzata (Folstein, Folstein, & McHugh, 1975), anche se MMSE è relativamente insensibile nell’identificare rilevare disfunzioni cognitive nei disturbi parkinsoniani principalmente perché non indaga il dominio fronto-esecutivo (Hoops et al., 2009). Al contrario, il Montreal Cognitive Assessment (MoCA), un altro strumento di screening cognitivo ampiamente utilizzato nei pazienti con PD (Nasreddine et al., 2005), ha mostrato un’elevata sensibilità e specificità nell’identificazione di alterazioni cognitive nei PD (Gill, Freshman, Blender, & Ravina, 2008; Hoops et al., 2009; Zadikoff et al., 2008), come anche in altre malattie neurodegenerative come l’Alzheimer, la demenza da corpi di Lewy (DLB) e la malattia di Huntington (Biundo et al., 2016b; Hoops et al., 2009; Nasreddine et al., 2005; Videnovic et al., 2010). Tuttavia, vi sono poche evidenze sull’uso del MoCA nei parkinsonismi atipici, in particolare nella PSP ed MSA (Kawahara et al., 2015). Pertanto, lo scopo del presente studio era di determinare se il MoCA fosse più sensibile del comunemente utilizzato MMSE nel rilevare alterazioni cognitive nei pazienti con probabile PSP e MSA, rispetto al PD. In questo studio multicentrico, che ha coinvolto altri tre centri europei, sono state somministrate le scale MMSE e MoCA a 130 pazienti: 35 MSA, 30 PSP e 65 pazienti PD appaiati per età, scolarità e sesso. Sono state valutate le differenze tra i gruppi per MMSE, MoCA, e i loro subitem; infine sono state calcolate le curve ROC (Receiver-Operating Characteristic). Dai risultati emerge che la media del MMSE è superiore al punteggio medio del MoCA in ogni gruppo di pazienti: MSA (27.7 ± 2.4 vs. 22.9 ± 3.0, p<0.0001), PSP (26.0 ± 2.9 vs. 18.2 ± 3.9, p<0.0001), e PD (27.3 ± 2.0 vs. 22.3 ± 3.5, p<0.0001). Inoltre, il punteggio totale MoCA così come il suo subitem di fluenza fonemica è in grado di differenziare la PSP da MSA e PD con un’alta specificità e moderata sensibilità. Specificamente, un punteggio uguale o inferiore a sette parole al minuto sembra supportare una diagnosi di PSP (PSP vs PD: 86% specificità, sensibilità al 70%, PSP vs MSA: 71% specificità, sensibilità al 70%). Al contrario, nel MMSE è stato possibile osservare un ‘effetto-soffitto’ per la maggior parte dei subitem, ad eccezione del subitem dei ‘due pentagoni’, in cui i pazienti con PSP hanno una prestazione peggiore rispetto a MSA e PD. I nostri risultati suggeriscono che PSP ed MSA, similmente al PD, possono presentare una prestazione normale al MMSE ma deficitaria al MoCA. In conclusione, il MoCA è più sensibile del MMSE nel rilevare disfunzioni cognitive nei parkinsonismi atipici ed insieme al suo subitem di fluenza verbale sembra essere un valido test per supportare una diagnosi di PSP. Capitolo 4: Valutazione prospettica delle disfunzioni cognitive nei disturbi parkinsoniani Evidenze in ambito clinico e di ricerca suggeriscono che le disfunzioni cognitive nei disturbi parkinsoniani siano progressive. Tuttavia, in letteratura vi sono pochi studi longitudinali che indagano la progressione cognitiva in pazienti con PSP ed MSA rispetto a pazienti PD (Dubois & Pillon, 2005; Rittman et al., 2013; Soliveri, 2000). In particolare, i precedenti studi si basano solo su scale globali di screening cognitivo, oppure su valutazioni neuropsicologiche parziali che non esaminano l'intero spettro delle abilità cognitive nei cinque domini (i.e., attenzione/memoria di lavoro, esecutivo, mnesico, visuospaziale e del linguaggio). Inoltre, sebbene siano stati formulati criteri clinici per la diagnosi di declino cognitivo lieve (MCI) e di demenza in pazienti PD (Dubois et al., 2007; Litvan et al., 2012), rimane ancora da investigare se tali criteri possano essere applicati anche nei parkinsonismi atipici (Marras et al., 2014). Date tali premesse, gli obiettivi del presente studio sono stati: i) valutare la severità delle alterazioni cognitive in pazienti PSP ed MSA utilizzando i criteri validati nei pazienti PD, per identificare gli stati cognitivi (i.e., MCI o demenza); ii) esaminare la sensibilità di due strumenti di screening cognitivo ampiamente utilizzati, (i.e., MMSE e MoCA), nel differenziare il profilo cognitivo globale di pazienti MSA, PSP e PD; iii) caratterizzare la progressione del declino cognitivo nei cinque domini, il profilo comportamentale e infine confrontare il profilo cognitivo al follow-up tra i vari disturbi parkinsoniani. Il nostro campione includeva 18 pazienti con PSP, 12 MSA e 30 pazienti con PD appaiati per età, scolarità e sesso, che sono stati valutati alla baseline e al follow-up a 15 mesi. Sono stati raccolti dati demografici e clinici; inoltre dal punto di vista cognitivo è stata selezionata una batteria di test neuropsicologici completa, specifica per l’identificazione di deficit cognitivi in pazienti PD, secondo i criteri pubblicati di ‘Livello II’ (Dubois et al., 2007; Litvan et al., 2012; Marras et al., 2014). Abbiamo quindi applicato tali criteri anche a pazienti MSA e PSP, dato che non esistono criteri pubblicati per i parkinsonismi atipici. Infine, sono state utilizzate analisi statistiche di tipo non-parametrico. Dai nostri risultati emerge che i pazienti con PSP hanno un declino cognitivo più severo rispetto a pazienti PD ed MSA. Nello specifico, al follow-up è stato possibile osservare un marcato declino a carico del dominio esecutivo e del linguaggio nel gruppo con PSP. Le valutazioni cognitive alla baseline e al follow-up erano concordanti, ed entrambe confermano che i pazienti PSP hanno una prestazione peggiore rispetto ai pazienti PD ed MSA: in particolare, nello Stroop test, nelle fluenze verbali (semantica e fonematica) e nel MoCA. Valutando la severità dei deficit cognitivi, abbiamo inoltre trovato diverse percentuali di diagnosi cognitive (i.e., profilo nella norma, MCI vs. demenza) tra i tre gruppi. In particolare, la percentuale più elevata di pazienti con demenza era nel gruppo con PSP rispetto ai pazienti MSA (i.e., 33% vs. nessun paziente con demenza), anche se la durata di malattia era simile. Inoltre, tra i pazienti MSA e PSP con un profilo MCI-multidominio alla baseline, solo pazienti con PSP passano ad una diagnosi di demenza al follow-up. Infine nel gruppo di pazienti PD, nonostante avessero una durata di malattia più lunga, la percentuale di soggetti che passano ad una diagnosi di demenza era inferiore rispetto al gruppo con PSP (7% vs. 16%), nonostante entrambi i gruppi avessero una gravità di MCI simile alla baseline. Complessivamente questi risultati suggeriscono un più rapido e severo declino cognitivo in soggetti PSP, mentre i pazienti MSA mostrano generalmente deficit più limitati. La scala globale MoCA sembra essere maggiormente sensibile, rispetto al MMSE, nel rilevare cambiamenti cognitivi, in particolare nella PSP. Tuttavia il MoCA mostra una sensibilità inferiore rispetto al MMSE nell’identificare un declino cognitivo al follow-up in pazienti PD; quindi il MMSE sembra essere uno strumento migliore per monitorare longitudinalmente cambiamenti cognitivi in pazienti PD. Riguardo al profilo comportamentale, i pazienti PSP riportano più comunemente rispetto ai pazienti PD: apatia, ansia e depressione. Infine, l'analisi dei subitem rivela che i pazienti PSP mostrano un peggioramento ‘clinicamente significativo’ dopo 15 mesi soprattutto nei subitem attentivo-esecutivi (Trial Making Test parte B e il disegno di un orologio). Tuttavia è stato possibile osservare che alcuni pazienti hanno anche un miglioramento in specifici subitem al follow-up. Questo miglioramento potrebbe essere attribuibile ad una più elevata dose farmacologica (nonostante il trattamento dopaminergico alla baseline non fosse significativamente diverso al follow-up). Tuttavia, è importante notare che tali alterazioni erano presenti soprattutto in subitem sensibili alle problematiche motorie (i.e., disegno di figure e collegamento di cerchi con una penna) che quindi potrebbero aver alterato la performance. Questi limiti della scala MoCA e MMSE sono già stati osservati in precedenza nei pazienti con PD (Biundo et al., 2016b; Hu et al., 2014), e possibilmente sono ancora più pronunciati nei parkinsonismi atipici. In conclusione i nostri risultati rivelano che i pazienti PSP hanno una performance notevolmente alterata rispetto agli altri disturbi parkinsoniani (MSA e PD), e dopo circa 6 anni di durata di malattia, il 33% dei pazienti PSP ha una diagnosi di demenza. Questa severa progressione è probabilmente associata ad una diffusione di aggregati tau che coinvolge anche strutture corticali. Al contrario, il pattern di compromissione cognitiva in pazienti con MSA è meno severo, e probabilmente è associato ad una predominanza sottocorticale della patologia, con un coinvolgimento corticale solo secondario alle alterazioni sottocorticali. Pertanto, i nostri risultati suggeriscono che la valutazione neuropsicologica può essere utile nella differenziazione dei profili cognitivi nei parkinsonismi atipici e per monitorare la progressione della malattia. PARTE III – Studi di neuroimmagine sulle sinucleinopatie Capitolo 5: Effetti dei depositi di amiloide sulle manifestazioni cognitive e motorie nella malattia di Parkinson Alterazioni cognitive, in particolare deficit esecutivi, possono essere osservati anche nelle prime fasi del PD (Aarsland, Bronnick, Larsen, Tysnes & Alves, 2009). La disfunzione frontostriatale del sistema dopaminergico può influenzare la presenza di problemi esecutivi ed attentivi (Bruck, Aalto, Nurmi, Bergman, & Rinne, 2005), tuttavia al momento le evidenze relative al trasportatore striatale di dopamina (DAT) sono inconsistenti (Delgado-Alvarado, Gago, Navalpotro-Gomez, Jimenez-Urbieta, & Rodriguez-Oroz, 2016). I meccanismi neuropatologici che stanno alla base delle alterazioni cognitive nei PD sono eterogenei (Irwin, Lee, & Trojanowski, 2013; Kehagia, Barker & Robbins, 2010), ed il contributo del deposito di amiloide in aggiunta alla sinucleinopatia rimane ancora poco definito, soprattutto nelle prime fasi della malattia. Pertanto, lo scopo del presente studio è stato quello di indagare l'interazione tra depositi di amiloide nel circuito frontostriatale, deficit dopaminergico striatale, grado di atrofia cerebrale ed il loro contributo nelle alterazioni cognitive (i.e., funzioni fronto-esecutive) nelle prime fasi del PD. Una coorte multicentrica di 33 pazienti con PD ricavata dal ‘Parkinson's Progression Markers Initiative’ è stata sottoposta a una tomografia ad emissione di positroni (PET) con radiofarmaco [18F]florbetaben, tomografia ad emissione di fotone singolo (SPECT) con radiofarmaco [123I]FP-CIT, risonanza magnetica (MRI) strutturale, valutazione clinica e cognitiva. Dai nostri risultati emerge che elevati livelli di depositi di amiloide erano associati ad una riduzione del deficit dopaminergico nello striato dorsale (rispetto ai bassi livelli di depositi di amiloide), ad un aumento dell’atrofia cerebrale in regioni frontali ed occipitali, e ad una tendenza a manifestare più frequentemente alterazioni cognitive globali (come valutato dal MoCA), ed in test fronto-esecutivi. Inoltre, le deposizioni di amiloide nelle regioni frontostriatali erano inversamente correlate alla performance cognitiva. Nel complesso i nostri risultati suggeriscono che pazienti con PD in fase iniziale di malattia e amiloidosi hanno un più elevato grado di atrofia cerebrale e possono esperire maggiori deficit cognitivi (i.e., disfunzioni esecutive) e alterazioni motorie rispetto a soggetti negativi all’amiloide. I nostri risultati sembrano essere in linea con una recente ipotesi neuropatologica che considera il danno e disfunzione assonale a livello sinaptico come un elemento caratteristico del PD (Tagliaferro & Burke, 2016). Infatti, i neuroni del sistema dopaminergico sono particolarmente vulnerabili alla sinucleinopatia a causa delle loro caratteristiche assonali: gli assoni sono lunghi, sottili e non mielinizzati. Questa ipotesi è confermata anche da studi di neuroimmagine PET con traccianti che si legano al DAT (Caminiti et al., 2017), suggerendo che le aggregazioni di sinucleina nel PD possono influenzare la funzione sinaptica e la trasmissione di segnale sin dalle prime fasi della malattia. I nostri risultati suggeriscono quindi una possibile interazione tra depositi di amiloide e sinucleinopatia, in cui la presenza di amiloide può facilitare la diffusione di sinucleina (i.e., corpi di Lewy) (Toledo et al., 2016), pertanto questa interazione può contribuire ulteriormente alla vulnerabilità assonale. In linea con questa ipotesi, i nostri risultati sembrano confermare che le deposizioni di amiloide agiscono sinergicamente con la sinucleinopatia, influenzando le manifestazioni cliniche del PD. Capitolo 6: Profilo neurostrutturale dell’atrofia multisistemica con alterazioni cognitive A differenza di altre sinucleinopatie (e.g., PD e DLB), la presenza di demenza è considerata un criterio di esclusione nella diagnosi di MSA (Gilman et al., 2008), tuttavia vi è una crescente evidenza che pazienti affetti da MSA possano manifestare alterazioni cognitive, che includono disfunzioni esecutive ma anche deficit cognitivi multidominio, e in alcuni casi anche demenza (Gerstenecker, 2017). Il MMSE è una scala cognitiva globale comunemente utilizzata nella pratica clinica, e recentemente uno studio multicentrico ha suggerito l’utilizzo di un cutoff <27 per aumentare la sensibilità di tale scala nell'identificare alterazioni cognitive in pazienti MSA (Auzou et al., 2015). I meccanismi che sottendono le disfunzioni cognitive in soggetti MSA non sono ancora stati identificati ed evidenze da studi di MRI suggeriscono un discreto contributo corticale e sottocorticale per spiegare tali alterazioni cognitive (Kim et al., 2015; Lee et al., 2016a). Tuttavia questi risultati sono basati su un numero relativamente piccolo di pazienti e in vari stadi di malattia, inoltre sono studi basati su singoli centri. Pertanto, lo scopo del nostro studio multicentrico è stato quello caratterizzare i cambiamenti anatomici associati ad alterazioni cognitive in pazienti MSA e di investigare le differenze strutturali corticali e sottocorticali rispetto ad un campione di soggetti sani. Abbiamo quindi esaminato retrospettivamente 72 pazienti MSA, e definito 50 MSA come cognitivamente normali (MSA-NC) e 22 con alterazioni cognitive (MSA-CI) utilizzando il cutoff del MMSE <27. Abbiamo inoltre confrontato direttamente i due sottogruppi di MSA, e comparato l’intero gruppo di MSA ad un campione di 36 controlli sani (HC) utilizzando un’analisi di ‘morfometria basata sui voxel’ che analizzava la sostanza grigia e bianca. Inoltre, abbiamo applicato anche una segmentazione automatizzata dei volumi sottocorticali. Dai nostri risultati emerge che i pazienti MSA, rispetto a soggetti sani, hanno una diffusa atrofia corticale (i.e., che coinvolge bilateralmente aree frontali, occipito-temporali e parietali), sottocorticale ed alterazioni alla sostanza bianca. Tuttavia, nel confronto diretto, i soggetti MSA-CI mostrano solo una focale riduzione del volume a carico della corteccia prefrontale dorsolaterale sinistra rispetto a pazienti MSA-NC. Tali risultati suggeriscono che la patologia corticale abbia un effetto marginale sulle alterazioni cognitive nei pazienti MSA. Suggeriamo quindi che le alterazioni cognitive siano piuttosto determinate da una degenerazione frontostriatale focale, che sembra essere in linea con il concetto di ‘alterazioni cognitive sottocorticali’.

The objectives were to explore cognitive function in older adults with Type 2 Diabetes Mellitus (T2DM) through two studies: 1) a pilot study involving the metabolic stress of glucose ingestion and the environmental stress of a functional magnetic resonance imaging (fMRI) environment and 2) an fMRI study exploring the neural mechanisms through hippocampal and prefrontal functional imaging during memory and executive functioning tasks. In T2DM subjects, environmental stress produced greater impairment in memory performance and metabolic stress produced overestimation of memory performance, with similar executive functioning, relative to healthy subjects (pilot study). T2DM subjects also sowed reduced hippocampal and greater prefrontal activation compared to healthy subjects (fMRI study). Moreover, the metabolic stress caused greater hippocampal and prefrontal activation in healthy subjects relative to placebo (fMRI study). These results indicate plausible neural mechanisms behind T2DM- and stress-associated cognitive impairments that can be used for future improvements in cognitive retention and rehabilitation.

Vascular brain diseases are a significant cause of dementia, and their presence, alone or associated with degenerative conditions, increases the risk of conversion to progressive cognitive decline. Neuropsychiatric manifestations vary according to the affected brain territory and disrupted neuronal circuits. In the current chapter, epidemiological prevalence, the harmonization of the diagnostic criteria of vascular subtypes, and the impact of age and socio-demographic aspects are critically reviewed. Another explored topic refers to the diagnostic and therapeutic approach. Structural imaging, including magnetic resonance (MRI) and computer tomography (CT), and a thorough neuropsychological and clinical exam, may help establish the differential diagnosis and substantially impact clinical evolution. Treatment involves various strategies, including controlling cardiovascular and metabolic risk factors, such as hypertension, atrial fibrillation, cardiopathies, and adopting a healthy lifestyle. Treatment relies on preventive and health promotion strategies related to the timely control of vascular risk factors and symptomatic approaches. The use of acetylcholinesterase inhibitors aims at stabilizing symptoms and is recommended in all stages of dementia.

Alzheimer’s disease (AD) is a neurodegenerative disorder that accounts for nearly 70% of the more than 50 million dementia cases estimated worldwide. There is no cure for AD. Currently, AD diagnosis is carried out using neuropsychological tests, neuroimaging scans, and laboratory tests. In the early stages of AD, brain computed tomography (CT) and magnetic resonance imaging (MRI) findings may be normal, but in late periods, diffuse cortical atrophy can be detected more prominently in the temporal and frontal regions. Electroencephalogram (EEG) is a test that records the electrical signals of the brain by using electrodes that directly reflects cortical neuronal functioning. In addition, EEG is noninvasive and widely available at low cost, has high resolution, and provides access to neuronal signals, unlike functional MR or PET which indirectly detects metabolic signals. Accurate, specific, and cost-effective biomarkers are needed to track the early diagnosis, progression, and treatment response of AD. The findings of EEG in AD are now identified as biomarkers. In this chapter, we reviewed studies that used EEG or event-related potential (ERP) indices as a biomarker of AD.

Patient selection is critical for optimizing clinical outcomes after deep brain stimulation (DBS) surgery. Patient expectations need to be addressed before DBS surgery to avoid disappointment. There are generally accepted criteria for DBS candidacy for treatment of Parkinson disease (PD), essential tremor (ET), and dystonia. For PD, selection criteria include a diagnosis of idiopathic PD and the presence of disabling or troubling motor symptoms such as motor fluctuations or dyskinesia (despite optimized pharmacologic treatment). Medication-resistant tremor is also an indication. The response of problematic motor symptoms to dopaminergic drugs is an important predictor of DBS response, favoring selection of patients for whom levodopa substantially improves tremor, bradykinesia, and rigidity. Rarely, gait is improved with DBS, and in some cases freezing can improve, although this is not a predictable post-DBS feature. Exclusion criteria include serious medical comorbidities, uncontrolled psychiatric illness (thought and mood disorders), and dementia. Preoperative magnetic resonance imaging with extensive white matter changes, vascular malformations, severe cerebral atrophy, or hydrocephalus can also be exclusions. The patient should clearly understand the risks and benefits of DBS, which should be assessed using a preoperative multidisciplinary evaluation (neurology, neurosurgery, neuropsychology, psychiatry, and rehabilitation). Use of a social worker and/or nutritionist can also be helpful in select cases.

The neurological complications of AIDS (neuro AIDS) represent the principal cause of disability and death in HIV-patients (Gray et al., 1993; McArthur, et al., 1993). Several types of lesions affect the brain tissue: direct infection of the nervous tissue by HIV, opportunistic infections (such as toxoplasmosis, cytomegalovirus encephalitis, tuberculosis, progressive rnultifocal encephalopathy....), and lymphomas. The AIDS-related dementia complex (ADC) affects about 60% of patients in the late stage of AIDS. ADC is characterized by the occurrence of sub-cortical dementia with cognitive, behavioral, and motor decline, psychomotor slowing and apathy. ADC is related to the presence of a diffuse encephalopathy leading to a cortical and sub-cortical atrophy, as well as diffuse white-matter lesions. There is a distinct advantage in diagnosing as early as possible the neurological complications (e.g. encephalopathy) of AIDS, since early treatment can improve significantly the quality of life in patients by slowing down or even stopping the neurological and psychological degradation. Neuroimaging techniques, and mainly magnetic resonance imaging (MRI), constitute so far the best diagnostic tools of neuro-AIDS (Kent et al., 1993; Mundinger et al., 1992). In addition, localized magnetic resonance spectroscopy (MRS) of the brain provides a non-invasive exploration of intracerebral metabolism in vivo, and can be performed following a standard MRI examination [for a review see Vion-Dury et al. (1994)]. Several key molecules of brain metabolism can be detected, including N-acetyl-aspartic acid which is thought to be a neuronal marker, choline-containing molecules (involved in phospholipid metabolism), glutamate, glutamine, inositol, phosphocreatine and creatine, and lactate. Recently, significant modifications in the concentration of brain metabolites detected by phosphorus and proton MRS have been described in patients with ADC (Bottomley et al., 1992; Deicken et al., 1991; Menon et al., 1992; Chong et al., 1993; Meyerhoff et al., 1993; Confort-Gouny et al., 1993). In a preliminary study, we have observed that even, if MR images are normal (without atrophy, focal or diffuse lesions) or if the patients are neuroasymptomatic, the values of metabolic parameters measured by MRS are often modified (Vion-Dury et al., 1994).