"I Didn't Sign Up for This": Perspectives from Persons Living with Dementia and Care Partners on Challenges, Supports, and Opportunities to Add Geriatric Neuropalliative Care to Dementia Specialty Care.

BACKGROUND: In the United States, dementia specialty centers affiliated with centers of excellence for research hold promise as locations to develop innovative, holistic care in care systems otherwise siloed by discipline or payer. OBJECTIVE: We conducted foundational research to inform development of patient-and family-centered palliative care interventions for dementia specialty centers. METHODS: We interviewed persons living with dementia (PLWD), current, and former care partners (CP) recruited from a specialty dementia clinic and purposively selected for variation across disease syndrome and stage. A framework method of thematic analysis included coding, analytic matrices, and pattern mapping. RESULTS: 40 participants included 9 PLWD, 16 current CPs, and 15 former CPs of decedents; 48% impacted by Alzheimer's disease dementia. While help from family, support groups and adult day centers, paid caregiving, and sensitive clinical care were invaluable to PLWD, CPs, or both, these supports were insufficient to navigate the extensive challenges. Disease-oriented sources of distress included symptoms, functional impairment and falls, uncertainty and loss, and inaccessible care. Social and relational challenges included constrained personal and professional opportunities. The obligation and toll of giving or receiving caregiving were challenging. Clinical care challenges for PLWD and/or CPs included care fragmentation, insufficient guidance to inform planning and need for expert interdisciplinary clinical care at home. CONCLUSION: Findings highlight the breadth and gravity of gaps, which surpass the disciplinary focus of either behavioral neurology or palliative care alone. Results can inform the development of novel interventions to add principles of geriatrics and neuropalliative care to dementia care.

Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. METHODS: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. RESULTS: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. INTERPRETATION: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency.

Aberrant aggregation of the RNA-binding protein TDP-43 in neurons is a hallmark of frontotemporal lobar degeneration caused by haploinsufficiency in the gene encoding progranulin1,2. However, the mechanism leading to TDP-43 proteinopathy remains unclear. Here we use single-nucleus RNA sequencing to show that progranulin deficiency promotes microglial transition from a homeostatic to a disease-specific state that causes endolysosomal dysfunction and neurodegeneration in mice. These defects persist even when Grn-/- microglia are cultured ex vivo. In addition, single-nucleus RNA sequencing reveals selective loss of excitatory neurons at disease end-stage, which is characterized by prominent nuclear and cytoplasmic TDP-43 granules and nuclear pore defects. Remarkably, conditioned media from Grn-/- microglia are sufficient to promote TDP-43 granule formation, nuclear pore defects and cell death in excitatory neurons via the complement activation pathway. Consistent with these results, deletion of the genes encoding C1qa and C3 mitigates microglial toxicity and rescues TDP-43 proteinopathy and neurodegeneration. These results uncover previously unappreciated contributions of chronic microglial toxicity to TDP-43 proteinopathy during neurodegeneration.

Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers.

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

What role does the anterior temporal lobe play in sentence-level processing? Neural correlates of syntactic processing in semantic variant primary progressive aphasia.

Neuroimaging and neuropsychological studies have implicated the anterior temporal lobe (ATL) in sentence-level processing, with syntactic structure-building and/or combinatorial semantic processing suggested as possible roles. A potential challenge to the view that the ATL is involved in syntactic aspects of sentence processing comes from the clinical syndrome of semantic variant primary progressive aphasia (semantic PPA; also known as semantic dementia). In semantic PPA, bilateral neurodegeneration of the ATLs is associated with profound lexical semantic deficits, yet syntax is strikingly spared. The goal of this study was to investigate the neural correlates of syntactic processing in semantic PPA to determine which regions normally involved in syntactic processing are damaged in semantic PPA and whether spared syntactic processing depends on preserved functionality of intact regions, preserved functionality of atrophic regions, or compensatory functional reorganization. We scanned 20 individuals with semantic PPA and 24 age-matched controls using structural MRI and fMRI. Participants performed a sentence comprehension task that emphasized syntactic processing and minimized lexical semantic demands. We found that, in controls, left inferior frontal and left posterior temporal regions were modulated by syntactic processing, whereas anterior temporal regions were not significantly modulated. In the semantic PPA group, atrophy was most severe in the ATLs but extended to the posterior temporal regions involved in syntactic processing. Functional activity for syntactic processing was broadly similar in patients and controls; in particular, whole-brain analyses revealed no significant differences between patients and controls in the regions modulated by syntactic processing. The atrophic left ATL did show abnormal functionality in semantic PPA patients; however, this took the unexpected form of a failure to deactivate. Taken together, our findings indicate that spared syntactic processing in semantic PPA depends on preserved functionality of structurally intact left frontal regions and moderately atrophic left posterior temporal regions, but no functional reorganization was apparent as a consequence of anterior temporal atrophy and dysfunction. These results suggest that the role of the ATL in sentence processing is less likely to relate to syntactic structure-building and more likely to relate to higher-level processes such as combinatorial semantic processing.

Sound naming in neurodegenerative disease.

Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases associated with cognitive and motor deficits. Subjects were presented with 56 environmental sounds: 28 sounds were of objects that required manipulation when producing the sound, and 28 sounds were of objects that required no manipulation. Subjects were asked to provide the name of the object that produced the sound and also complete a sound-picture matching condition. Subjects included 33 individuals from four groups: CBD/PSP, Alzheimer disease, frontotemporal dementia, and normal controls. We hypothesized that CBD/PSP patients would exhibit impaired naming performance compared with controls, but the impairment would be most apparent when naming sounds associated with actions. We also explored neural correlates of naming environmental sounds using voxel-based morphometry (VBM) of brain MRI. As expected, CBD/PSP patients scored lower on environmental sounds naming (p<0.007) compared with the controls. In particular, the CBD/PSP patients scored the lowest when naming sounds of manipulable objects (p<0.05), but did not show deficits in naming sounds of non-manipulable objects. VBM analysis across all groups showed that performance in naming sounds of manipulable objects correlated with atrophy in the left pre-motor region, extending from area six to the middle and superior frontal gyrus. These results indicate an association between impairment in the retrieval of action-related names and the motor system, and suggest that difficulty in naming manipulable sounds may be related to atrophy in the pre-motor cortex. Our results support the hypothesis that retrieval of action-related semantic knowledge involves motor regions in the brain.

Creativity and dementia: emerging diagnostic and treatment methods for Alzheimer's disease.

Alzheimer's disease research is beginning to yield promising treatments and prevention strategies. Current Alzheimer's disease treatments benefit symptoms, but do not appreciably alter the basic disease process. The new generation of Alzheimer's disease medications, however, will likely include disease-modifying treatments, which will slow disease progression or stop it entirely. These new treatments pursue four points of intervention: increasing the clearance of amyloid-beta42 (Abeta42) proteins in the brain, blocking Abeta42 production, decreasing Abeta42 production, and decreasing Abeta42 aggregation. Neurogenerative therapies are being explored as well, suggesting future treatments may not only stop disease progression but also reverse it. Risk factors for developing Alzheimer's disease and factors associated with a lower risk of Alzheimer's disease have been identified. Future Alzheimer's disease management may come to resemble routine cardiovascular disease prevention and management, which involves the control of modifiable risk factors and the use of medications that decrease or stop underlying pathology. The hope is that such management will arrest the disease process before cognitive symptoms have begun. Like other neurologic illnesses, Alzheimer's disease has a profound impact on creativity. Alzheimer's disease attacks the right posterior part of the brain, which enables people to retrieve internal imagery and copy images. Alzheimer's disease patients may lose the ability to copy images entirely. However, people with Alzheimer's disease can continue to produce art by using their remaining strengths, such as color or composition instead of shapes or realism. Studying art and dementia is a model for identifying the strengths of psychiatric patients. Remarkably, art emerges in some patients even in the face of degenerative disease. In this expert roundtable supplement, Jeffrey L. Cummings, MD, offers an overview of recent advances in Alzheimer's disease research. Bruce L. Miller, MD, discusses creativity in patients with neurologic illnesses. Daniel D. Christensen, MD, discusses emerging Alzheimer's disease therapies. Debra Cherry, PhD, discusses the advocacy needs of Alzheimer's disease patients and their caregivers. In addition, Patricia Utermohlen, MA, provides a testimonial of the impact of Alzheimer's disease on an accomplished artist.

Deformation-based morphometry reveals brain atrophy in frontotemporal dementia.

OBJECTIVE: To compare deformation-based maps of local anatomical size between subjects with frontotemporal dementia (FTD) and healthy subjects to identify regions of the brain involved in FTD. DESIGN: Structural magnetic resonance images were obtained from 22 subjects with FTD and 22 cognitively normal, age-matched controls. We applied deformation-based morphometry and compared anatomy between groups using an analysis of covariance model that included a categorical variable denoting group membership and covaried for head size. SETTING: University of California, San Francisco, Memory and Aging Center, and the San Francisco Veterans Affairs Medical Center. PATIENTS: Twenty-two subjects with FTD and 22 cognitively normal, age-matched controls. INTERVENTIONS: Neurological, neuropsychological, and functional evaluations and magnetic resonance imaging. MAIN OUTCOME MEASURE: Deformation maps of local anatomical size. RESULTS: Patients with FTD showed extensive, significant atrophy of the frontal lobes, affecting both gray matter and white matter. Atrophy of similar magnitude but less significance was observed in the anterior temporal lobes. The subcortical and midbrain regions, particularly the thalamus, pons, and superior and inferior colliculi, showed strongly significant atrophy of smaller magnitude. CONCLUSIONS: We confirmed frontal and anterior temporal gray matter atrophy in FTD. The observed white matter loss, thalamic involvement, and midbrain atrophy are consistent with pathological findings in late-stage FTD. Dysfunction of ventral-frontal-brainstem circuitry may underlie some of the unique clinical features of FTD.

Effects of Alzheimer disease on fronto-parietal brain N-acetyl aspartate and myo-inositol using magnetic resonance spectroscopic imaging.

Previous magnetic resonance (MR) spectroscopy studies of Alzheimer disease (AD) reporting reduced N-acetyl aspartate (NAA) and increased myo-Inositol (mI) used single voxel techniques, which have limited ability to assess the regional distribution of the metabolite abnormalities. The objective of this study was to determine the regional distribution of NAA and mI alterations in AD by using MR spectroscopic imaging. Fourteen patients with AD and 22 cognitively normal elderly were studied using structural MR imaging and MR spectroscopic imaging. Changes of NAA, mI, and various metabolite ratios were measured in frontal and parietal lobe gray matter (GM) and white matter. This study found: (1) when compared with cognitively normal subjects, AD patients had increased mI and mI/creatine (Cr) ratios primarily in parietal lobe GM, whereas frontal lobe GM and white matter were spared; (2) in the same region where mI was increased, AD patients had also decreased NAA and NAA/Cr ratios, replicating previous findings; (3) however, increased mI or mI/Cr ratios did not correlate with decreased NAA or NAA/Cr ratios; and (4) using mI/Cr and NAA/Cr together improved sensitivity and specificity to AD from control as compared with NAA/Cr alone. In conclusion, decreased NAA and increased mI in AD are primarily localized in parietal lobe GM regions. However, the NAA and mI changes are not correlated with each other, suggesting that they represent different processes that might help staging of AD.