Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood. This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.

This article reports the severity and profile of neuropsychological impairment on a prevalent cohort of patients with a clinical diagnosis of either multiple system atrophy (n=372) or progressive supranuclear palsy (n=311) from the Neuroprotection and Natural History in Parkinson Plus Syndromes cohort. The Dementia Rating Scale and Frontal Assessment Battery were used to assess global cognition and executive dysfunction. For the Dementia Rating Scale impairment was observed in approximately 57% of the progressive supranuclear palsy group and 20% of the multiple system atrophy group. In the former, impairment in a single cognitive domain was observed in 40%, with the same number showing impairment in multiple domains, while in the latter the figures were 28.6 and 13.5%, respectively. On the Frontal Assessment Battery, impairment was observed in 62.0% of patients with progressive supranuclear palsy and 31.8% of those with multiple system atrophy. Although the progressive supranuclear palsy group performed worse overall, the cognitive profiles of the two groups on the Dementia Rating Scale subscales were identical, with the main impairment of the Initiation and Perseveration subscale. The impaired patients in the two groups were largely indistinguishable, qualitatively and quantitatively. Impairment was associated with greater age and clinical disability in both groups and was evident even in the early stages (22% in multiple system atrophy and 50% in progressive supranuclear palsy). Where a pathological diagnosis was available, the original clinical diagnosis was confirmed in the majority of cases, including those with significant cognitive impairment. The rate of impairment in those with a confirmed pathological diagnosis was comparable to that of the sample as a whole. These results demonstrate, in the largest prospectively recruited cohort of patients with progressive supranuclear palsy and multiple system atrophy studied to date, the existence of a cognitive profile similar to that previously reported in idiopathic Parkinson's disease. The results indicate a high level of cognitive impairment associated with progressive supranuclear palsy, but also point to comparable dysfunction in a substantial proportion of the patients with multiple system atrophy. Significant cognitive impairment appears consistent with a diagnosis of multiple system atrophy, even early in the disease, with important implications for diagnosis, research and management.

No abstract

A heterozygous R1101K mutation of the p150 subunit of dynactin (DCTN1) is reported in a family with amyotrophic lateral sclerosis (ALS) and co-occurrence of frontotemporal dementia (FTD). Two members of our kindred were affected with motor neuron disease and two with dementia in an autosomal dominant pattern of inheritance. We excluded the involvement of the ALS and FTD-linked genes for copper/zinc superoxide dismutase (SOD1) and tau. The R1101K sequence alteration of the DCTN1 gene may predispose subjects to ALS and FTD.

This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.

We performed a longitudinal study of frontal and temporal lobe functions in patients with amyotrophic lateral sclerosis (ALS) and compared the evolution of cognitive performance with that of motor deficits in patients with spinal and bulbar-onset of the disease. Fifty two patients suffering from sporadic ALS according to the El Escorial criteria were examined; 37 patients had a spinal, 15 a bulbar onset of the disease. The data profile included examinations at entry (E1), every four months at follow-up (E2, E3, E4) and after 18 months (E5), if possible. Neuropsychological testing covered the domains of executive functions, memory and attentional control. ALS patients showed executive dysfunctions that were most prominently represented by deficits of non-verbal and verbal fluency and concept formation. Memory-related deficits were also present but less expressed. The same held true for phasic and tonic alertness and divided attention. In contrast to motor functions declining concomitantly with disease progression, cognitive deficits appeared in early disease, were essentially present at initial testing and did not substantially decline on follow-up. A subgroup analysis revealed that bulbar-onset ALS patients performed consistently poorer in many cognitive tests than spinal-onset ones with special reference to verbal and non-verbal fluency and interference control. This subgroup difference persisted or even increased throughout follow-up. We conclude that there is a fronto-temporal pattern of cognitive dysfunction in ALS expressing itself early in the course of the disease and mainly with bulbar forms. The cognitive deficits do not progress in synchrony with motor decline, but distinctly more slowly. We suggest that cognitive dysfunctions reflect functional and possibly morphological deficits outside the primary motor system that is specific for the nature and evolution of the disease and might also give clues to etiopathogenesis.

In our cohort of JME patients, we could not reproduce the findings of frontal gray matter changes from previous studies, and we could not detect an fMRI correlate of previously reported differences in working memory in JME. The neuropsychological deficits may be attributed partially to antiepileptic medication. We conclude that structural and functional frontal lobe deficits in JME patients have to be interpreted with care. One reason for a variation between different cohorts may be the genetic heterogeneity of the disease.

The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) has recently been developed as a fast and easy cognitive screening tool specifically designed for patients with motor impairments in routine clinical use. The German/Swiss-German version of the ECAS was validated in a German-Swiss consortium. One hundred and thirty-six non-demented ALS patients and 160 healthy controls were included in the study. In addition, the Frontal Assessment Battery (FAB), Montreal Cognitive Assessment (MoCA) and Consortium to Establish a Registry for Alzheimer's Disease plus Scale (CERAD plus) were administered to subgroups of patients. Results showed that administration of ECAS was fast (mean 24 min). Similar to the population in the UK version, ALS patients performed significantly worse in the ALS-specific functions (p < 0.001), specifically in the domain of language (p < 0.001), verbal fluency (p = 0.005) and executive functions (p = 0.02), but not for the non-ALS-specific functions. Carers reported behavioural abnormalities in about 30% and psychotic symptoms in 6% of the patients. Compared to ECAS, FAB, MoCA and CERAD were more generic and performance was not adjusted to motor speed. We conclude that the German/Swiss-German version of the ECAS is a fast and easy to administer cognitive screening instrument sensitive for ALS-specific dysfunctions and behaviour change.