The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

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The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

We review evidence for partially segregated networks of brain areas that carry out different attentional functions. One system, which includes parts of the intraparietal cortex and superior frontal cortex, is involved in preparing and applying goal-directed (top-down) selection for stimuli and responses. This system is also modulated by the detection of stimuli. The other system, which includes the temporoparietal cortex and inferior frontal cortex, and is largely lateralized to the right hemisphere, is not involved in top-down selection. Instead, this system is specialized for the detection of behaviourally relevant stimuli, particularly when they are salient or unexpected. This ventral frontoparietal network works as a 'circuit breaker' for the dorsal system, directing attention to salient events. Both attentional systems interact during normal vision, and both are disrupted in unilateral spatial neglect.

Control of goal-directed and stimulus-driven attention in the brain

Co-Planar Stereotaxic Atlas of the Human Brain—3-Dimensional Proportional System: An Approach to Cerebral Imaging, J. Talairach, P. Tournoux. Georg Thieme Verlag, New York (1988), 122 pp., 130 figs. DM 268

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

http://science.sciencemag.org/content/sci/314/5796/130.full.pdf

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a "research framework" because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

Cognitive function and cognitive change in dementia, mild cognitive impairment, and healthy aging: The EDAR study

/pdf/correction-cerebrospinal-fluid-tau-levels-are-associated-e8ik2ez8.pdf

Correction: Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease

We report a case of cytarabine-induced intracranial hypertension. Liposomal cytarabine, a standard intrathecal chemotherapeutic, is a slow-release formulation of cytarabine produced by encapsulating the aqueous drug solution in spherical 20 lm diameter multivesicular lipid foam particles. With the 50 mg standard adult dose, sustained cytotoxic drug levels can be reached in the CSF over a 14 day period [1–5]. Neurological complications are arachnoiditis, myelitis, epilepsy, cauda equina syndrome, and toxic leukoencephalopathy [4–9]. A 27-year-old man was diagnosed with T-cell acute lymphoblastic leukemia (T-ALL). After a low dose of intravenous (IV) cyclophosphamide and corticosteroids during 5 days, treatment was initiated consisting of cyclophosphamide 1,200 mg/m IV on the first day of chemotherapy (indexed as day 1), vincristin 2 mg IV on days 3-10-17, daunorubicin 45 mg/m IV on days 3–4, asparaginase 10,000 U/m IV on days 3-5-7-9-11-13-15, and oral methylprednisolone 80 mg from day 3 until day 24. Corticosteroids were tapered from day 24 onwards and stopped on day 39. Cerebrospinal fluid (CSF) analysis on day 2 revealed the presence of blast-like cells (in the absence of peripheral blood blasts) (Table 1). A gadolinium-enhanced brain magnetic resonance imaging (MRI) scan did not reveal any abnormalities. On days 2, 13 and 27 liposomal cytarabine was administered intrathecally. CSF analysis on day 27 was strictly normal (Table 1). An ophthalmological evaluation prior to each of these lumbar punctures was negative. On day 28, the patient developed an intense headache and lumbosacral pain associated with nausea, photophobia and sonophobia, and neck flexion rigidity. Mental status examination was normal. On day 28, he was on methylprednisolone 16 mg/d. Computerized tomography (CT) of the brain and CSF analysis (including cultures for bacteria and fungi and Cryptococcus antigen detection) were normal (Table 1). On day 33, the patient complained of diplopia and worsening headache. Clinical examination revealed a left abducens paresis and bilateral papilledema, with an elevated and hyperemic disc, more severe to the right with presence of numerous peripapillary retinal hemorrhages. Contrast-enhanced MRI of the brain and MRI venography were negative. A repeat lumbar puncture on day 34 revealed an elevated opening pressure of 46 mmHg, without other abnormalities (Table 1), leading to a diagnosis of liposomal cytarabine-induced intracranial hypertension. Intrathecal chemotherapy was discontinued, a single evacuating lumbar puncture was performed and acetazolamide was started (3 9 500 mg IV daily for 2 weeks, followed by 3 9 250 mg orally for 5 weeks). The abducens palsy recovered fully. A mild form of papilledema persisted, without visual loss. Six months later the patient was still symptom-free neurologically. Four similar cases of intracranial hypertension following intrathecal administration of liposomal cytarabine, most often after the third or fourth administration, have been reported before, three with acute myeloid leukemia and one with ALL [7–9]. The temporal sequence of events, with onset shortly after the third administration of liposomal cytarabine, and the nearly complete and prolonged recovery following discontinuation of cytarabine and initiation of acetazolamide, strongly argue against a neoplastic origin in S. Lunskens B. Bergmans R. Vandenberghe (&) Department of Neurology, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium e-mail: rik.vandenberghe@uz.kuleuven.ac.be

Rik Vandenberghe

Papers

Cognitive function and cognitive change in dementia, mild cognitive impairment, and healthy aging: The EDAR study

Correction: Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease

Intracranial hypertension following intrathecal administration of liposomal cytarabine.

Functional anatomy of a common semantic system for proper names and faces

Deficits in rhythm processing in PPA are linked to SMA atrophy