Frontotemporal Lobar Degeneration

The MDS-PSP criteria were generated by the MDS-PSP study group in a three-step approach.
First, we performed a systematic literature review covering the time since publication of the NINDS-SPSP criteria. In brief, the steering committee (G.U.H., M.S., A.L.B., L.I.G., and I.L.) assembled expert working groups for specific questions relevant to the diagnosis of PSP. We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles, systematic reviews, and meta-analyses published in English from 1996 to 2015, applying either postmortem diagnosis or the NINDS-SPSP criteria. Study group members were encouraged to add relevant articles to be considered throughout the project period (end of 2016), particularly those published after 2015. The literature was analyzed following the Scottish Intercollegiate Guidelines Network recommendations.³⁷ From N = 5,903 identified articles, N = 462 met the inclusion standards. The literature-based evidence was then summarized by the working groups for imaging and clinical aspects and is published in detail in accompanying papers in this issue of Movement Disorders.^{38 ,39} Second, we collected the largest autopsy-confirmed case series reported so far for PSP and disease controls (CBD, MSA-P, PD, and FTLD-bvFTD) from nine brain banks with a proven track record of a close collaboration with tertiary clinical referral centers, both with excellent experience in neurodegenerative diseases (Amsterdam, Netherlands; Baltimore, MD; Barcelona, Spain; Bordeaux, France; London, UK; Lund, Sweden; Munich, Germany; Philadelphia, PA; and Saskatchewan, Canada). High-quality original natural history data were available from patients with autopsy-confirmed PSP (N = 206), CBD (N = 54), MSA-P (N = 51), PD (N = 53), and FTLD-bvFTD (N = 73). We extracted demographic data and predefined clinical features (absence/presence/onset) in a standardized manner locally from the clinical records and collected them centrally. These data were used to estimate and stratify the diagnostic value of the clinical items selected from a comprehensive literature review and are reported in detail in an accompanying paper.³⁸ Third, on the basis of the evidence obtained in the first two steps, the steering committee drafted an initial proposal of the criteria, which was distributed to the MDS-PSP study group members. They provided written feedback to the process coordinator (G.U.H.), who incorporated the comments into optimized criteria in two modified Delphi rounds. In March 2016, the group convened for a 2-day consensus meeting in Munich to present and discuss all aspects of the criteria (structure, basic features, exclusion criteria, core functional domains, operationalized clinical features, supportive findings, imaging, biomarkers, and genetics). For each of these items, the data obtained in the first two steps were presented by the subgroup coordinators. Thereafter, the written draft of the criteria was discussed stepwise. Modifications were integrated until the entire group unanimously agreed to the items under discussion. After the meeting, the written document was circulated again and optimized in three further Delphi rounds, in particular, dealing with precise wording, operationalized definition of clinical examination guidelines, and newly evolving aspects, such as tau PET imaging. After final approval, the current manuscript was written (G.U.H.) and circulated to incorporate final modifications.
Here, we present the MDS clinical diagnostic criteria for PSP.

We included 76 patients with a clinical diagnosis of ALS (Table 1) in accordance with modified El Escorial Criteria¹⁵ and a confirmed neuropathological diagnosis of ALS, who underwent autopsy in the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania between 1985 and 2012. Informed written consent was obtained previously from all patients or for autopsy cases from their next of kin. Detailed clinical characteristics (age at onset, age at death, site of onset, disease duration, ALS global disease severity as measured by a functional rating score [ALSFRS-R],^{16 (link)} the Mini Mental Status Examination,^{17 (link)} and gender), were ascertained from an integrated clinical and autopsy database, as described previously,¹⁸ and by retrospective chart review of clinical visits within the University of Pennsylvania Health System (Table 1).
The majority of the ALS patients were seen by two neurologists (LE, LM). We excluded all ALS cases in the CNDR Brain Bank (N=35) for which clinical data relating to site of onset or disease duration was incomplete or equivocal. Also excluded were 6 cases, for which ≥ 3/22 CNS regions examined (see below) were unavailable, and 2 cases lacking pTDP-43 pathology, leaving a cohort of N=76 (N=30 females, N=46 males; age range 42-87 years; mean age ± SD: 63.0 ± 10.6 years from a total of 119 autopsy cases (Tables 1-2). For the subjects with missing data, their gender, disease duration, and age of death were compared to the other cases and no differences were found (data not shown). Different ALS syndromes were defined according to clinical onset of disease: cervical lower motor neuron (CLMN) ALS, lumbar lower motor neuron (LLMN) ALS, lumbar upper motor neuron (LUMN) ALS, bulbar lower motor neuron (BLMN) ALS, and bulbar upper motor neuron (BUMN) ALS.¹⁹ None of the cases in the cohort had cervical UMN onset of disease (Table 1). Unless otherwise specified, results of clinical testing used in this study were from the visits at initial presentation or disease onset (first occurrence of paresis or bulbar symptoms, e.g., dysarthria, dysphagia) as well as the visit most proximate to death, i.e., occurring within 3 months of death. Of the ALS cases included here, 5 (6.6%) had a clinical history of dementia (ALS-D) (Table 2), and met criteria for FTLD.^{20 (link)-22 (link)}