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Behavioural variant frontotemporal dementia can present with episodic memory deficits as severe as those in Alzheimer's disease. Little is known of the integrity of grey matter areas and white matter tracts of the Papez memory circuit in these diseases. The integrity of the Papez circuit (hippocampus, fornix, mammillary bodies, anterior thalamus, cingulate cortex) was investigated in vivo and at post-mortem in behavioural variant frontotemporal dementia and Alzheimer's disease cohorts using voxel-based morphometry, diffusion tensor imaging and manual volumetric tracing. Our findings indicate that behavioural variant frontotemporal dementia and Alzheimer's disease show similar degrees of hippocampal atrophy in vivo, but patients with behavioural variant frontotemporal dementia show greater hippocampal atrophy at post-mortem, with the frontotemporal lobar degeneration with TDP-43 inclusions subtype being particularly affected. Cingulate cortex findings show an expected atrophy pattern with behavioural variant frontotemporal dementia being affected more anteriorly and Alzheimer's disease showing more posterior atrophy. More importantly, subcortical Papez circuit regions (fornix and anterior thalamus) were affected in behavioural variant frontotemporal dementia only, with atrophy in these regions determining the degree of amnesia in behavioural variant frontotemporal dementia. Hippocampal atrophy does not appear to be an efficient diagnostic marker for underlying behavioural variant frontotemporal dementia or Alzheimer's disease pathology, although for behavioural variant frontotemporal dementia, episodic memory deficits in conjunction with marked hippocampal atrophy emerge as potential biomarkers for frontotemporal lobar degeneration with TDP-43 inclusions pathology. Sub-regions of the Papez circuit were differentially affected in behavioural variant frontotemporal dementia and Alzheimer's disease with subcortical regions determining the degree of episodic memory deficits in behavioural variant frontotemporal dementia. Subcortical atrophy should be taken into account when establishing whether the severe amnesia observed in a patient is likely to be due to behavioural variant frontotemporal dementia or Alzheimer's disease pathology.

SEE SCHMAHMANN DOI101093/BRAIN/AWW064 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Neurodegenerative diseases are associated with distinct and distributed patterns of atrophy in the cerebral cortex. Emerging evidence suggests that these atrophy patterns resemble intrinsic connectivity networks in the healthy brain, supporting the network-based degeneration framework where neuropathology spreads across connectivity networks. An intriguing yet untested possibility is that the cerebellar circuits, which share extensive connections with the cerebral cortex, could be selectively targeted by major neurodegenerative diseases. Here we examined the structural atrophy in the cerebellum across common types of neurodegenerative diseases, and characterized the functional connectivity patterns of these cerebellar atrophy regions. Our results showed that Alzheimer's disease and frontotemporal dementia are associated with distinct and circumscribed atrophy in the cerebellum. These cerebellar atrophied regions share robust and selective intrinsic connectivity with the atrophied regions in the cerebral cortex. These findings for the first time demonstrated the selective vulnerability of the cerebellum to common neurodegenerative disease, extending the network-based degeneration framework to the cerebellum. Our work also has direct implications on the cerebellar contribution to the cognitive and affective processes that are compromised in neurodegeneration as well as the practice of using the cerebellum as reference region for ligand neuroimaging studies.

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IMPORTANCE While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. OBJECTIVES To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)-FTD cohort. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD-amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. MAIN OUTCOMES AND MEASURES Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. RESULTS In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. CONCLUSIONS AND RELEVANCE The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.

Summary Background Pituitary pars intermedia dysfunction (PPID) is a commonly described endocrine disorder in higher latitudes of the Northern hemisphere but the description of the disease at lower latitudes and in the Southern hemisphere is limited. Objectives Document the clinical features of PPID at different Australian latitudes and climates, and investigate factors associated with survival, laminitis and insulin dysregulation (ID). Study design Retrospective study of 274 equids from eight institutions across Australia. Methods A diagnosis of PPID was based on endogenous ACTH, overnight dexamethasone suppression test, thyrotropin‐releasing hormone stimulation test or necropsy. Clinical and clinicopathologic characteristics of PPID and therapeutic responses were investigated. Laminitis was diagnosed by radiographic or histologic changes and ID was diagnosed based on endogenous insulin, an oral glucose test or a 2‐step insulin‐response test. Results Being a pony, having a higher body condition score and pergolide administration were associated with survival. The clinical presentation of PPID changed with latitude and climate, with anhidrosis and polyuria/polydipsia more commonly recognised at lower latitudes. Laminitis was diagnosed in 89.9% of cases and ID was present in 76.5% of cases in which they were investigated. Main limitations Despite the sample size, the lack of uniform testing at all locations (primary or referral cases) and the incompleteness of data sets limited the power of the statistical analyses. Conclusions PPID can present with variable signs at different latitudes and climates, and ID should be investigated in equids diagnosed with PPID. Adequate body condition and administration of pergolide are fundamental in PPID management.

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.