Focal Neurodegenerative Diseases Research Articles

Pre-therapeutic modulation of language impairments in early-onset focal neurodegenerative diseases by means of transcranial direct current stimulation: Comparative outcomes between bv-FTD, PPA and PSP patient populations

Pre-therapeutic modulation of language impairments in early-onset focal neurodegenerative diseases by means of transcranial direct current stimulation: Comparative outcomes between bv-FTD, PPA and PSP patient populations

Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases.

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the “simple task” of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity, or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with global atrophy. MD regions displayed increased functional but decreased effective connectivity as a function of neurodegeneration, suggesting partially effective compensation. Overall, we show that damage to any of the nodes of the MD network is sufficient to impair top-down control of sensation, providing a common mechanism for impaired change detection across dementia syndromes.SIGNIFICANCE STATEMENT Previous evidence for fronto-parietal networks controlling perception is largely associative and may be confounded by task difficulty. Here, we use a preattentive measure of automatic auditory change detection [mismatch negativity (MMN) magnetoencephalography (MEG)] to show that neurodegeneration in any frontal or parietal multiple demand (MD) node impairs primary auditory cortex (A1) neurophysiological response to change through top-down mechanisms. This explains why the impaired ability to respond to change is a core feature across dementias, and other conditions driven by brain network dysfunction, such as schizophrenia. It validates theoretical frameworks in which neurodegenerating networks upregulate connectivity as partially effective compensation. The significance extends beyond network science and dementia, in its construct validation of dynamic causal modeling (DCM), and human confirmation of frequency-resolved analyses of animal neurodegeneration models.

Genome Wide Association Study and Next Generation Sequencing: A Glimmer of Light Toward New Possible Horizons in Frontotemporal Dementia Research.

Frontotemporal Dementia (FTD) is a focal neurodegenerative disease, with a strong genetic background, that causes early onset dementia. The present knowledge about the risk loci and causative mutations of FTD mainly derives from genetic linkage analysis, studies of candidate genes, Genome-Wide Association Studies (GWAS) and Next-Generation Sequencing (NGS) applications. In this review, we report recent insights into the genetics of FTD, and, specifically, the results achieved thanks to GWAS and NGS approaches. Linkage studies of large FTD pedigrees have prompted the identification of causal mutations in different genes: mutations in C9orf72, MAPT, and GRN genes explain the large majority of cases with a high family history of the disease. In cases with a less clear inheritance, GWAS and NGS have contributed to further understand the genetic picture of FTD. GWAS identified several common genetic variants with a modest risk effect. Of interest, many of these variants are in genes belonging to the endo-lysosomal pathway, the immune response and neuronal survival. On the opposite, the NGS approach allowed the identification of rare variants with a strong risk effect. These variants were identified in known FTD-associated genes and again in genes involved in the endo-lysosomal pathway and in the immune response. Interestingly, both approaches demonstrated that several genes are associated to multiple neurodegenerative disorders including FTD. Thanks to these complementary approaches, the genetic picture of FTD is becoming more clear and novel key molecular processes are emerging. This will foster opportunities to move toward prevention and therapy for this incurable disease.

Dissociation of quantifiers and object nouns in speech in focal neurodegenerative disease

Quantifiers such as many and some are thought to depend in part on the conceptual representation of number knowledge, while object nouns such as cookie and boy appear to depend in part on visual feature knowledge associated with object concepts. Further, number knowledge is associated with a frontal-parietal network while object knowledge is related in part to anterior and ventral portions of the temporal lobe. We examined the cognitive and anatomic basis for the spontaneous speech production of quantifiers and object nouns in non-aphasic patients with focal neurodegenerative disease associated with corticobasal syndrome (CBS, n=33), behavioral variant frontotemporal degeneration (bvFTD, n=54), and semantic variant primary progressive aphasia (svPPA, n=19). We recorded a semi-structured speech sample elicited from patients and healthy seniors (n=27) during description of the Cookie Theft scene. We observed a dissociation: CBS and bvFTD were significantly impaired in the production of quantifiers but not object nouns, while svPPA were significantly impaired in the production of object nouns but not quantifiers. MRI analysis revealed that quantifier production deficits in CBS and bvFTD were associated with disease in a frontal-parietal network important for number knowledge, while impaired production of object nouns in all patient groups was related to disease in inferior temporal regions important for representations of visual feature knowledge of objects. These findings imply that partially dissociable representations in semantic memory may underlie different segments of the lexicon.

Cognitive and anatomic double dissociation in the representation of concrete and abstract words in semantic variant and behavioral variant frontotemporal degeneration

We examine the anatomic basis for abstract and concrete lexical representations in semantic memory by assessing patients with focal neurodegenerative disease. Prior evidence from healthy adult studies suggests that there may be an anatomical dissociation between abstract and concrete representations: abstract words more strongly activate the left inferior frontal gyrus relative to concrete words, while concrete words more strongly activate left anterior-inferior temporal regions. However, this double dissociation has not been directly examined. We test this dissociation in two patient groups with focal cortical atrophy in each of these regions, the behavioral variant of Frontotemporal Degeneration (bvFTD) and the semantic variant of Primary Progressive Aphasia (svPPA). We administered an associativity judgment task for abstract and concrete words, where subjects select which of two words is best associated with a given target word. Both bvFTD and svPPA patients were significantly impaired in their overall performance compared to controls. While controls treated concrete and abstract words equally, we found a category-specific double dissociation in patients’ judgments: bvFTD patients showed a concreteness effect (CE), with significantly worse performance for abstract compared to concrete words, while svPPA patients showed reversal of the CE, with significantly worse performance for concrete over abstract words. Regression analyses also revealed an anatomic double dissociation: The CE is associated with inferior frontal atrophy in bvFTD, while reversal of the CE is associated with left anterior-inferior temporal atrophy in svPPA. These results support a cognitive and anatomic model of semantic memory organization where abstract and concrete representations are supported by dissociable neuroanatomic substrates.

Neural substrates of spontaneous narrative production in focal neurodegenerative disease

Conversational storytelling integrates diverse cognitive and socio-emotional abilities that critically differ across neurodegenerative disease groups. Storytelling patterns may have diagnostic relevance and predict anatomic changes. The present study employed mixed methods discourse and quantitative analyses to delineate patterns of storytelling across focal neurodegenerative disease groups, and to clarify the neuroanatomical contributions to common storytelling characteristics. Transcripts of spontaneous social interactions of 46 participants (15 behavioral variant frontotemporal dementia (bvFTD), 7 semantic variant primary progressive aphasia (svPPA), 12 Alzheimer’s disease (AD), and 12 healthy older normal controls (NC)) were analyzed for storytelling frequency and characteristics, and videos of the interactions were rated for patients' level of social attentiveness. Compared to controls, svPPAs told more stories and autobiographical stories, and perseverated on aspects of self during the interaction, whereas ADs told fewer autobiographical stories than NCs. svPPAs and bvFTDs were rated as less attentive to social cues. Aspects of storytelling were related to diverse cognitive and socio-emotional functions, and voxel-based anatomic analysis of structural magnetic resonance imaging revealed that temporal organization, narrative evaluations patterns, and social attentiveness correlated with atrophy corresponding to known intrinsic connectivity networks, including the default mode, limbic, salience, and stable task control networks. Differences in spontaneous storytelling among neurodegenerative groups elucidated diverse cognitive, socio-emotional, and neural contributions to narrative production, with implications for diagnostic screening and therapeutic intervention.

Estimating frontal and parietal involvement in cognitive estimation: a study of focal neurodegenerative diseases

We often estimate an unknown value based on available relevant information, a process known as cognitive estimation. In this study, we assess the cognitive and neuroanatomic basis for quantitative estimation by examining deficits in patients with focal neurodegenerative disease in frontal and parietal cortex. Executive function and number knowledge are key components in cognitive estimation. Prefrontal cortex has been implicated in multilevel reasoning and planning processes, and parietal cortex has been associated with number knowledge required for such estimations. We administered the Biber cognitive estimation test (BCET) to assess cognitive estimation in 22 patients with prefrontal disease due to behavioral variant frontotemporal dementia (bvFTD), to 17 patients with parietal disease due to corticobasal syndrome (CBS) or posterior cortical atrophy (PCA) and 11 patients with mild cognitive impairment (MCI). Both bvFTD and CBS/PCA patients had significantly more difficulty with cognitive estimation than controls. MCI were not impaired on BCET relative to controls. Regression analyses related BCET performance to gray matter atrophy in right lateral prefrontal and orbital frontal cortices in bvFTD, and to atrophy in right inferior parietal cortex, right insula, and fusiform cortices in CBS/PCA. These results are consistent with the hypothesis that a frontal-parietal network plays a crucial role in cognitive estimation.

Narcolepsy: clinical differences and association with other sleep disorders in different age groups

Narcolepsy-cataplexy (N-C) is a focal neurodegenerative disease with a genetic predisposition and autoimmune etiology; the pathogenesis of narcolepsy without cataplexy (Nw/oC) is less clear. One hundred and forty eight patients underwent clinical face-to face interviews, polysomnography, multiple sleep latency testing and HLA-DQB1*0602 typing. The cohort was divided into four age groups: children and adolescents under 19years (N=31), adults aged 20-39years (N=51), 40-59years (N=28) and over 60years (N=38). N-C was found in 93 adults (79.5%) compared with 16 pediatric patients (51.6%) (p<0.01), suggesting that at least some of the children were candidates for developing cataplexy in the future. Statistical evaluation showed an increasing age-related proportion of associated sleep disorders-obstructive sleep apnea, periodic leg movements and restless leg syndrome (p<0.001). Nw/oC patients showed sleep comorbidities less frequently than N-C group. A close connection with N-C was found particularly in REM behavior disorder (RBD) (p<0.05). RBD affected a third of the patients in the youngest as well as in the oldest groups. However, association with other sleep disorders had no significant effect on nocturnal sleep (with the exception of obstructive sleep apnea), and the sleep comorbidities under study had no noticeable effect on daytime sleepiness.

Some is not enough: Quantifier comprehension in corticobasal syndrome and behavioral variant frontotemporal dementia

Quantifiers are very common in everyday speech, but we know little about their cognitive basis or neural representation. The present study examined comprehension of three classes of quantifiers that depend on different cognitive components in patients with focal neurodegenerative diseases. Patients evaluated the truth-value of a sentence containing a quantifier relative to a picture illustrating a small number of familiar objects, and performance was related to MRI grey matter atrophy using voxel-based morphometry. We found that patients with corticobasal syndrome (CBS) and posterior cortical atrophy (PCA) are significantly impaired in their comprehension of cardinal quantifiers (e.g. “At least three birds are on the branch”), due in part to their deficit in quantity knowledge. MRI analyses related this deficit to temporal–parietal atrophy found in CBS/PCA. We also found that patients with behavioral variant frontotemporal dementia (bvFTD) are significantly impaired in their comprehension of logical quantifiers (e.g. “Some of the birds are on the branch”), associated with a simple form of perceptual logic, and this correlated with their deficit on executive measures. This deficit was related to disease in rostral prefrontal cortex in bvFTD. These patients were also impaired in their comprehension of majority quantifiers (e.g. “At least half of the birds are on the branch”), and this too was correlated with their deficit on executive measures. This was related to disease in the basal ganglia interrupting a frontal–striatal loop critical for executive functioning. These findings suggest that a large-scale frontal–parietal neural network plays a crucial role in quantifier comprehension, and that comprehension of specific classes of quantifiers may be selectively impaired in patients with focal neurodegenerative conditions in these areas.

Hierarchical organization of scripts: converging evidence from FMRI and frontotemporal degeneration.

The present study examined the organization of complex familiar activities, known as "scripts" (e.g., "going fishing"). We assessed whether events in a script are processed in a linear-sequential manner or clustered-hierarchical manner, and we evaluated the neural basis for this processing capacity. Converging evidence was obtained from functional neuroimaging in healthy young adults and from behavioral and structural magnetic resonance imaging (MRI) data in patients with focal neurodegenerative disease. In both studies, participants judged the order of consecutive event pairs taken from a script. Event pairs either were clustered together within a script or were from different clusters within the script. Controls judged events more accurately and quickly if taken from the same cluster within a script compared with different clusters, even though all event pairs were consecutive, consistent with the hierarchical organization of a script. Functional magnetic resonance imaging associated this with bilateral inferior frontal activation. Patients with progressive nonfluent aphasia or behavior-variant frontotemporal dementia did not distinguish between event pairs from the same cluster or from different clusters within a script. Structural MRI associated this deficit with significant frontal cortical atrophy. Our findings suggest that frontal cortex contributes to clustering events during script comprehension, underlining the role of frontal cortex in the hierarchical organization of a script.

Categorization of novel animals by patients with Alzheimer's disease and corticobasal degeneration.

We taught a novel animal category by rule-based and similarity-based processes to participants with Alzheimer's disease (AD), corticobasal degeneration (CBD), and healthy age-matched participants. Healthy participants successfully categorized by either process. AD patients' rule-based categorization was impaired, while their similarity-based categorization resembled that of healthy participants. Correlations of AD patients' performance with measures of executive functioning suggested a deficit in the cognitive resources necessary for engaging rule-based categorization. The contribution of limited executive resources to categorization difficulty in AD was further demonstrated in a second experiment in which features determining category membership were of lower salience. CBD patients were relatively impaired at similarity-based processing, suggesting that qualitatively distinct categorization processes can be selectively compromised in patients with focal neurodegenerative diseases. Moreover, AD patients' impaired categorization correlated with performance on a measure of semantic memory, implicating this categorization deficit in AD patients' semantic memory difficulty.

Quantifier comprehension in corticobasal degeneration

In this study, we investigated patients with focal neurodegenerative diseases to examine a formal linguistic distinction between classes of generalized quantifiers, like “some X” and “less than half of X.” Our model of quantifier comprehension proposes that number knowledge is required to understand both first-order and higher-order quantifiers. The present results demonstrate that corticobasal degeneration (CBD) patients, who have number knowledge impairments but little evidence for a deficit understanding other aspects of language, are impaired in their comprehension of quantifiers relative to healthy seniors, Alzheimer’s disease (AD) and frontotemporal dementia (FTD) patients [ F(3, 77) = 4.98; p < .005]. Moreover, our model attempts to honor a distinction in complexity between classes of quantifiers such that working memory is required to comprehend higher-order quantifiers. Our results support this distinction by demonstrating that FTD and AD patients, who have working memory limitations, have greater difficulty understanding higher-order quantifiers relative to first-order quantifiers [ F(1, 77) = 124.29; p < .001]. An important implication of these findings is that the meaning of generalized quantifiers appears to involve two dissociable components, number knowledge and working memory, which are supported by distinct brain regions.

Local and global gene therapy in the central nervous system

AbstractFor focal neurodegenerative diseases or brain tumors, localized delivery of protein or genetic vectors may be sufficient to alleviate symptoms, halt disease progression, or even cure the disease. One may circumvent the limitation imposed by the blood-brain barrier by transplantation of genetically altered cell grafts or focal inoculation of virus or protein. However, permanent gene replacement therapy for diseases affecting the entire brain will require global delivery of genetic vectors. The neurotoxicity of currently available viral vectors and the transient nature of transgene expression invivomust be overcome before their use in human gene therapy becomes clinically applicable.