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Background Hypothalamic dysregulation plays an established role in eating abnormalities in behavioural variant frontotemporal dementia (bvFTD) and amyotrophic lateral sclerosis (ALS). Its contribution to cognitive and behavioural impairments, however, remains unexplored. Methods Correlation between hypothalamic subregion atrophy and cognitive and behavioural impairments was examined in a large sample of 211 participants (52 pure ALS, 42 mixed ALS-FTD, 59 bvFTD, and 58 age- and education- matched healthy controls). Results Graded variation in hypothalamic involvement but relative sparing of the inferior tuberal region was evident across all patient groups. Bilateral anterior inferior, anterior superior, and posterior hypothalamic subregions were selectively implicated in memory, fluency and processing speed impairments in addition to apathy and abnormal eating habits, taking into account disease duration, age, sex, total intracranial volume, and acquisition parameters (all p ≤ .001). Conclusions These findings revealed that subdivisions of the hypothalamus are differentially affected in the ALS-FTD spectrum and contribute to canonical cognitive and behavioural disturbances beyond eating abnormalities. The anterior superior and superior tuberal subregions containing the paraventricular nucleus (housing oxytocin-producing neurons) displayed the greatest volume loss in bvFTD and ALS-FTD, and ALS, respectively. Importantly, the inferior tuberal subregion housing the arcuate nucleus (containing different groups of neuroendocrine neurons) was selectively preserved across the ALS-FTD spectrum, supporting pathophysiological findings of discrete neuropeptide expression abnormalities that may underlie the pathogenesis of autonomic and metabolic abnormalities and potentially certain cognitive and behavioural symptom manifestations, representing avenues for more refined symptomatic treatment targets. National Health and Medical Research Council of Australia program (#1037746 and #1132524) and dementia team (#1095127) grants and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Program (#CE110001021). Dr E.M. Devenney is supported by a MNDRIA post-doctoral fellowship. Dr S. Tu is supported by a NHMRC post-doctoral fellowship (APP1121859). Dr R.M. Ahmed is supported by a NHMRC post-doctoral fellowship. Prof G.M. Halliday is a NHMRC Leadership Fellow (#1176607). Prof M.C. Kiernan received funding support from NHMRC Partnership Grant (#1153439) and Practitioner Fellowship (#115609). Prof O. Piguet is supported by a NHMRC Leadership Fellowship (GNT2008020). Dr M. Bocchetta is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). Dr M. Bocchetta’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Dr M. Bocchetta acknowledges the support of NVIDIA Corporation with the donation of the Titan V GPU used for part of the analyses in this research. Prof J. D Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH).

Changes in social behavior are recognized as potential symptoms of behavioral-variant frontotemporal dementia (bvFTD) and semantic dementia (SD), yet objective ways to assess these behaviors in natural social situations are lacking. This study takes a truly social (or second-person) approach and examines changes in real-world social behavior in different dementia syndromes, by analyzing non-scripted social interactions in bvFTD patients (n = 20) and SD patients (n = 20), compared to patients with Alzheimer's disease (AD) (n = 20). Video recordings of 10-min conversations between patients and behavioral neurologists were analyzed for the presence of socially engaging (e.g., nodding, smiling, gesturing) and disengaging behavior (e.g., avoiding eye contact, self-grooming, interrupting). Results demonstrated disease-specific profiles, with bvFTD patients showing less nodding and more looking away than AD, and SD patients showing more gesturing than AD. A principal components analysis revealed the presence of four unobserved components, showing atypical disengaging patterns of behavior. Whole-brain voxel-based morphometry analyses revealed distinct neurobiological bases for each of these components, with the brain regions identified previously associated with behavior selection, abstract mentalization and processing of multi-sensory and socially-relevant information, in mediating socially engaging and disengaging behavior. This study demonstrates the utility of systematic behavioral observation of social interactions in the differential diagnosis of dementia.

Although characterized primarily as a language disorder, mounting evidence indicates episodic amnesia in Logopenic Progressive Aphasia (LPA). Whether such memory disturbances extend to information encoded pre-disease onset remains unclear. To address this question, we examined autobiographical memory in 10 LPA patients, contrasted with 18 typical amnestic Alzheimer's disease and 16 healthy Control participants. A validated assessment, the Autobiographical Interview, was employed to explore autobiographical memory performance across the lifespan under free and probed recall conditions. Relative to Controls, LPA patients showed global impairments across all time periods for free recall, scoring at the same level as disease-matched cases of Alzheimer's disease. Importantly, these retrieval deficits persisted in LPA, even when structured probing was provided, and could not be explained by overall level of language disruption or amount of information generated during autobiographical narration. Autobiographical memory impairments in LPA related to gray matter intensity decrease in predominantly posterior parietal brain regions implicated in memory retrieval. Together, our results suggest that episodic memory disturbances may be an under-appreciated clinical feature of LPA.

Sleep disorders in amyotrophic lateral sclerosis (ALS) present a significant challenge to the management of patients. Issues include the maintenance of adequate ventilatory status through techniques such as non-invasive ventilation, which has the ability to modulate survival and improve patient quality of life. Here, a multidisciplinary approach to the management of these disorders is reviewed, from concepts about the underlying neurobiological basis, through to current management approaches and future directions for research.

Scene construction refers to the capacity to imagine richly detailed scenes in one's mind's eye and has been demonstrated to be compromised across a range of clinical disorders in which episodic memory processes are also affected. It remains unclear however, how task demands modulate the content of the to-be-simulated scenes. Here, we sought to investigate the capacity for social forms of scene construction in the behavioural-variant of frontotemporal dementia (bvFTD), a progressive neurodegenerative disorder characterised by pronounced social cognitive and executive dysfunction, alongside episodic memory impairments. Twenty bvFTD patients, 14 Alzheimer's disease (AD) patients, and 20 healthy controls completed a scene construction task involving imagining social (e.g., busy restaurant, crowded train), and non-social (e.g., forest, abandoned warehouse) scenes, as well as a comprehensive neuropsychological battery. Relative to Controls, patient groups provided significantly fewer contextual details during scene construction, irrespective of condition, with no difference between the patient groups. A significant group by condition interaction reflected the fact that bvFTD patients were disproportionately impaired on social relative to non-social scenes, whereas performance was comparable across conditions within Control and AD groups. Social construction impairments correlated with response inhibition and verbal episodic memory in bvFTD, with no such associations emerging in the AD group. A multiple regression confirmed that response inhibition and verbal episodic memory were significant predictors of social construction capacity, accounting for ~54% of the overall variance on the task. Our findings suggest that the capacity to simulate social scenes represents a special class of mental construction that relies upon a number of interacting cognitive processes, including aspects of executive function and episodic memory. How the process of social construction relates to acts of prosocial behaviour or empathy will be important for future studies to address.

We reviewed retrospectively the outcomes of interventional endovascular treatment of direct or dural (indirect) carotid cavernous fistulas in 24 consecutive patients requiring endovascular treatment at Royal Prince Alfred Hospital between 1994 and 2009. Data was collected from each patient’s neurological, ophthalmological and radiological reports. Of the 12 patients with direct fistulas all had signs of orbital and ocular venous congestion and ophthalmoplegia; nine also had reduced vision ranging from 6/9 to nil perception of light, two had normal vision and one was unconscious. Nine of the 12 direct fistulas were embolized transarterially, two transvenously, one by a combination of both approaches and all were successfully closed. After treatment, seven of the nine patients with reduced vision had complete or nearly complete restoration of vision, while two who presented with nil perception of light (one in both eyes) had no recovery of vision. In contrast, seven of the 12 patients with dural fistulas had ophthalmoplegia, three had reduced vision, down to 6/24 and one did not have any sign of venous congestion. Vision recovered in all three patients after embolization of the dural fistula. Dural fistulas were embolized transvenously in 11 and transarterially in one patient. Apart from ophthalmoplegia, all other ocular signs and symptoms rapidly resolved after closure of the fistula in each of the 24 patients. The diagnosis was delayed by being missed either during the first admission or at the first specialist consultation in three of the 12 patients with direct fistulas, and in seven of the 12 patients with dural fistulas. One patient with a direct and another with a dural fistula had limited cerebral infarctions during embolization. In this series, endovascular interventional treatment of carotid cavenous fistulas restored visual loss in 10 of 12 patients with visual loss. The two who did not recover had presented with nil perception of light, one after a delay in diagnosis of 6 weeks. Some degree of ophthalmoplegia tended to remain. This emphasizes the need for early diagnosis and treatment before visual loss or ophthalmoplegia becomes severe.

Background Primary lateral sclerosis (PLS), a rare upper motor neuron disorder, remains a debated entity as an upper motor neuron extreme form of amyotrophic lateral sclerosis (ALS) or a distinct disease. It is now well established that ALS and frontotemporal dementia (FTD) lie on two ends of the frontal neurodegenerative spectrum. While early descriptions of PLS excluded cognitive dysfunction, there is accumulating evidence of varying degrees of frontal lobe deficits accompanying structural and functional changes in the brain in PLS. Methodology This study examined the neurophysiological features using transcranial magnetic stimulation (TMS) and neuropsychological profile in a cohort of patients (n = 21) with PLS. Clinical, neuropsychological and TMS findings in PLS patients were compared with two distinct cohorts of patients who had pure ALS (n = 27) and ALSFTD (n = 12). Multivariable regression analysis was used to examine independent predictors of global cognitive function on the Addenbrooke’s cognitive examination (ACE) score and motor disability on the ALS functional rating scale (ALSFRS). Kaplan Meier curves were used to determine survival times for the three groups. Results Mean age in PLS was 60.9 ± 10.4, 47.6% of patients were males and 95% had limb onset disease. The mean survival time was longest in PLS (217.43 ± 22.4 months) and shortest in ALSFTD (38.54 ± 4.5 months). In addition to prominent upper motor neuron (UMN) dysfunction, ACE score was impaired in PLS (mean total ACE score 82.5 ± 13.6), lying intermediately between pure ALS (mean total ACE score 93.4 ± 3.9) and ALSFTD (mean total ACE score 76.3 ± 7.7). Behavioural impairments were not prominent in PLS as indicated by a higher total Motor Neuron Disease Behaviour (MiND-B) score than ALSFTD (PLS 32.1 ± 5.6, ALSFTD 22.4 ± 6.8, p = 0.005). In terms of cortical function, resting motor threshold (RMT) was significantly higher in PLS (93.2 ± 11.7, p RMT predicted higher global cognition score on the ACE ( β = 0.57, p = 0.001), independent of motor progression and clinical upper motor neuron dysfunction. Average SICI predicted motor disability ( β = 0.5, p = 0.008), on the ALS functional rating scale (ALSFRS), independent of disease duration and upper motor neuron score across the three groups. Conclusions There is a distinctive cognitive profile in PLS which resembles ALSFTD, without the behavioural disturbances typical of the FTD spectrum disorders. Cortical motor neuronal hyperexcitability was associated with poorer global cognitive function, independent of motor disease progression, while dysfunction of inhibitory interneuronal circuits predicted motor disability, across ALS, ALSFTD and PLS. Overall, these findings make a strong case for PLS being on the ALS FTD spectrum and suggest that cortical excitability contributes to neuropsychological and motor dysfunction by distinct pathophysiological mechanisms.

Abnormal eating behavior is a core diagnostic feature for behavioral frontotemporal dementia (bvFTD). We aimed to define the patterns of eating behavior and intake in bvFTD and semantic dementia (SD) compared to Alzheimer’s disease (AD) and controls. We hypothesized that these changes are not the result of increased hunger/decreased satiety, but may relate to disinhibition and dysfunction of hypothalamic pathways that control appetite. We examined the association between eating behaviors and metabolic health of FTD compared with motor neuron disease (MND), which shares a common pathology with FTD, and where the metabolic profile has been hypothesized to affect disease progression. Carers of 75 dementia patients (21 bvFTD, 26 SD, 28 AD) and 18 healthy control subjects completed validated questionnaires on appetite and eating behavior. All participants completed surveys on their hunger and satiety. Body mass index (BMI), and blood samples measuring cholesterol and insulin levels were prospectively collected. BMI measurements were compared to a cohort of 100 MND (bulbar and limb) and FTD/ MND patients. bvFTD patients displayed significant abnormalities in all domains of eating compared to AD patients. bvFTD patients had significantly increased carbohydrate intake and SD patients significantly increased sugar intake. Despite increased intake in the FTD groups, their hunger/satiety scores did not differ from the control group. BMI measurements were significantly higher in the FTD and FTD/MND groups than in the MND (bulbar and limb) and control groups. Increased BMI in the bvFTD and SD groups was also significantly associated with abnormal eating behavior. BvFTD patients had significantly increased insulin levels, triglyceride, cholesterol ratios, and lower high-density lipoprotein cholesterol levels compared to controls. Abnormal eating behavior is prominent in bvFTD and SD patients, and is associated with increased sugar and carbohydrate intake, and is not the result of increased hunger and lower satiety. Similar findings have been shown in obese patients, attributed to disinhibition, orbitofrontal pathology and dysfunction of hypothalamic pathways that control appetite, suggesting similar pathways may be affected in FTD. Abnormal eating behavior in FTD is associated with changes in BMI, and a blood metabolic profile similar to that seen in MND. Despite similar pathology however, BMI in all forms of MND appears lower than in FTD.